Prevalence of consanguineous marriages and associated factors among Israeli Bedouins.

PubMed

Na'amnih, Wasef; Romano-Zelekha, Orly; Kabaha, Ahmed; Rubin, Liza Pollack; Bilenko, Natalya; Jaber, Lutfi; Honovich, Mira; Shohat, Tamy

2014-10-01

The Bedouin population in Israel is a semi-nomadic traditional patriarchal society. Consanguineous marriages are very common, contributing to high rates of congenital malformations and genetic diseases, resulting in high infant mortality. Data on consanguineous marriages among Bedouins in Israel are limited. This study examined the current prevalence of consanguineous marriages and their determinants among Israeli Bedouins. One thousand two hundred ninety Bedouin women who delivered in the maternity wards of the only hospital serving the Bedouin population were interviewed between November 2009 and January 2010. The prevalence of consanguineous marriages was 44.8 %. The most common type of spousal relationship was first cousins (65.7 % of all consanguineous marriages). The mean inbreeding coefficient was 0.0238. Factors significantly associated with consanguinity were less years of schooling (OR 0.94, 95 % CI (0.88-0.99), p = 0.02) and younger age at marriage of the wife (OR 0.90, 95 % CI (0.80-0.96), p = 0.0002). In conclusion, the rate of consanguineous marriages among Bedouins is very high, making this population at risk for congenital malformations and genetic diseases. Efforts should be directed at better education and provision of premarital and prenatal counseling on the health consequences of consanguineous marriages and the possibilities to lower those risks.

Effect of Consanguinity on Low Birth Weight: A Meta-Analysis.

PubMed

Poorolajal, Jalal; Ameri, Pegah; Soltanian, Alireza; Bahrami, Masoud

2017-03-01

Consanguinity (when couples share at least one common ancestor) is a public health issue with a variety of distributions and incidence rates worldwide. Several epidemiological studies have explored the association between consanguinity and low birth weight (LBW). However, the results are inconsistent. This meta-analysis aimed to explore the overall association between consanguineous marriage and LBW. We searched PubMed, Web of Science, Scopus, ScienceDirect, and reference lists of articles up to May 2015. We included cohort, case-control, and cross-sectional studies addressing the association between consanguinity and LBW. We assessed heterogeneity using Q-test and I2 statistic. We explored publication bias using the Egger's and Begg's tests and the funnel plot. We meta-analyzed the data and reported the overall odds ratio (OR) and mean difference with 95% confidence intervals (CI) using the random-effects model. We included 24 out of 3941 retrieved studies, with 44,131 participants. We indicated that LBW was associated significantly with first-cousin marriages (OR = 1.36; 95% CI: 1.03, 1.69) and non-significantly with second-cousin marriages (OR = 1.20; 95% CI: 0.49, 1.91). Furthermore, first-cousin marriages can reduce the birth weight of siblings of consanguineous couples 144 g more compared to non-consanguineous marriages. This meta-analysis measured the association between consanguinity and LBW. Based on the current evidence, consanguineous marriage can increase the risk for LBW. However, further evidence based on large cohort studies conducted in different settings is required to make a robust conclusion regarding the effect of consanguinity on LBW.

Consanguineous marriage in an urban area of Saudi Arabia: rates and adverse health effects on the offspring.

PubMed

al-Abdulkareem, A A; Ballal, S G

1998-02-01

The objective of this cross-sectional study was to determine the pattern and time trend of consanguineous marriage and its adverse health effects on the offspring in Dammam city, Eastern Province, in the Kingdom of Saudi Arabia. This city is known to attract Saudis from different parts of the country because it is in the heart of this industrial region. Five primary health care centers were randomly selected from different sectors of the city in addition to the city's only Maternity and Children's Hospital. For inclusion in the study a wife must have at least one pregnancy that terminated in either full term liveborn baby, still birth, or abortion. A total of 1307 ever-married Saudis completed a pre-structured questionnaire during an interview. The rate of consanguineous marriage was 52.0% with an average inbreeding coefficient of 0.0312. First-cousin marriages were the commonest (39.3%) of all matings. The consanguineous groups had a significantly higher number of pregnancies. The mean birth weight of the offspring of consanguineous couples was not statistically significant being less than that of the non-consanguineous. However, within the consanguineous groups the more closely related couples had smaller babies on average. No significant differences were noted for the rates of inherited diseases and reproductive wastage. The rate of consanguineous marriage in this city was high and so was the inbreeding coefficient. These figures place this nation among the countries with a high rate of consanguineous marriages. A nationwide study to determine accurately the relationship between consanguinity and inherited diseases has much to commend it.

Pre-marital genetic counselling to consanguineous couples: attitudes, beliefs and decisions among counselled, noncounselled and unrelated couples in Israel.

PubMed

Shiloh, S; Reznik, H; Bat-Miriam-Katznelson, M; Goldman, B

1995-11-01

Semi-structured interviews were conducted with 65 Israeli subjects who received genetic counselling while considering marriage to a close relative, 40 subjects married to a close relative who did not receive pre-marital genetic counselling, and 125 controls married to a nonrelative and never having considered marrying a relative. It was found that 72% of the consanguineous couples who received pre-marital genetic counselling proceeded with their plans and married their relative; 86% of them reported that the counselling influenced their final decision to some degree. Counsellees' appraisals of genetic counselling revealed unfulfilled expectations to obtain more definitive answers, and mixed reactions to the nondirective approach applied by the counsellors. Comparisons between consanguineous and control couples revealed different views about consanguinity in general, and genetic risks in particular. Consanguineous couples, unlike controls, perceived consanguinity as an ordinary form of marriage, and had more favorable attitudes towards it. Compared to the noncounselled consanguineous group, consanguineous couples who received pre-marital genetic counselling had fewer children, estimated their genetic risk as lower but its subjective significance as higher, and perceived genetic disorders as more severe. The implications of these results are discussed from both theoretical and practical standpoints.

Consanguineous marriages in the province of Antalya, Turkey.

PubMed

Alper, O M; Erengin, H; Manguoğlu, A E; Bilgen, T; Cetin, Z; Dedeoğlu, N; Lüleci, G

2004-01-01

To assess the trends in the frequency and the medical effects of consanguinity in the south coast of Turkish population using local and national data in the last 11 years. This cross-sectional study was carried out in Manavgat province, which is a major tourism center on the Mediterranean coast of Turkey. The authors studied consanguineous marriages in rural and urban population in the Mediterranean coast, Manavgat province, Turkey, via a 1500 random survey sample of married couples. There has been a significant increase in the incidence of consanguineous marriages in rural areas (40.7%) since 1989 in the southern population of Turkey. The results showed that the most frequent type of marriage was between the first cousins. It is found that there is no statistically significant difference between the consanguineous and non-consanguineous marriages in the different age groups. The results were discussed on the basis of educational status, reasons for having consanguineous marriages and the general medical effects as well as with the relation of congenital malformations. The custom of consanguineous unions in the Mediterranean population of Turkey is still extremely high, and preventive measures should be done to decrease its frequency and associated complications.

Consanguinity and family clustering of male factor infertility in Lebanon.

PubMed

Inhorn, Marcia C; Kobeissi, Loulou; Nassar, Zaher; Lakkis, Da'ad; Fakih, Michael H

2009-04-01

To investigate the influence of consanguineous marriage on male factor infertility in Lebanon, where rates of consanguineous marriage remain high (29.6% among Muslims, 16.5% among Christians). Clinic-based, case-control study, using reproductive history, risk factor interview, and laboratory-based semen analysis. Two IVF clinics in Beirut, Lebanon, during an 8-month period (January-August 2003). One hundred twenty infertile male patients and 100 fertile male controls, distinguished by semen analysis and reproductive history. None. Standard clinical semen analysis. The rates of consanguineous marriage were relatively high among the study sample. Patients (46%) were more likely than controls (37%) to report first-degree (parental) and second-degree (grandparental) consanguinity. The study demonstrated a clear pattern of family clustering of male factor infertility, with patients significantly more likely than controls to report infertility among close male relatives (odds ratio = 2.58). Men with azoospermia and severe oligospermia showed high rates of both consanguinity (50%) and family clustering (41%). Consanguineous marriage is a socially supported institution throughout the Muslim world, yet its relationship to infertility is poorly understood. This study demonstrated a significant association between consanguinity and family clustering of male factor infertility cases, suggesting a strong genetic component.

Health problems, complex life, and consanguinity among ethnic minority Muslim women in Nepal.

PubMed

Bhatta, Dharma Nand; Haque, Anwarul

2015-01-01

Marriage between blood relatives is common among Muslim ethnic minority population in Nepal. Albeit, the adverse effects of such a consanguineous marriage on health are controversial. To determine the prevalence, characteristics and health outcomes related to consanguineous marriage. A cross-sectional survey was carried out using a cluster sampling technique to select the respondents. A total of 400 women aged 15-49 years were interviewed from September 2011 to February 2012. A structured questionnaire was administered through face-to-face meetings. Adjusted odds ratios (AOR) were estimated by a stepwise likelihood ratio method with binary logistic regression. The overall prevalence of consanguinity was 36.7%. The median age at marriage and age at first childbirth was 15 and 18 years, respectively. The association of being in a consanguineous marriage among women whose husband's education level were secondary or higher was 3.35 (95% CI 1.56, 7.12) times greater than among those whose husbands were unable to read and write. Woman who have consanguineous marriage were less likely to have (AOR 0.46, 95% CI 0.26, 0.82) used contraceptive than those who have non-consanguineous marriage. Women who have consanguineous marriage were more (AOR 1.80; 95% CI 0.90, 3.61) likely to have birth defect in their children than those who have non-consanguineous marriage. The association of having a history of death after live birth among women who experienced emotional violence was 2.60 (95% CI 1.36, 5.00) and physical violence 2.15 (95% CI 1.16, 3.93) times greater than among those who did not experience violence. Several factors like husband's education and dowry practices are associated with consanguineous marriage. Further, these factors including consanguineous marriage and marital violence are also accountable for negative health consequences. Thus, multicomponent interventions are needed in order to improve the health condition of Nepalese Muslim community in rural area.

The Implications of Parental Consanguinity on the Care of Neonates.

PubMed

Ng, Diana

2016-08-01

Approximately 6% of births worldwide, 7.9 million children, are born with a serious genetic congenital abnormality each year. A factor thought to increase the prevalence of birth defects is parental consanguinity, which is a social custom practiced in at least 20% of the world's population. The purpose of this article is to explore the relationship between consanguinity and congenital defects. This article also aims to enhance neonatal healthcare practitioners' comprehension of its implications for practice and research. A review of literature was compiled from a search of the online databases Cumulative Index of Nursing and Allied Health (CINAHL), PubMed, EBSCO MegaFILE, and Google Scholar. Literature pertinent to this topic primarily consists of research studies that examine the inbreeding depression phenomenon through comparison of the prevalence of birth defects among the offspring of consanguineous and nonconsanguineous couples. Current studies indicate that the progeny of consanguineous couples are at an increased risk of congenital defects compared with those of nonconsanguineous couples. Consanguinity is one risk factor among many that can lead to a major birth defect. Relationships between consanguineous populations and neonatal healthcare practitioners such as registered nurses, advanced practice nurses, and physicians could significantly alter neonatal health outcomes. Specific recommendations such as genetic counseling and therapeutic communication are discussed. Further studies need to investigate the connection between consanguinity and birth defects while controlling for nongenetic variables. Moreover, a focus on consanguineous communities in the United States would prove beneficial.

The changing pattern and determinants of declining consanguinity in Jordan during 1990-2012.

PubMed

Islam, M Mazharul

2018-03-01

Consanguinity is a deep rooted cultural trait in Jordan. To examine the patterns and determinants of declining rates of consanguineous marriage in Jordan during 1990-2012 in the context of the changing pattern of socio-economic and demographic conditions. The data come from the 1990 and 2012 Jordan Population and Family Health Surveys (JPFHSs). A total of 6461 women in 1990 and 11,352 women in 2012 were successfully interviewed. Descriptive and multivariate statistical techniques were used for data analysis. Consanguinity was found to be widely practiced (35% in 2012) until recent times in Jordan. However, there has been a secular declining trend over the last few decades as the practice of consanguinity has declined from 56% in 1990 to 35% in 2012. Increasing age at marriage and female education, higher level of education of husbands, declining family size, increasing rate of urbanisation and female employment, exposure to mass media and higher economic status appeared as significant predictors of declining consanguinity in Jordan. The findings of this study support Goode's hypothesis of a decrease of consanguinity with modernisation. Although consanguinity is a deeply rooted cultural trend in Jordan, it is gradually losing ground due to modernisation and socio-demographic transition of the country.

Effects of consanguineous marriage on reproductive behaviour, adverse pregnancy outcomes and offspring mortality in Oman.

PubMed

Islam, M Mazharul

2013-05-01

The long tradition of high prevalence of consanguineous marriages in Omani society may have ramifications for reproductive behaviour and health of offspring. To examine the relevance of consanguinity to reproductive behaviour, adverse pregnancy outcome and offspring mortality in Oman. The data analysed came from the 2000 Oman National Health Survey. Selected indicators that are related to reproductive behaviour, adverse pregnancy outcome and offspring mortality were considered as explanatory variables. Various statistical methods and tests were used for data analysis. Consanguineous marriage was found to be associated with lower age at first birth, higher preference for larger family size, lower level of husband-wife communication about use of family planning methods and lower rate of contraceptive use. Although bivariate analysis showed elevated fertility and childhood mortality among the women with consanguineous marriage, after controlling for relevant socio-demographic factors in multivariate analysis, fertility, childhood mortality and foetal loss showed no significant association with consanguinity in Oman. Consanguinity plays an important role in determining some of the aspects of reproduction and health of newborns, but did not show any detrimental effects on fertility and offspring mortality. The high level of consanguinity and its relevance to reproduction in Oman need to be considered in its public health strategy in a culturally acceptable manner.

The relationship between consanguineous marriage and death in fetus and infants.

PubMed

Mohammadi, Majid Mehr; Hooman, Heidar Ali; Afrooz, Gholam Ali; Daramadi, Parviz Sharifi

2012-05-01

Given the high prevalence of consanguineous marriages in rural and urban areas of Iran, the aim of this study was to identify its role in increasing fetal and infant deaths. This was a cross-sectional study in which 494 mothers with more than one exceptional child (mentally retarded and physically-dynamically disabled) or with normal children were selected based on multi-stage random sampling method. Data was gathered using the features of parents with more than one exceptional child questionnaire. The validity and reliability of this questionnaire was acceptable. Hierarchical log-linear method was used for statistical analysis. Consanguineous marriage significantly increased the number of births of exceptional children. Moreover, there was a significant relation between the history of fetal/infant death and belonging to the group. There was a significant relation between consanguineous marriage and the history of fetal/infant death which means consanguineous marriage increased the prevalence of fetal/infant death in parents with exceptional children rather than in parents with normal children. The rate of fetal/infant death in exceptional births of consanguineous marriages was higher than that of non-consanguineous marriages.

Congenital abnormalities in newborns of consanguineous and nonconsanguineous parents.

PubMed

Naderi, S

1979-02-01

The aim of this study was to determine the types, patterns, and frequencies of congenital anomalies among newborns of both consanguineous and nonconsanguineous parents in southern Iran. From 9526 consecutive pregnancies observed, 9623 newborns resulted (9431 singleton and 95 sets of multiple gestation). There were 7261 newborns from nonconsanguineous parents and 2362 (24.5%) babies from consanguineous marriages. Of the total pregnancies, 1.54% resulted in malformed children (1.53% of singleton and 2.1% of multiple gestations). The incidence of congenital abnormalities in newborns of nonconsanguineous parents was 1.66% as compared to 4.02% for newborns of the consanguineous group. Major and multiple malformations were found to be slightly more common in the consanguinous group. Prematurity, prenatal mortality rate, and congenital abnormalities were more common in the consanguineous group. Probably the closer the familial relationship of the parents, the greater the chances of congenital abnormalities.

The Prevalence of Congenital Malformations and its Correlation with Consanguineous Marriages

PubMed Central

Tayebi, Naeimeh; Yazdani, Katayon; Naghshin, Nazila

2010-01-01

Objectives Consanguinity has been a long standing social habit among some Iranians. This study is aimed at determining the role of consanguinity on congenital malformations and the correlation of inbreeding coefficient with anomalies. Methods In this cross-sectional study, all the newborns who were born during 9 months period from April to December 2008. (n=1195) at Shahid Sadoughi hospital, Yazd, Iran were studied. Results From 1195 neonates, 300 (25%) were from consanguineous marriages and 895 (75%) were from non-familial marriages. From 45 cases with anomalies, 34 (2.8%) cases were from familial marriages, while only 11 (0.9%) cases were from non-familial marriages. There was a significant correlation between parental marriages and the prevalence of anomaly (p=0.018). Conclusion The prevalence of congenital anomalies was mostly observed in consanguineous marriages compared to non consanguineous marriages. PMID:22125696

The prevalence and correlates of consanguineous marriages in Yemen: similarities and contrasts with other Arab countries.

PubMed

Jurdi, Rozzet; Saxena, Prem C

2003-01-01

Using data on 9762 women from the 1997 Yemen Demographic and Maternal and Child Health Survey, this paper examines the prevalence and socioeconomic correlates of consanguineous marriages in Yemen. The results indicate that 40% of marriages are consanguineous, over 85% of which are between first cousins. The prevalence of consanguineous marriages appears to have increased over time, particularly for the last marriage cohort. As for socioeconomic correlates, the study confirms the inverse association between consanguineous marriages and women's education and occupation, age at marriage and economic status. However, no statistically significant difference in the prevalence of consanguinity has been found by place of residence and geographical region. Somewhat unexpected results have been obtained by husband's background characteristics, with higher educated men and those working in the modern sector of the economy being more likely to be married to cousins.

Consanguinity and isolated atrial septal defect in North East of Iran.

PubMed

Moghaddam, Hasan Mottaghi; Esfehani, Reza Jafarzadeh; Panah, Nader Yazdan; Esfehani, Ali Jafarzadeh

2014-01-01

The rate of consanguineous marriage is high in Middle Eastern countries such as Iran. The relationship between consanguineous marriage and congenital heart disease is discussed in some studies, but there is not much data for relationship between atrial septal defect (ASD) and consanguineous marriage. The aim of this study was to evaluate the relationship between consanguineous marriage and ASD echocardiographic characteristics. This was a cross-sectional study approved by Mashhad University of Medical Sciences ethics committee and took place in Mashhad, Iran, for a period of 3 years from August 2008 till September 2011. In this cross-sectional study, 113 ASD patients participated and they were categorized into 3 groups on the basis of family relationship between their parents: first group-"no relationship," second group- "third degree relationship," and third group- "far relationship." Among the 54 male and 59 female ASD patients, the most prevalent type of ASD was ASD secundum (85.0%) followed by sinus venosus (8.8%). A total of 56% patients were present in the first group and 15% and 29% in the second group and the third group, respectively." The relationship between consanguinity and type of ASD (P < .001) and gender (P < .001 each) was observed. The relationship between the age of onset of disease and consanguinity (P=.003) was also observed. Considering the fact that there is a high prevalence of ASD and consanguineous marriage in Iran and bearing in mind the results of the present study, we recommend educating couples about the outcomes of consanguineous marriage in pre-marriage counseling.

Consanguinity, prematurity, birth weight and pregnancy loss: a prospective cohort study at four primary health center areas of Karnataka, India.

PubMed

Bellad, M B; Goudar, S S; Edlavitch, S A; Mahantshetti, N S; Naik, V; Hemingway-Foday, J J; Gupta, M; Nalina, H R; Derman, R; Moss, N; Kodkany, B S

2012-06-01

To determine whether consanguinity adversely influences pregnancy outcome in South India, where consanguinity is a common means of family property retention. Data were collected from a prospective cohort of 647 consenting women, consecutively registered for antenatal care between 14 and 18 weeks gestation, in Belgaum district, Karnataka in 2005. Three-generation pedigree charts were drawn for consanguineous participants. χ (2)-Test and Student's t-test were used to assess categorical and continuous data, respectively, using SPSS version 14. Multivariate logistic regression adjusted for confounding variables. Overall, 24.1% of 601 women with singleton births and outcome data were consanguineous. Demographic characteristics between study groups were similar. Non-consanguineous couples had fewer stillbirths (2.6 vs 6.9% P=0.017; adjusted P=0.050), miscarriages (1.8 vs 4.1%, P=0.097; adjusted P=0.052) and lower incidence of birth weight <2500 g (21.8 vs 29.5%, P=0.071, adjusted P=0.044). Gestation <37 weeks was 6.2% in both the groups. Adjusted for consanguinity and other potential confounders, age <20 years was protective of stillbirth (P=0.01), pregnancy loss (P=0.023) and preterm birth (P=0.013), whereas smoking (P=0.015) and poverty (P=0.003) were associated with higher rates of low birth weight. Consanguinity significantly increases pregnancy loss and birth weight <2500 g.

Prevalence of hereditary cancer susceptibility syndromes in children with cancer in a highly consanguineous population.

PubMed

Jastaniah, Wasil; Aljefri, Abdullah; Ayas, Mouhab; Alharbi, Musa; Alkhayat, Nawaf; Al-Anzi, Faisal; Yassin, Fawwaz; Alkasim, Fawaz; Alharbi, Qasim; Abdullah, Shaker; Abrar, Mohammed Burhan; Alsultan, Abdulrahman

2018-05-30

Hereditary cancer susceptibility syndromes (HCSS) are reported in up to one-third of children with cancer. Diagnosis of HCSS is crucial for implementation of surveillance protocols. We identified children who fulfilled criteria for HCSS in Saudi Arabia using the American College of Medical Genetics and Genomics (ACMG) guidelines, addressing the utility of these guidelines in a highly consanguineous population. This multi-center cross-sectional study recruited 1858 children with cancer between January 2011 and December 2014. HCSS criteria were based on the ACMG guidelines. Seven hundred and four (40.4%) out of 1742 eligible patients fulfilled criteria for HCSS. Consanguinity was reported in 629 (38%) patients, with 50 (2.9%) first-degree, 535 (30.7%) second-degree, and 272 (15.6%) third-degree relatives affected with cancer. Two hundred and eighty eight (17.4%) leukemia and 87 (5.3%) brain tumour patients fulfilled HCSS criteria, with parental consanguinity being the most frequent criterion in both (leukemia 85.4%, brain tumors 83.9%). However, leukemia was less frequent in patients of consanguineous parents (p = 0.023). Four out of 10 children with cancer fulfilled criteria for HCSS, most often due to consanguinity. This higher than expected prevalence suggests the need to validate consanguinity as a criterion for HCSS in highly consanguineous populations. Copyright © 2018 Elsevier Ltd. All rights reserved.

Parental consanguinity and susceptibility to drug abuse among offspring, a case-control study.

PubMed

Saadat, Mostafa; Vakili-Ghartavol, Roghayyeh

2010-11-30

Consanguineous marriage is the union of individuals having at least one common ancestor. It is well established that consanguinity is a potential risk factor for many adverse health outcome of offspring. In the present case-control study we tested the hypothesis of an association between parental consanguinity marriages and risk of offspring substance abuse. The study was performed in Shiraz (Fars province, Iran). Here 156 male drug abusers (case group) and 264 randomly selected healthy blood donors, matched for age and gender as control group, were included in the study. The prevalence of parental consanguineous marriages in the studied sample was 39.1 and 28.0% among cases and controls, respectively. The difference was statistically significant. The substance abusers were more smokers and drinkers compared with the control group. There was significant negative linear trend between drug abuse and level of education. The participants stratified using drinking habits and then the analysis was carried out separately for drinker and non-drinker subjects. Among drinkers, neither before nor after adjusting for smoking status and educational level, parental consanguinity did not show association with risk of substance abuse. Among non-drinkers, after adjusting for smoking status and educational level, parental consanguineous marriage was significantly associated with increased risk of substance abuse. Our study supports a significant relationship between parental consanguinity and drug abuse among non-drinker subjects. Copyright © 2010 Elsevier Ltd. All rights reserved.

A Family Study of Consanguinity in Children with Intellectual Disabilities in Barwani, India.

PubMed

Lakhan, Ram; Bipeta, Rajshekhar; Yerramilli, Srinivasa S R R; Nahar, Vinayak K

2017-01-01

Intellectual disability (ID) can be inherited in families through consanguineous marriage. The ID in an individual can be associated with the ID, epilepsy, and mental illness in their parents. Such connections can be seen more closely among consanguineous marriages in tribal and nontribal population in India. This study shows a few common patterns of the consanguineous relationship in the parents of children with ID in India. This is a case series research design. Extreme or deviant case sampling was applied. Data were collected in homes, camps, and clinical settings in the Barwani district of Madhya Pradesh, India. The patterns of consanguineous marriages and the relationship between children with ID and their relatives with ID, epilepsy, and mental illness were analyzed and reported with pedigree charts. Multiple patterns of consanguineous marriages in tribal and nontribal populations were observed. ID was found to be associated in children with their relatives of the first, second, and third generations. ID may inherit in individuals from their relatives of the first, second, and third generations who have ID, epilepsy, or mental illness and married in the relationship. Appropriate knowledge, guidance, and counseling may be provided to potential couples before planning a consanguineous marriage.

The relationship between consanguineous marriage and death in fetus and infants

PubMed Central

Mohammadi, Majid Mehr; Hooman, Heidar Ali; Afrooz, Gholam Ali; Daramadi, Parviz Sharifi

2012-01-01

Background: Given the high prevalence of consanguineous marriages in rural and urban areas of Iran, the aim of this study was to identify its role in increasing fetal and infant deaths. Materials ans Methods: This was a cross-sectional study in which 494 mothers with more than one exceptional child (mentally retarded and physically-dynamically disabled) or with normal children were selected based on multi-stage random sampling method. Data was gathered using the features of parents with more than one exceptional child questionnaire. The validity and reliability of this questionnaire was acceptable. Hierarchical log-linear method was used for statistical analysis. Results: Consanguineous marriage significantly increased the number of births of exceptional children. Moreover, there was a significant relation between the history of fetal/infant death and belonging to the group. There was a significant relation between consanguineous marriage and the history of fetal/infant death which means consanguineous marriage increased the prevalence of fetal/infant death in parents with exceptional children rather than in parents with normal children. Conclusions: The rate of fetal/infant death in exceptional births of consanguineous marriages was higher than that of non-consanguineous marriages. PMID:23626609

Consanguineous marriage in PR China: a study in rural Man (Manchu) communities.

PubMed

Wang, W; Qian, Cong; Bittles, A H

2002-01-01

Although there is a long history of consanguineous marriage in China, information on its prevalence is very limited. The Man (Qing) dynasty ruled China for over 250 years, but no consanguinity studies have been reported on this important population. The objective of the present investigation was to determine the present-day level of consanguineous marriage in the Man community, and to compare the data with existing consanguinity information on other Chinese populations. The study was conducted in a group of 11 rural Man communities in the north-eastern Chinese province of Liaoning. Household-based interviews were conducted by local staff on 513 couples, 418 of whom were Man with another 95 Man-Han inter-ethnic marriages. Basic pedigrees were constructed to determine the biological relationship between each set of spouses. Thirty of the 418 couples were in a consanguineous union, with a mean coefficient of inbreeding alpha = 0.0012. The small population sizes of the study may have contributed to the spatial variation in the patterns of inbreeding. Across generations there was a reduction in consanguineous marriages and an increase in inter-ethnic unions, which paralleled changes in civil marriage regulations.

Consanguinity and its relationship to differential fertility and mortality in the Kotia: a tribal population of Andhra Pradesh, India.

PubMed

Yasim; Naidu, J M; Mascie-Taylor, C G

1997-04-01

Data on patterns of marriage, differential fertility and mortality were collected from 211 Kotia women residing in Visakhapatnam district of Andhra Pradesh, India. Consanguineous marriages made up just over a quarter of the total, and of these, father's sister's daughter (FSD) were more common than mother's brother's daughter (MBD). The mean inbreeding coefficient for the sample (F) was 0.0172. Women in consanguineous marriages had a lower mean number of total conceptions, live births and living offspring (net fertility) than women in non-consanguineous marriages. Significant heterogeneity was found in the means of living offspring for FSD, MBD and non-consanguineous couples, but not for conceptions and live births.

Consanguineous Marriage and Marital Adjustment in Turkey.

ERIC Educational Resources Information Center

Fisiloglu, Hurol

2001-01-01

Investigates the relationship between consanguineous marriage and marital adjustment in Turkey. The results of the study show that the consanguineous marriage group had significantly lower marital adjustment and had more conflict with extended family than the nonconsanguineous marriage group. The finding is discussed in the context of research and…

Consanguineous marriages and matrimonial distance: a study among three South Indian caste groups.

PubMed

Reddy, P G

1988-12-01

Reddy studies consanguineous marriages and matrimonial distance in 3 castes of Nellore district, Andhra Pradesh, South India. The castes include the well-to-do agricultural caste, the Desuri Kapu; the 2nd, artisan caste in the middle of the hierarchy, the Devanga; and the third caste at the bottom of the social ladder, the Mala. During field work conducted in 1978-1979, prominent elders of the villages were approached; information on the consanguinity of marriage and matrimonial distance was gathered through intensive interviews of both men and women from all the households of the 3 castes. Among the total of 979 marriages, 28.9% occurred within the village, the proportion of intra-village marriages being significantly higher in Nellore taluk than in Sullurpet. The 3 castes overall show little difference in the incidence of intra-village marriages, but there is some within caste regional variation in the incidence of intra-village marriages, the Devanga showing a significantly higher incidence in Nellore than in Sullurpet. Intra-village marriages are more common among consanguineous couples (41.5%) than among non-consanguineous (18.3%), a highly significant excess in each of the caste groups. In short, Reddy concludes that intra-village marriages are more common among consanguineous couples than non-consanguineous, and mean matrimonial distance is also lower.

A Family Study of Consanguinity in Children with Intellectual Disabilities in Barwani, India

PubMed Central

Lakhan, Ram; Bipeta, Rajshekhar; Yerramilli, Srinivasa S. R. R.; Nahar, Vinayak K.

2017-01-01

Background: Intellectual disability (ID) can be inherited in families through consanguineous marriage. The ID in an individual can be associated with the ID, epilepsy, and mental illness in their parents. Such connections can be seen more closely among consanguineous marriages in tribal and nontribal population in India. Objective: This study shows a few common patterns of the consanguineous relationship in the parents of children with ID in India. Materials and Methods: This is a case series research design. Extreme or deviant case sampling was applied. Data were collected in homes, camps, and clinical settings in the Barwani district of Madhya Pradesh, India. The patterns of consanguineous marriages and the relationship between children with ID and their relatives with ID, epilepsy, and mental illness were analyzed and reported with pedigree charts. Results: Multiple patterns of consanguineous marriages in tribal and nontribal populations were observed. ID was found to be associated in children with their relatives of the first, second, and third generations. Conclusion: ID may inherit in individuals from their relatives of the first, second, and third generations who have ID, epilepsy, or mental illness and married in the relationship. Appropriate knowledge, guidance, and counseling may be provided to potential couples before planning a consanguineous marriage. PMID:29204013

Consanguinity in Qatar: knowledge, attitude and practice in a population born between 1946 and 1991.

PubMed

Sandridge, A L; Takeddin, J; Al-Kaabi, E; Frances, Y

2010-01-01

From March 2007 to March 2008 a cross-sectional study was conducted in Qatar to estimate the prevalence of consanguinity among Qataris and to assess their knowledge of the risks and their attitudes towards the practice. A secondary objective was to test the acceptability of sixteen Likert-style questions within the Qatari population. Face-to-face interviews using a 70-item structured questionnaire were conducted by three native Arabic-speaking medical students with 362 Qatari employees. Where consanguinity existed between the employee's parents, a diagram of the consanguinal relationship (phylogram) was completed. The response rate was 93%. By phylogram, 22% of participants reported a cousin relationship between their parents (consanguinal relationship) and another 15% reported that their parents were from the same tribe (affinal relationship). With respect to their own marital decision, 68% of the respondents had been married at least once. By phylogram, 35% of these reported a consanguineous relationship (first marriage), 9% reported only an affinal relationship and 56% reported that they were not married to a blood relative. Results on the sixteen Likert-style attitude questions were stratified by consanguinity status of parents and of self. In the stratification by consanguinity status of parents the top five attitudes differed by group but there appeared to be more similarity between the consanguinal and only tribal groups. Attitudinal results were stratified by sex. Results showed that the males had a stronger belief in several of the attitudes than females with the exception of causation of genetic abnormalities and health problems. The phylogram was shown to collect more detailed and explicit data than hard-coding. With respect to knowledge, the results showed that knowledge was imperfect with high proportions of participants not knowing that consanguinity has been implicated in autosomal recessive diseases such as thalassaemia, inborn errors of metabolism, deafness, anomalies of the extremities and specific congenital heart defects. Additionally, a sizeable proportion of the participants did not know that a more distant cousin marriage (e.g. third cousin) theoretically could be a less genetically risky choice to potential offspring than a closer cousin marriage (half-first cousin). These results indicate that more effort needs to be made in developing public health strategies to improve the population's understanding of the cost-benefit analysis involved in contracting consanguineous marriages given the goal of healthy offspring.

Do consanguineous parents of a child affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related parents with healthy offspring? Design of a case-control study

PubMed Central

2010-01-01

Background The offspring of consanguineous relations have an increased risk of congenital/genetic disorders and early mortality. Consanguineous couples and their offspring account for approximately 10% of the global population. The increased risk for congenital/genetic disorders is most marked for autosomal recessive disorders and depends on the degree of relatedness of the parents. For children of first cousins the increased risk is 2-4%. For individual couples, however, the extra risk can vary from zero to 25% or higher, with only a minority of these couples having an increased risk of at least 25%. It is currently not possible to differentiate between high-and low-risk couples. The quantity of DNA identical-by-descent between couples with the same degree of relatedness shows a remarkable variation. Here we hypothesize that consanguineous partners with children affected by an autosomal recessive disease have more DNA identical-by-descent than similarly-related partners who have only healthy children. The aim of the study is thus to establish whether the amount of DNA identical-by-descent in consanguineous parents of children with an autosomal recessive disease is indeed different from its proportion in consanguineous parents who have healthy children only. Methods/Design This project is designed as a case-control study. Cases are defined as consanguineous couples with one or more children with an autosomal recessive disorder and controls as consanguineous couples with at least three healthy children and no affected child. We aim to include 100 case couples and 100 control couples. Control couples are matched by restricting the search to the same family, clan or ethnic origin as the case couple. Genome-wide SNP arrays will be used to test our hypothesis. Discussion This study contains a new approach to risk assessment in consanguineous couples. There is no previous study on the amount of DNA identical-by-descent in consanguineous parents of affected children compared to the consanguineous parents of healthy children. If our hypothesis proves to be correct, further studies are needed to obtain different risk figure estimates for the different proportions of DNA identical-by-descent. With more precise information about their risk status, empowerment of couples can be improved when making reproductive decisions. PMID:20637082

Modernization and Consanguineous Marriage in Iran.

ERIC Educational Resources Information Center

Givens, Benjamin P.; Hirschman, Charles

1994-01-01

Used data on 4,667 women from the Iran Fertility Survey to examine trends and social correlates of consanguineous marriage. Found modest increase in proportion of marriages between cousins in Iran from 1940s to 1970s. Results suggest that modernization may be eroding social bases on consanguinity, whereas increased availability of cousins may lead…

Parental consanguinity and associated factors in congenital talipes equinovarus.

PubMed

Sreenivas, T; Nataraj, A R

2012-03-01

The cause of congenital talipes equinovarus (CTEV) is multifactorial and, consanguinity could be one of the causative factors in its development. The purpose of this study was, to determine the prevalence of parental consanguinity in CTEV and other factors like associated, congenital anomalies, maternal and fetal factors and also the severity of CTEV in these patients. The above factors were studied in 54 patients of less than 1 month of age with parental, consanguinity and 91 feet were evaluated for its severity using Dimeglio classification at the time of presentation. Out of 174 children presented to our department with CTEV, 54 (31%) children were born out, of consanguineous marriage. Thirty seven (68.5%) patients had bilateral CTEV. Twenty five (46.3%), patients had associated congenital anomalies and myelomeningocele being the commonest anomaly, associated. Out of 91 feet 61 (67%) were of grade 4 severity. High grade of severity observed in both idiopathic and non idiopathic CTEV suggests the, probable role of consanguinity as an etiological factor in the development of CTEV especially in our, part of the world. Copyright © 2011 Elsevier Ltd. All rights reserved.

Prevalence of consanguineous marriages in Syria.

PubMed

Othman, Hasan; Saadat, Mostafa

2009-09-01

Consanguineous marriage is the union of individuals having at least one common ancestor. The present cross-sectional study was done in order to illustrate the prevalence and types of consanguineous marriages in the Syrian Arab Republic. Data on consanguineous marriages were collected using a simple questionnaire. The total number of couples in this study was 67,958 (urban areas: 36,574 couples; rural areas: 31,384 couples) from the following provinces: Damascus, Hamah, Tartous, Latakia, Al Raqa, Homs, Edlep and Aleppo. In each province urban and rural areas were surveyed. Consanguineous marriage was classified by the degree of relationship between couples: double first cousins (F=1/8), first cousins (F=1/16), second cousins (F=1/64) and beyond second cousins (F<1/64). The coefficient of inbreeding (F) was calculated for each couple and the mean coefficient of inbreeding (alpha) estimated for the population of each province, stratified by rural and urban areas. The results showed that the overall frequency of consanguinity was 30.3% in urban and 39.8% in rural areas. Total rate of consanguinity was found to be 35.4%. The equivalent mean inbreeding coefficient (alpha) was 0.0203 and 0.0265 in urban and rural areas, respectively. The mean proportion of consanguineous marriages ranged from 67.5% in Al Raqa province to 22.1% in Latakia province. The alpha-value ranged from 0.0358 to 0.0127 in these two provinces, respectively. The western and north-western provinces (including Tartous, Lattakia and Edlep) recorded lower levels of inbreeding than the central, northern and southern provinces. The overall alpha-value was estimated to be about 0.0236 for the studied populations. First cousin marriages (with 20.9%) were the most common type of consanguineous marriages, followed by double first cousin (with 7.8%) and second cousin marriages (with 3.3%), and beyond second cousin was the least common type.

The Effect of Consanguineous Marriage on Mental Health among the Students of the Shahrekord University of Medical Sciences.

PubMed

Hosseinpour, Maryam; Deris, Fatemeh; Solati-Dehkordi, Kamal; Heidari-Soreshjani, Sheida; Karimi, Negar; Teimori, Hossein

2016-11-01

In Iran, after unintentional accidents, mental health problems are the second leading burden of disease. Consanguineous marriage is very common in Iran and the association between parental consanguinity and mental health is an important issue that has not yet been studied sufficiently in Iran. To investigate the effect of consanguinity and the degree of relationship on different levels of mental health. In this cross-sectional study, conducted in the Shahrekord University of Medical Sciences, two groups of students were enrolled. The first group consisted of 156 students that had consanguineous parent (case group) and the second group was 156 students whose parents had non-blood relationship (control group). The students were evaluated using General Health Questionnaire (GHQ-28). Statistical analysis was conducted by Pearson's correlation coefficient, independent t-test and the one-way analysis of variance. Odd ratio was used to estimate the relative risk. Over 30% of the individuals were suffering from mental health problems. The most and least common mental health problems in both groups were social dysfunction (54.5% in the case group and the control group 50%) and depression (15.4% in the case group and 17.3% in the control group), respectively. No statistically significant difference was observed in the frequency of overall mental health and its subscales between student with non-consanguineous parent (control group) and the students that had consanguineous parent (case group) (p>0.05) and the status of mental health was not significantly different among student with different degree of kinship (p>0.05). The study revealed that social dysfunction was very common among the study students and also there were no relationship between parental consanguineous marriage and mental health. Parental consanguinity and genetic factors may not be the major causes of high prevalence of mental health problems in Iran and the effects of the environmental factors on these problems may be greater than those of the inherited ones.

ASSESSMENT OF KNOWLEDGE, ATTITUDE AND PRACTICE TOWARDS CONSANGUINEOUS MARRIAGES AMONG A COHORT OF MULTIETHNIC HEALTH CARE PROVIDERS IN SAUDI ARABIA.

PubMed

Alnaqeb, Dhekra; Hamamy, Hanan; Youssef, Amira M; Al-Rubeaan, Khalid

2018-01-01

This study aimed to assess knowledge, attitude and practice related to consanguinity among multiethnic health care providers in the Kingdom of Saudi Arabia. Using a cross-sectional study design, a validated, self-administered close-ended questionnaire was randomly distributed to health care providers in different health institutions in the country between 1st August 2012 and 31st July 2013. A total of 1235 health care providers completed the study questionnaire. Of the 892 married participants (72.23% of total), 11.43% were married to a first cousin, and were predominantly Arabs, younger than 40 years and male. Only 17.80% of the patients seen by the health care providers requested consanguinity related counselling. A knowledge barrier was expressed by 27.49% of the participants, and 85.67% indicated their willingness to have more training in basic genetic counselling. A language barrier was expressed as a limiting factor to counselling for consanguinity among non-Arabs. The health care providers had a major dearth of knowledge that was reflected in their attitude and practice towards consanguinity counselling. This finding indicates the need for more undergraduate and postgraduate medical and nursing education and training in the counselling of consanguineous couples. It is recommended that consanguinity counselling is included in the current premarital screening and counselling programmes in the Kingdom.

Consanguinity Among Parents of Iranian Deaf Children.

PubMed

Ajallouyan, Mohammad; Radfar, Shokofeh; Nouhi, Sima; Tavallaie, Seid Abbas; Amirsalari, Susan; Yousefi, Jaleh; Hasanali Fard, Mahdieh

2016-11-01

It seems that there is a relationship between consanguinity and profound hearing loss but there is little data about the association of consanguinity and hearing loss in Iran. The aim of this study is to demonstrate the causes of profound bilateral sensorineural hearing loss among Iranian samples who are candidates for cochlear implantation. This study was retrospective, analytical, and designed to collect information about profound hearing impaired cases referred to the Baqiyatallah Cochlear implantation center using enumeration. A total of 310 children with profound hearing impairments participated in this study. They were aged from 6 months to 4 years old. The study was done between January 2007 and April 2009. Chi-square tests were used to show whether there was any statistical difference between the incidence of marital consanguinity of their parents and the normal population. Sixty-five percent of those 310 children had parents who had married with their relatives. Of the 203 (65%) parents that had consanguineous marriages, 132 were first cousins, which includes the children of two brothers (37 [11.8%] patrilateral parallel cousins), the children of two sisters (38 [12.2%] multi-lateral parallel cousins), or the children of a brother and a sister (57 [18.3%] cross cousins). Fifty-four (17.4%) of the parents were second cousins and 17 (5.2%) were beyond second cousins. Also, hearing loss etiology was obvious in 237 (76.3%) of the patients with profound hearing loss but was unknown in 73 (23.7%). Hereditary was identified as the most common cause in 33% of the cases. Our data demonstrated a 65% occurrence of consanguineous marriage among the parents of deaf children, which is statistically different from the percentage of consanguineous marriage among Iranian population (38%). This indicates an obvious relationship between severe hearing loss and consanguineous marriage.

Inbreeding in Gredos mountain range (Spain): contribution of multiple consanguinity and intervalley variation.

PubMed

Fuster, V; Jiménez, A M; Colantonio, S E

2001-04-01

The present paper examines consanguineous marriages occurring between 1874 and 1975 in three valleys (Tormes, Alberche, and Tiétar) in the Sierra de Gredos mountain range, Avila province, Spain. Information was obtained from parish registers of 42 localities, corresponding to a total of 41,696 weddings. Consanguineous marriages were defined as those up to the third degree of consanguinity (second cousins). From 1874 to 1975 the percentage of related mates was 4.45% and the inbreeding coefficient was 0.0011868 (for 1874 to 1917 corresponding figures up to the fourth degree were 16.44% and 0.00 19085, respectively). In order to ascertain the characteristics and evolution of mating patterns in Gredos, the contribution of each degree of kinship was analyzed as a whole and then for each valley separately. Regarding total consanguineous marriages in Gredos, there is a low frequency of uncle-niece matings (0.21%) and a first-second cousin mating ratio (C22/C33) of 0.23 (up to the third degree of consanguinity). Before 1918 multiple matings (i.e., those involving more than a single relationship) accounted for 19.16% of consanguineous marriages (up to the fourth degree). The observed frequencies of multiple consanguineous marriages was, on average, about twice that expected at random, and the proportion of such marriages to total inbreeding was 34.65%. The temporal change of the Gredos inbreeding pattern was characterized by a recent decrease; the highest inbreeding levels correspond to the period from 1915 to 1944. Finally, intervalley differences (maximum inbreeding coefficient in the Tormes, minimum in the Tiétar) are interpreted considering the geography, population size, and population mobility for each valley

Consanguineous marriage and reproduction in Beirut, Lebanon.

PubMed

Khlat, M

1988-08-01

Effects of consanguineous marriages on couples' fertility and on offspring mortality were investigated in Beirut through a population-based health survey of 2,752 households. A multistage random sampling procedure was used, and information was obtained from all ever-married women in the household about their reproductive performance and genealogical relationship with spouse; demographic and socioeconomic information was also recorded. Twenty-five percent of all marriages were between relatives, and the spouses were first cousins in approximately 57% of all consanguineous marriages. Total pregnancies, live births, and living children were significantly higher among consanguineous couples than among nonconsanguineous ones, as was the proportion dead among children ever born. However, no difference remained in either fertility or mortality, when allowance was made for socioeconomic status, religious affiliation, and marriage duration. The issue of confounding is discussed, and the lack of significant pattern in the final analysis is interpreted as resulting from a long-term practice of consanguineous marriages.

Genome-wide inbreeding estimation within Lebanese communities using SNP arrays

PubMed Central

Jalkh, Nadine; Sahbatou, Mourad; Chouery, Eliane; Megarbane, André; Leutenegger, Anne-Louise; Serre, Jean-Louis

2015-01-01

Consanguineous marriages have been widely practiced in several global communities with varying rates depending on religion, culture, and geography. In consanguineous marriages, parents pass to their children autozygous segments known as homozygous by descent segments. In this study, single-nucleotide polymorphisms were analyzed in 165 unrelated Lebanese people from Greek Orthodox, Maronite, Shiite and Sunni communities. Runs of homozygosity, total inbreeding levels, remote consanguinity, and population admixture and structure were estimated. The inbreeding coefficient value was estimated to be 1.61% in offspring of unrelated parents over three generations and 8.33% in offspring of first cousins. From these values, remote consanguinity values, resulting from genetic drift or recurrent consanguineous unions, were estimated in offspring of unrelated and first-cousin parents to be 0.61 and 1.2%, respectively. This remote consanguinity value suggests that for any unrelated marriages in Lebanon, the mates could be related as third cousins or as second cousins once removed. Under the assumption that 25% of marriages occur between first cousins, the mean inbreeding value of 2.3% may explain the increased incidence of recessive disease in offspring. Our analysis reveals a common ancestral population in the four Lebanese communities we studied. PMID:25424710

Genome-wide inbreeding estimation within Lebanese communities using SNP arrays.

PubMed

Jalkh, Nadine; Sahbatou, Mourad; Chouery, Eliane; Megarbane, André; Leutenegger, Anne-Louise; Serre, Jean-Louis

2015-10-01

Consanguineous marriages have been widely practiced in several global communities with varying rates depending on religion, culture, and geography. In consanguineous marriages, parents pass to their children autozygous segments known as homozygous by descent segments. In this study, single-nucleotide polymorphisms were analyzed in 165 unrelated Lebanese people from Greek Orthodox, Maronite, Shiite and Sunni communities. Runs of homozygosity, total inbreeding levels, remote consanguinity, and population admixture and structure were estimated. The inbreeding coefficient value was estimated to be 1.61% in offspring of unrelated parents over three generations and 8.33% in offspring of first cousins. From these values, remote consanguinity values, resulting from genetic drift or recurrent consanguineous unions, were estimated in offspring of unrelated and first-cousin parents to be 0.61 and 1.2%, respectively. This remote consanguinity value suggests that for any unrelated marriages in Lebanon, the mates could be related as third cousins or as second cousins once removed. Under the assumption that 25% of marriages occur between first cousins, the mean inbreeding value of 2.3% may explain the increased incidence of recessive disease in offspring. Our analysis reveals a common ancestral population in the four Lebanese communities we studied.

Social structure and consanguinity in a French mountain Population (1550-1849).

PubMed

Rabino-Massa, Emma; Prost, Michel; Boëtsch, Gilles

2005-04-01

Sociocultural factors play a crucial role in the variation of consanguinity in a population. The choice of specific matrimonial strategies can favor the closure or opening of the group to the outside, whereas differential fertility affects the gene flow from one generation to another. In the present study we analyzed the role of socioprofessional groups in the maintenance of endogamy and consanguinity in a French Alpine valley: Vallouise in the Briançon area. In mountain environments, where the reproductive space is limited and quickly saturated, the autochthonous families adopt diversified matrimonial strategies. These marriage practices tend to prevent fragmentation of agricultural property. We analyzed the matrimonial behavior in the two main social groups of this population (décideurs and farmers) from 1550 to 1849. To better understand the behavior of the two social groups, we considered the two components of consanguinity, close and distant. Our study showed that the two groups had similar behavior regarding consanguinity. The way to prevent fragmentation of the patrimony was to choose a consanguineous spouse. This type of strategy inevitably leads to a high percentage of endogamy, which in this region of the Alps exceeded 90% through many centuries.

Challenges in the care for consanguineous couples: an exploratory interview study among general practitioners and midwives

PubMed Central

2012-01-01

Background It is often suggested that an effort must be made to increase awareness among consanguineous couples of their reproductive risk, and to refer them for genetic counseling if needed. Primary care professionals are considered most appropriate for addressing the subject and identifying couples at risk during consultations in their practice. This Dutch study aims to explore the experiences, attitudes and beliefs of such professionals regarding their care for consanguineous couples. Methods Sixteen semi-structured interviews were conducted with midwives and general practitioners. Results Although most primary care professionals considered it their task to inform couples about the risks of consanguinity, during consultations the topic was generally only briefly touched upon and quickly abandoned. Important reasons for this were professionals’ beliefs about religious and social values of couples, their low perception of the couples’ reproductive risk and expected limited feasibility of referral. Feelings of embarrassment regarding addressing consanguinity did not seem to play a significant role. Conclusions Primary care professional beliefs about their clients’ religious and social values, their attitudes toward the risk, and perceived limited options for referral seem to conflict with the professional norm to address the topic of consanguinity. PMID:23102514

An insight into recent consanguinity within the Basque area in Spain. Effects of autochthony, industrialization and demographic changes.

PubMed

Alfonso-Sanchez, M A; Peña, J A; Aresti, U; Calderón, R

2001-01-01

The importance of studying the genetic kinship of those human groups characterized by a deeply rooted ethnicity has traditionally been and still is an interesting goal of anthropological and population genetic studies. However, only a few surveys have aimed to learn about the impact of industrial development on the consanguinity of these populations and even those have concentrated on industrialized regions. This approach is worth analysing in Spain, where industrialization was late in relation to other western European countries. In this work we analyse the characteristics of inbreeding in Guipúzcoa from 1951 to 1995. This Basque province underwent industrial and tourist development earlier than other Spanish regions. It has the highest density of Basque speakers and has always occupied a central position within the map of distribution of the Basque language. Guipúzcoa is geographically placed in the core of the Basque area. SUDJECTS AND METHODS: Data on consanguineous marriages recorded in the province of Guipúzcoa between 1951 and 1995 were taken from Roman Catholic dispensations stored in the Diocesan Archives of San Sebastián, the province's capital city. Over the whole time period, a total of 1152 consanguineous marriages were registered. The high frequencies of first cousin (M22) (F = 1/16) and uncle-niece, aunt-nephew (M12) (F = 1/8) consanguineous marriages distinguish Guipúzcoa from the rest of Iberian populations. The M22/M33 ratio (with M33 being second cousins) has never dropped below 0.67, which represents a significant deviation from the expectation value of 0.25. When consanguineous marriages are classified according to marriage partner birthplaces interesting results emerge. Provincial endogamy shows the highest consanguinity rates (57%) and the proportion of M22/M33 is also rather high (0.63). However, a major contribution to the consanguinity levels and mean inbreeding coefficient recorded in Guipúzcoa over recent decades has been made by immigrant relative groups coming from other geographical areas of Spain. In this segment of population the observed M22/M33 rates are 1.44. This study shows again how important preferentiality (or avoidance) is in human consanguinity, and also how human groups, in spite of being spatially settled in the same territory, present differential attitudes for given consanguinity patterns.

Prevalence of consanguineous marriages in west and south of Afghanistan.

PubMed

Saadat, Mostafa; Tajbakhsh, Khadijeh

2013-11-01

The prevalence of consanguinity in eight provinces of Afghanistan has recently been reported by Saify & Saadat (2012). The present cross-sectional study was done in order to illustrate the prevalence and types of consanguineous marriages among other populations of Afghanistan. Data on types of marriages were collected using a simple questionnaire. The total number of couples in this study was 5200 from the following provinces: Farah, Ghazni, Herat, Hilmand, Kabul, Kandahar, Logar, Parwan and Wardak. Consanguineous marriages were classified by the degree of relationship between couples: double first cousins, first cousins, first cousins once removed, second cousins and beyond second cousins. The coefficient of inbreeding (F) was calculated for each couple and the mean coefficient of inbreeding (α) estimated for each population. The α in the country was 0.0226, ranging from 0.0203 in Farah province to 0.0246 in Herat province. There were significant differences between provinces for frequencies of different types of marriages (p<0.001). First cousin marriages (21.7%) were the most common type of consanguineous marriages, followed by second cousins (16.0%), first cousins once removed (14.0%), beyond second cousins (6.9%) and double first cousins (1.6%). There was significant difference between ethnic groups for the types of marriages (p<0.001). Tajiks (Soni) and Sadats showed the lowest (α=0.0215) and highest (α=0.0242) levels of consanguinity among ethnic groups in Afghanistan, respectively. The present study shows that the Afghani populations, the same as other Islamic populations, have high levels of consanguinity.

The Effect of Consanguineous Marriage on Mental Health among the Students of the Shahrekord University of Medical Sciences

PubMed Central

Hosseinpour, Maryam; Deris, Fatemeh; Solati-Dehkordi, Kamal; Heidari-Soreshjani, Sheida; Karimi, Negar; Teimori, Hossein

2016-01-01

Introduction In Iran, after unintentional accidents, mental health problems are the second leading burden of disease. Consanguineous marriage is very common in Iran and the association between parental consanguinity and mental health is an important issue that has not yet been studied sufficiently in Iran. Aim To investigate the effect of consanguinity and the degree of relationship on different levels of mental health. Materials and Methods In this cross-sectional study, conducted in the Shahrekord University of Medical Sciences, two groups of students were enrolled. The first group consisted of 156 students that had consanguineous parent (case group) and the second group was 156 students whose parents had non-blood relationship (control group). The students were evaluated using General Health Questionnaire (GHQ-28). Statistical analysis was conducted by Pearson’s correlation coefficient, independent t-test and the one-way analysis of variance. Odd ratio was used to estimate the relative risk. Results Over 30% of the individuals were suffering from mental health problems. The most and least common mental health problems in both groups were social dysfunction (54.5% in the case group and the control group 50%) and depression (15.4% in the case group and 17.3% in the control group), respectively. No statistically significant difference was observed in the frequency of overall mental health and its subscales between student with non-consanguineous parent (control group) and the students that had consanguineous parent (case group) (p>0.05) and the status of mental health was not significantly different among student with different degree of kinship (p>0.05). Conclusion The study revealed that social dysfunction was very common among the study students and also there were no relationship between parental consanguineous marriage and mental health. Parental consanguinity and genetic factors may not be the major causes of high prevalence of mental health problems in Iran and the effects of the environmental factors on these problems may be greater than those of the inherited ones. PMID:28050399

Modernization or cultural maintenance: the practice of consanguineous marriage in Iran.

PubMed

Jalal Abbasi-Shavazi, Mohammad; McDonald, Peter; Hosseini-Chavoshi, Meimanat

2008-11-01

Consanguineous marriage has been the culturally preferred form of marriage in Iran. This paper examines the extent to which education, urbanization and changes in modes of economic production have affected the incidence of consanguineous marriage and attitudes towards consanguineous marriages. The 2002 Iran Fertility Transition Survey conducted in the four provinces of Gilan, Sistan and Baluchistan, Yazd and West Azarbaijan provides information on the degree of relationship of marriage partners from around 6550 ever-married women aged 15-49. Attitudinal data were also obtained. Overall, the level of marriage to biological relatives ranged from 23% in Gilan to 78% in Sistan and Baluchistan. The paper finds that the practice of marriage to biological relatives has remained surprisingly resilient in the face of modernizing influences and that ethnicity, province and area of residence remain important determinants. On the other hand, attitudes have shifted towards marriage with a non-relative. Anthropological research would illuminate the processes of consanguineous marriage in Iran.

Consanguinity and epilepsy in Oran, Algeria: A case-control study.

PubMed

Chentouf, Amina; Talhi, Randa; Dahdouh, Aicha; Benbihi, Latifa; Benilha, Soumia; Oubaiche, Mohand Laid; Chaouch, Malika

2015-03-01

The goal of this case-control study was to identify the significance of consanguinity and other risk factors for epilepsy in Oran, Algeria. Unrelated epileptic patients upwards of 16 years, who attended the Neurology Department between October 2013 and March 2014 were included in the study. Controls, matched for age and sex, were selected among non-epileptic patients attending the same department during the same period. The risk factors evaluated were: consanguinity, family history of epilepsy, perinatal complications, infection of the central nervous system, mental retardation, neurological impairment, history of febrile seizures, severe head trauma, cerebrovascular diseases, and addiction. 101 cases and 202 controls participated in the study. Multivariate logistic regression identified five factors significantly associated with epilepsy: first-degree of consanguinity (odds ratio (OR)=2.15), history of epilepsy in first-degree relatives (OR=4.03), antecedent of febrile seizures (OR=5.38), severe head injury (OR=2.94) and mental retardation (OR=9.32). Consanguinity, family history of epilepsy, history of febrile seizures, severe head trauma and mental retardation are risk factors for epilepsy. The implementation of a strategy for prevention and awareness of the impact of consanguineous marriages as well as genetic counseling for couples with a family history of epilepsy are needed. Copyright © 2015 Elsevier B.V. All rights reserved.

Consanguinity Among Parents of Iranian Deaf Children

PubMed Central

Ajallouyan, Mohammad; Radfar, Shokofeh; Nouhi, Sima; Tavallaie, Seid Abbas; Amirsalari, Susan; Yousefi, Jaleh; Hasanali Fard, Mahdieh

2016-01-01

Background It seems that there is a relationship between consanguinity and profound hearing loss but there is little data about the association of consanguinity and hearing loss in Iran. Objectives The aim of this study is to demonstrate the causes of profound bilateral sensorineural hearing loss among Iranian samples who are candidates for cochlear implantation. Methods This study was retrospective, analytical, and designed to collect information about profound hearing impaired cases referred to the Baqiyatallah Cochlear implantation center using enumeration. A total of 310 children with profound hearing impairments participated in this study. They were aged from 6 months to 4 years old. The study was done between January 2007 and April 2009. Chi-square tests were used to show whether there was any statistical difference between the incidence of marital consanguinity of their parents and the normal population. Results Sixty-five percent of those 310 children had parents who had married with their relatives. Of the 203 (65%) parents that had consanguineous marriages, 132 were first cousins, which includes the children of two brothers (37 [11.8%] patrilateral parallel cousins), the children of two sisters (38 [12.2%] multi-lateral parallel cousins), or the children of a brother and a sister (57 [18.3%] cross cousins). Fifty-four (17.4%) of the parents were second cousins and 17 (5.2%) were beyond second cousins. Also, hearing loss etiology was obvious in 237 (76.3%) of the patients with profound hearing loss but was unknown in 73 (23.7%). Hereditary was identified as the most common cause in 33% of the cases. Conclusions Our data demonstrated a 65% occurrence of consanguineous marriage among the parents of deaf children, which is statistically different from the percentage of consanguineous marriage among Iranian population (38%). This indicates an obvious relationship between severe hearing loss and consanguineous marriage. PMID:28191326

Epilepsy and consanguinity in Shiraz, Iran.

PubMed

Asadi-Pooya, Ali Akbar

2005-01-01

The importance of consanguinity and its association with epilepsy has been suggested in some studies, but in one study the risk contributed to consanguinity for childhood epilepsy was not significanta. In the present study, there was an attempt to determine if consanguinity has any important association with epilepsy. All the epileptic children and adolescents up to the age of 18 years, who had been referred to Motahary Clinic in Shiraz, Iran, during a six-month period, were included in this cross-sectional study. The percentage of consanguinity in parents of the epileptic patients was compared to a sample of the general population in the same geographical area. In total, 181 unrelated epileptic children were included in this study. The mean age of these children was 7+/-4.6 years. The male/female ratio in these patients was 1.29. Overall, 61(33.7%) of the parents were first cousins (OR=2.264, 95%-CI: 1.618-3.169 in comparison to the general population), 37 (20.4%) were second cousins (OR=3.557, 95%-CI: 2.389-5.296), and 83 (45.9%) were not related. The percentage of consanguinity in parents of the epileptic patients was significantly higher in comparison to a sample of the general population (OR=2.612, 95%-CI: 1.929-3.536, P<0.0001) which signifies the importance of consanguinity as a potential risk factor for epilepsy. In this regard, more education and awareness of young individuals about the increased risk of epilepsy after familial marriages (at least by 2.2 folds), as well as pre-marriage counseling for couples who have a family history of epilepsy are necessary as an effective preventive program.

CONSANGUINITY AND INBREEDING COEFFICIENT IN TRIBAL PASHTUNS INHABITING THE TURBULENT AND WAR-AFFECTED TERRITORY OF BAJAUR AGENCY, NORTH-WEST PAKISTAN.

PubMed

Ahmad, Bashir; Rehman, Atta Ur; Malik, Sajid

2016-01-01

The north-western populations of Pakistan in the Federally Administered Tribal Areas (FATA) adjoining the Pakistan-Afghanistan border are an amalgamation of native and migrated Pashtun tribes. These tribal populations are in transition due to war conditions and geo-political turmoil on both sides of the border since the Soviet invasion in 1979. Bio-demographic and epidemiological data for these tribes are scarce. A prospective cross-sectional sample of 967 males was selected from a representative Pashtun population of Bajaur Agency, and information obtained on bio-demographic variables and marital union types. Analysis of these data revealed that consanguinity was 22.34% and the inbreeding coefficient F was calculated to be 0.0134. The inbreeding coefficient was observed to be higher in subjects who were illiterate, had unskilled jobs and who belonged to younger age categories, extended families and the Tarkalani tribe. Further analyses with respect to temporal variables like subject's age, year of marriage and age at marriage revealed that after a transition in marital union types in the early 80s, there has been a declining trend in the rate of consanguineous unions. Further, consanguineous unions in the parental generation were only 5%, but parental marriage types were predictors of subjects' marital union types. The data further establish that, contrary to a general notion about a high consanguinity rate in Pakistan, consanguineous unions are not common in Bajaur Agency and first cousin marriage is not the preferred type. Furthermore, this research shows that there is a great regional variation in the pattern of consanguinity in Pakistan that needs to be documented in order to draw a more comprehensive picture of the inbreeding coefficient in the country.

Race, consanguinity and social features in Birmingham babies: a basis for prospective study.

PubMed Central

Bundey, S; Alam, H; Kaur, A; Mir, S; Lancashire, R J

1990-01-01

STUDY OBJECTIVE--The aim of the study was to investigate the influence of consanguinity on children's health. DESIGN--The study is a prospective survey from birth to five years of a cohort of babies born in a multiracial community. This report details the initial findings on consanguinity. SETTING--Participating families live predominantly in three health districts of Birmingham, and were recruited in three local maternity hospitals. PARTICIPANTS--Babies of 2432 European mothers, 509 Afro-Caribbean mothers, 625 Indian mothers, 956 Pakistani mothers, and 216 Bangladeshi mothers have been enrolled in the study. Eighty mothers refused to participate. MEASUREMENTS AND RESULTS--Sociodemographic information was obtained using a structured questionnaire administered at interview. Interview data were supplemented with obstetric information from the medical records. The highest prevalence of parental consanguinity was in Pakistani Muslims (69%), whereas in Muslims from other countries it was 23%, and it was less than 1% in non-Muslims. In the majority of consanguineous Muslim pedigrees the degree of inbreeding was greater than that for first cousin parents. CONCLUSIONS--This prospective study will allow an assessment to be made about any ill health in childhood arising from parental consanguinity, about whether screening programmes are indicated for particular autosomal recessive diseases, and about whether premarital health education might be beneficial. The study has also documented parental ages in different races and this, together with the levels of parental consanguinity in all races, will be useful in genetic methods for assessing the frequency of recessive genes, the possibility of genetic heterogeneity, and whether or not parental age effect exists for new mutations of specific genetic disorders. PMID:2370500

Inbreeding coefficients and degree of consanguineous marriages in Spain: a review.

PubMed

Fuster, Vicente; Colantonio, Sonia Edith

2003-01-01

The contribution of consanguineous marriages corresponding to uncle-niece or aunt-nephew (C12), first cousin (C22), first cousin once removed (C23), and second cousin (C33) to the inbreeding coefficient (alpha) was analyzed from a sample of Spanish areas and periods. Multiple regressions were performed taking as independent variables the different degrees of consanguinity previously selected (C12, C22, C23, and C33) and as dependent variable the inbreeding coefficient (alpha). According to the results obtained for any degree and period, rural frequencies always surpass urban. However, the pattern is similar in both areas. In the period where consanguinity was more elevated (1890-1929) the C22/C33 ratio increased. Its variation is not due to C22 and C33 changes in the same way. In rural areas, this ratio surpasses the expected value by a factor of 2-3, but in urban areas it was 7-10 times larger, in some cases due to migration. While in rural Spain the C33 frequency was approximately 1.5 times C22, in cities C22 was 1.5 times C33. The best fit among the various types of consanguineous matings and alpha involves a lineal relationship. Regardless of the number of variables contributing significantly to alpha, C22 matings are always present. Moreover, their standardized (beta) coefficients are the highest. The above indicates that this consanguineous relationship conditions the inbreeding coefficient the most. In the period of greater consanguinity, close relationships, uncle-niece C12, and first cousin once removed (C23) make a significant contribution to alpha. In rural Spain second cousins (C33) always significantly determined alpha; however, in cities the inbreeding variation was mainly due to C12 and C23. Copyright 2003 Wiley-Liss, Inc.

Genealogical and molecular analysis of a family-based cohort of congenital heart disease patients from the São Miguel Island (Azores, Portugal).

PubMed

Cabral, Rita; Pires, Renato; Anjos, Rui; Branco, Claudia C; Maciel, Paula; Mota-Vieira, Luisa

2016-11-01

Congenital heart disease (CHD) is one common birth malformation, accounting for ∼30% of total congenital abnormalities. Considering the unknown role of consanguinity in causing CHD, this study hypothesised that consanguineous unions and/or familial aggregation may be frequent in the Azorean Island of São Miguel (Portugal). To that end, a retrospective observational study was performed based on genealogical and molecular analyses. The study enrolled 112 CHD patients from São Miguel Island, which allowed the assessment of type of family (simplex or multiplex), parental consanguinity and grandparental endogamy. Based on 15 STR markers, inbreeding coefficients (F IS ) in the CHD cohort and healthy control group (n = 114) were estimated. Multiplex families were 37.6% (n = 41/109), a rate considerably higher than previously described in the literature (< 15%). Moreover, 9.2% (n = 10/109) of the CHD families were consanguineous, mostly derived from third cousin unions, and 20.2% (n = 22/109) presented full grandparental endogamy. Higher F IS values were found in patients with parental consanguinity (0.0371) and patent ductus arteriosus (0.0277). This study analysed several genealogical and genetic features related with CHD, revealing the presence of parental consanguinity and extensive familial aggregation in the CHD patients from São Miguel Island.

Consanguinity, endogamy and inborn errors of metabolism in Oman: a cross-sectional study.

PubMed

Al-Thihli, Khalid; Al-Murshedi, Fathiya; Al-Hashmi, Nadia; Al-Mamari, Watfa; Islam, M Mazharul; Al-Yahyaee, Said A

2014-01-01

The Sultanate of Oman, like many other Arab countries, has relatively high rates of consanguinity. Reports suggest that the incidence of inborn errors of metabolism (IEM) is also high in Oman. This retrospective cross-sectional study was designed to evaluate the number of patients with IEM being followed at the only two tertiary centers in Oman treating such patients, and to calculate the consanguinity rates among these families. The electronic medical records of all patients were reviewed for demographic and clinical characteristics. A total of 285 patients with IEM were being followed at the 2 centers involved; 162 (56.8%) were male and 123 (43.2%) were female. The history of consanguinity was documented or available for 241 patients: 229 patients (95%) were born to consanguineous parents related as second cousins or closer. First-cousin marriages were reported in 191 families (79.3%), while 31 patients (12.9%) were born to second cousins. The parents of 5 patients (2%) were related as double first cousins, and 2 patients (1%) were born to first cousins once removed. The average coefficient of inbreeding (F) in our study was 0.081. Seventeen patients (6%) had associated comorbid conditions other than IEM. Our study highlights the clinical burden of IEM in Oman and emphasizes the high consanguinity rates among the parents of affected patients. © 2014 S. Karger AG, Basel

Consanguinity and Its Sociodemographic Differentials in Bhimber District, Azad Jammu and Kashmir, Pakistan

PubMed Central

Jabeen, Nazish

2014-01-01

ABSTRACT Kashmiri population in the northeast of Pakistan has strong historical, cultural and linguistic affinities with the neighbouring populations of upper Punjab and Potohar region of Pakistan. However, the study of consanguineous unions, which are customarily practised in many populations of Pakistan, revealed marked differences between the Kashmiris and other populations of northern Pakistan with respect to the distribution of marriage types and inbreeding coefficient (F). The current descriptive epidemiological study carried out in Bhimber district of Mirpur division, Azad Jammu and Kashmir, Pakistan, demonstrated that consanguineous marriages were 62% of the total marriages (F=0.0348). First-cousin unions were the predominant type of marriages and constituted 50.13% of total marital unions. The estimates of inbreeding coefficient were higher in the literate subjects, and consanguinity was witnessed to be rising with increasing literacy level. Additionally, consanguinity was observed to be associated with ethnicity, family structure, language, and marriage arrangements. Based upon these data, a distinct sociobiological structure, with increased stratification and higher genomic homozygosity, is expected for this Kashmiri population. In this communication, we present detailed distribution of the types of marital unions and the incidences of consanguinity and inbreeding coefficient (F) across various sociodemographic strata of Bhimber/Mirpuri population. The results of this study would have implication not only for other endogamous populations of Pakistan but also for the sizeable Kashmiri community immigrated to Europe. PMID:25076667

Consanguinity and spousal concordance in Kuwait.

PubMed

al-Kandari, Y; Crews, D E; Poirier, F E

2002-12-01

Consanguineous marriage is favored in Kuwait. This research focuses on the relationship of physical and cultural traits to marriage types in Kuwait and examines concordance as a function of consanguinity and marriage duration. In a nonrandom opportunistic sample of 242 couples anthropometric and blood pressure data have been collected as well as data on acculturation, religiosity, Farsi proficiency, level of education, occupation, and attitudes regarding fertility. Significant concordances occur in cultural characteristics among couples in all three types of marriages with respect to the degree of religiosity, acculturation, language similarity, education, and occupation. Non-consanguineous spouses have the highest concordance in educational level, occupation, and degree of acculturation, but the lowest for religiosity and Farsi proficiency. Nonkin marriages seem to be based on personal preferences. In the wider potential nonkin marriage pool spouses show more concordance in stature and education indicating the positive assortative mating for those traits. Non-consanguineous spouses show a significant association for triceps and subscapular skinfold thicknesses hip and waist circumferences, and body fat distribution. Unrelated spouses exhibit more concordance for physical traits than do related spouses. There is a significant correlation between spouses in first and double cousin marriages as well as in spouses in second and less than second cousin unions for systolic and diastolic blood pressure, while non-consanguineous spouses show a significant association in diastolic blood pressure only.

CONSANGUINEOUS MARRIAGES AMONG IRANIAN MANDAEANS LIVING IN SOUTH-WEST IRAN.

PubMed

Saadat, Mostafa; Zarghami, Mahdis

2018-07-01

SummarySeveral studies have indicated that consanguineous marriages (unions between biologically related persons) are associated with increased risk of autosomal recessive diseases and several multifactorial traits. Mandaeans are a closed ethno-religious community living in areas of southern Iraq and Iran (Khuzestan Province). There are currently no data on the prevalence of consanguineous marriages among Mandaeans. The present study was carried out in 2016 to determine the prevalence of consanguinity among Iranian Mandaeans living in Khuzestan Province, south-west Iran. A total of 137 couples (urban areas: 79 couples; rural areas: 58 couples) were included in the study. Information on the consanguineous marriages of the subjects was collected through direct interviews. Marriages were classified by the degree of relationship between couples as double first cousins, first cousins, first cousin once removed, second cousins and unrelated marriages. The coefficient of inbreeding (F) was calculated for each couple and the mean coefficient of inbreeding (α) estimated for the population, stratified by rural and urban areas. The overall frequency of consanguinity was found to be 50.7% in urban and 86.2% in rural areas. There was a significant difference between rural and urban areas in types of marriages (χ 2=24.8, df=4, p<0.001) and first cousin marriages (51.8%) were the most common type. The overall α-value was estimated to be 0.0363 for the Iranian Mandaean population.

Inbreeding and immigration in urban and rural zones of Chile, with an endogamy index.

PubMed

Lazo, B; Campusano, C; Figueroa, H; Pinto-Cisternas, J; Zambra, E

1978-01-01

In order to establish relationships among immigration, inbreeding, and age at marriage in urban and rural zones in Chile, and to formulate an endogamy index, ecclesiastical and civil data on consanguinity from 1865-1914 were analyzed, and a random mating deviation index was developed, with resulting values indicating deviation toward endogamy in both zones. Data grouped by zones and decades include means of population and density, nuptiality, consanguineous marriages (number, types, frequencies, and inbreeding coefficients), and frequencies of immigrants among consanguineous and nonconsanguineous couples. All of these values differ markedly between zones, with values in the rural zone double those in the urban zone. In the 2 zones, there are no clear differences in age at marriage between consanguineous and nonconsanguineous couples, and this is an important finding. From the point of view of fertility, one can expect a similar length period of fertility for both groups of couples. In this case, lower fertility might be expected in consanguineous marriages, only because of a higher probability of homozygosis of deleterious genes.

Genetics of consanguineous marriage: Impact and importance of counseling.

PubMed

Akrami, Seyed Mohammad

2012-12-01

Consanguineous marriage, marriage between close biological kin, especially that between first cousins, is socially favored in some parts of North Africa, the Middle East and Asia. An increased rate of congenital anomalies and autosomal recessive disorders are significantly associated with such practice. In such communities, misunderstanding and external attempts to discourage such marriage without proper genetic counseling seem to be inappropriate and unsuccessful. Update in knowledge of clinicians especially pediatricians is the aim of this paper regarding importance and issues behind consanguineous marriage.

Genetics of consanguineous marriage: Impact and importance of counseling

PubMed Central

Akrami, Seyed Mohammad

2012-01-01

Consanguineous marriage, marriage between close biological kin, especially that between first cousins, is socially favored in some parts of North Africa, the Middle East and Asia. An increased rate of congenital anomalies and autosomal recessive disorders are significantly associated with such practice. In such communities, misunderstanding and external attempts to discourage such marriage without proper genetic counseling seem to be inappropriate and unsuccessful. Update in knowledge of clinicians especially pediatricians is the aim of this paper regarding importance and issues behind consanguineous marriage. PMID:27625826

Does anonymous sperm donation increase the risk for unions between relatives and the incidence of autosomal recessive diseases due to consanguinity?

PubMed

Serre, Jean-Louis; Leutenegger, Anne-Louise; Bernheim, Alain; Fellous, Marc; Rouen, Alexandre; Siffroi, Jean-Pierre

2014-03-01

In France gamete donation and notably sperm donation are anonymous. It has been claimed that anonymous artificial insemination by donor (AID) could highly contribute to an increase in the level of consanguinity and the incidence of autosomal recessive diseases, due to the unions between offspring of anonymous donors, unaware of their biological kinship, with the special case of unions between half-siblings. The actual incidence of consanguinity due to AID was compared with that resulting from the two other main sources of consanguinity and recessive diseases, i.e. voluntary unions between related individuals or inadvertent unions between the offspring of a common unknown male ancestor (false paternity). From these data, we estimated that expected unions in France between half sibs per year are 0.12 between offspring of sperm donors (1.2 every 10 years) and 0.5 between offspring of common male ancestors through false paternity (5 every 10 years). More generally, the inadvertent unions between false paternity offspring are roughly four times more frequent than those resulting from anonymous AID. We estimated that in the future, when AID has been in practice for several generations, out the 820 000 annual births in France, respectively, 6 and 25 births will be consanguineous through an unknown common ancestor related to anonymous AID and to a false paternity, both of which are negligible when compared with the 1256 children born from first-degree cousins. About 672 children per year are born with a recessive genetic disease due to the panmictic risk and additional affected cases due to consanguinity would be 34.54 for first-cousin offspring, 0.33 for offspring of individuals related due to false paternity and 0.079 for offspring of individuals related due to anonymous AID. Anonymous AID would therefore be responsible for 0.46% of consanguineous births and for 0.01% of recessive diseases. Therefore, the effect of anonymous AID on half-sibling unions, consanguinity and recessive disease incidence can be regarded as marginal.

Consanguinity and its socio-biological parameters in Rahim Yar Khan District, Southern Punjab, Pakistan.

PubMed

Riaz, Hafiza Fizzah; Mannan, Shaheen; Malik, Sajid

2016-05-20

Rahim Yar Khan (RYK) District is a multi-ethnic assemblage of both ancient and migrated communities in Southern Punjab, Pakistan. There is a paucity of knowledge on the bio-demographic structure of this endogamous population. We have carried out a cross-sectional epidemiological study in RYK District and recruited 2174 random Muslim married females. Detailed account of marital union types, level of consanguinity, and subject's fertility, was taken. The analyses of these data revealed that consanguineous unions (CU) were 58.46 %, rendering an inbreeding coefficient (IC-F) = 0.0355. The CU were observed to be significantly higher in subjects originating from rural areas, speaking Saraiki language, illiterate or having a religious/Madarsa education only, and belonging to nuclear family type. The rate of consanguinity was also higher in subjects whose husbands were engaged in unskilled manual or skilled manual jobs, and had consanguinity in the parental generation. Multivariate logistic regression analyses revealed that variables like Saraiki language, illiteracy, reciprocal marriages, and parental consanguinity, were the significant predictors of CU in the subject. Among the first cousin unions (which constituted 52 % of all marriages), parallel-cousin and patrilineal unions were in the majority (54 and 57 %, respectively), and father's brother's daughter type had the highest representation (31 %). The analyses further demonstrated that fertility and mean live-births were significantly higher in women who had CU compared to the non-consanguineous (NCU) group (p < 0.006); and significantly higher number of sons per women were born to the mothers who had CU compared with the NCU sample (p = 0.0002). However, there were no differences in the CU and NCU samples with respect to pre- or post-natal mortalities and child morbidities. The scientific findings in RYK District are distinct from the observations in other Pakistani populations and clue to a unique nature of this population. This study presents a comprehensive account of consanguinity and IC-F in RYK District and would be helpful in getting an insight into the structure of this population.

Prevalence of consanguineous marriages among shi'a populations of Lebanon.

PubMed

El-Kheshen, Ghadir; Saadat, Mostafa

2013-09-01

In genetics, a consanguineous marriage means union between couples who are related as second cousins or closer. The present cross-sectional study was carried out in order to illustrate the prevalence and types of consanguineous marriages in the Shi'a population living in widespread territories in Lebanon including the Bekaa Valley, the south of Lebanon and the southern suburb of Beirut. Data on types of marriages were collected using a simple questionnaire. The total number of couples in the study was 1203. Consanguineous marriage was classified by the degree of relationship between couples. The overall frequency of consanguinity was found to be 28.4%, with first cousin marriages (21.3%) being the most common type followed by first cousins once removed (5.5%), then double first cousins (0.8%). The frequencies of second cousin and beyond second cousin marriages were the same at 0.4% of all the marriages. The mean inbreeding coefficient (α) was estimated at about 0.0161 for the population. There were no significant differences between the three studied territories for frequencies of different types of marriages (p>0.1), nor were there significant differences between the rural and urban areas (p>0.1).

Genetics of intellectual disability in consanguineous families.

PubMed

Hu, Hao; Kahrizi, Kimia; Musante, Luciana; Fattahi, Zohreh; Herwig, Ralf; Hosseini, Masoumeh; Oppitz, Cornelia; Abedini, Seyedeh Sedigheh; Suckow, Vanessa; Larti, Farzaneh; Beheshtian, Maryam; Lipkowitz, Bettina; Akhtarkhavari, Tara; Mehvari, Sepideh; Otto, Sabine; Mohseni, Marzieh; Arzhangi, Sanaz; Jamali, Payman; Mojahedi, Faezeh; Taghdiri, Maryam; Papari, Elaheh; Soltani Banavandi, Mohammad Javad; Akbari, Saeide; Tonekaboni, Seyed Hassan; Dehghani, Hossein; Ebrahimpour, Mohammad Reza; Bader, Ingrid; Davarnia, Behzad; Cohen, Monika; Khodaei, Hossein; Albrecht, Beate; Azimi, Sarah; Zirn, Birgit; Bastami, Milad; Wieczorek, Dagmar; Bahrami, Gholamreza; Keleman, Krystyna; Vahid, Leila Nouri; Tzschach, Andreas; Gärtner, Jutta; Gillessen-Kaesbach, Gabriele; Varaghchi, Jamileh Rezazadeh; Timmermann, Bernd; Pourfatemi, Fatemeh; Jankhah, Aria; Chen, Wei; Nikuei, Pooneh; Kalscheuer, Vera M; Oladnabi, Morteza; Wienker, Thomas F; Ropers, Hans-Hilger; Najmabadi, Hossein

2018-01-04

Autosomal recessive (AR) gene defects are the leading genetic cause of intellectual disability (ID) in countries with frequent parental consanguinity, which account for about 1/7th of the world population. Yet, compared to autosomal dominant de novo mutations, which are the predominant cause of ID in Western countries, the identification of AR-ID genes has lagged behind. Here, we report on whole exome and whole genome sequencing in 404 consanguineous predominantly Iranian families with two or more affected offspring. In 219 of these, we found likely causative variants, involving 77 known and 77 novel AR-ID (candidate) genes, 21 X-linked genes, as well as 9 genes previously implicated in diseases other than ID. This study, the largest of its kind published to date, illustrates that high-throughput DNA sequencing in consanguineous families is a superior strategy for elucidating the thousands of hitherto unknown gene defects underlying AR-ID, and it sheds light on their prevalence.

Relationship between birth order of spouses with different degrees of consanguineous relationship.

PubMed

Reddy, B M; Malhotra, K C

1991-08-01

The relationship between birth order of spouses with different degrees of consanguinity is examined in a sample of 1826 couples belonging to the endogamous Vadde Fisherfolk of Kolleru Lake, Andhra Pradesh, India. We attempt to explain the wide variation in the frequency of different kinds of consanguineous marriages through the age-sex structure of the population in general and especially of the related families. This structure may also be manifested in the association between the birth orders of spouses. A highly significant and large correlation between the birth orders of spouses in uncle-niece marriages and a gradual decrease in the correlation with increase in remoteness of the relationship between the spouses were observed. Given the distribution of age differences between the spouses and assuming a standard age-sex structure, it seems possible to estimate the optimum frequency with which at least close consanguineous marriages occur in any particular population.

An empirical analysis of the effects of consanguineous marriages on economic development.

PubMed

Bildirici, Melike; Kökdener, Meltem; Ersin, Oezgür ömer

2010-01-01

In this study, development experiences toward economic development are investigated to provide an alternative analysis of economic development, human capital, and genetic inheritance in the light of consanguineous marriages. The countries analyzed in the study are discussed in accordance with consanguineous marriage practices and classified by their per capita gross domestic product (GDP) growth. A broad range of countries are analyzed in the study. Arab countries that experienced high rates of growth in their gross national income during the twentieth century but failed to fulfill adequate development measures as reflected in the growth in national income, countries undergoing transition from tight government regulation to free market democracy, and African nations that have experienced complications in the process of development show important differences in the process of economic development. It is shown that the countries that have reached high average development within the context of per capita GDP have overcome problems integral to consanguineous marriage.

Consanguineous marriages in Afghanistan.

PubMed

Saify, Khyber; Saadat, Mostafa

2012-01-01

The present cross-sectional study was done in order to illustrate the prevalence and types of consanguineous marriages among Afghanistan populations. Data on types of marriages were collected using a simple questionnaire. The total number of couples in the study was 7140 from the following provinces: Badakhshan, Baghlan, Balkh, Bamyan, Kabul, Kunduz, Samangan and Takhar. Consanguineous marriages were classified by the degree of relationship between couples: double first cousins, first cousins, first cousins once removed, second cousins and beyond second cousins. The coefficient of inbreeding (F) was calculated for each couple and the mean coefficient of inbreeding (α) estimated for each population. The proportion of consanguineous marriages in the country was 46.2%, ranging from 38.2% in Kabul province to 51.2% in Bamyan province. The equivalent mean inbreeding coefficient (α) was 0.0277, and ranged from 0.0221 to 0.0293 in these two regions. There were significant differences between provinces for frequencies of different types of marriages (p<0.001). First cousin marriages (27.8%) were the most common type of consanguineous marriages, followed by double first cousin (6.9%), second cousin (5.8%), beyond second cousin (3.9%) and first cousin once removed (1.8%). There were significant differences between ethnic groups for the types of marriages (χ2=177.6, df=25, p<0.001). Tajiks (Soni) and Turkmens (also Pashtuns) showed the lowest (α=0.0250) and highest (α=0.0297) mean inbreeding coefficients, respectively, among the ethnic groups in Afghanistan. The study shows that Afghanistan's populations, like other Islamic populations, have a high level of consanguinity.

Three clinical experiences with SNP array results consistent with parental incest: a narrative with lessons learned.

PubMed

Helm, Benjamin M; Langley, Katherine; Spangler, Brooke; Vergano, Samantha

2014-08-01

Single nucleotide polymorphism microarrays have the ability to reveal parental consanguinity which may or may not be known to healthcare providers. Consanguinity can have significant implications for the health of patients and for individual and family psychosocial well-being. These results often present ethical and legal dilemmas that can have important ramifications. Unexpected consanguinity can be confounding to healthcare professionals who may be unprepared to handle these results or to communicate them to families or other appropriate representatives. There are few published accounts of experiences with consanguinity and SNP arrays. In this paper we discuss three cases where molecular evidence of parental incest was identified by SNP microarray. We hope to further highlight consanguinity as a potential incidental finding, how the cases were handled by the clinical team, and what resources were found to be most helpful. This paper aims to contribute further to professional discourse on incidental findings with genomic technology and how they were addressed clinically. These experiences may provide some guidance on how others can prepare for these findings and help improve practice. As genetic and genomic testing is utilized more by non-genetics providers, we also hope to inform about the importance of engaging with geneticists and genetic counselors when addressing these findings.

Prevalence and characteristics of non-syndromic orofacial clefts and the influence of consanguinity.

PubMed

Alamoudi, N M; Sabbagh, H J; Innes, N P T; El Derwi, D; Hanno, A Z; Al-Aama, J Y; Habiballah, A H; Mossey, P A

2014-01-01

The Objective of this study was to identify the prevalence and describe the characteristics of non-syndromic orofacial cleft (NSOFC) in Jeddah, Saudi Arabia and examine the influence of consanguinity. Six hospitals were selected to represent Jeddah's five municipal districts. New born infants with NSOFC born between 1st of January 2010 to 31st of December 2011 were clinically examined and their number compared to the total number of infants born in these hospitals to calculate the prevalence of NSOFC types and sub-phenotypes. Referred Infants were included for the purpose of studying NSOFC characteristics and their relationship to consanguinity. Information on NSOFC infants was gathered through parents' interviews, infants 'files and patient examinations. Prospective surveillance of births resulted in identifying 37 NSOFC infants born between 1st of January 2010 to 31st of December 2011 giving a birth prevalence of 0.80/1000 living births. The total infants seen, including referred cases, were 79 children. Consanguinity among parents of cleft palate (CP) cases was statistically higher than that among cleft lip with or without cleft palate (CL/P) patients (P = 0.039). Although there appears to be a trend in the relationship between consanguinity and severity of CL/P sub-phenotype, it was not statistically significant (P = 0.248). Birth prevalence of NSOFC in Jeddah City was 0.8/1000 live births with CL/P: 0.68/1000 and CP: 0.13/1000. Both figures were low compared to the global birth prevalence (NSOFC: 1.25/1000, CL/P: 0.94/1000 and CP: 0.31/1000 live births). Consanguineous parents were statistically higher among CP cases than among other NSOFC phenotypes.

Consanguineous marriage and increased risk of idiopathic congenital talipes equinovarus: a case-control study in a rural area.

PubMed

Sahin, Orcun; Yildirim, Cengiz; Akgun, Rahmi C; Haberal, Bahtiyar; Yazici, Ayse C; Tuncay, Ismail C

2013-01-01

The purpose of this study is to evaluate if there is any relationship between consanguineous marriages and idiopathic congenital talipes equinovarus (CTEV). A case-control study on CTEV screening was conducted in a rural eastern city of Turkey between 2009 and 2011 and a total of 28 cases (infants with idiopathic CTEV) and 575 controls (healthy infants) were recruited. Sociodemographic status of the infants, including gestational age and birth weights, maternal characteristics and, if any, the degree of consanguinity, were recorded. As an inclusion criterion, only singleton, full-term, live births were accepted. A backward stepwise logistic regression model was used to evaluate the relationship between idiopathic CTEV and parental consanguinity. Unadjusted and adjusted odds ratios (OR) with 95% confidence interval (CI) were calculated. Among maternal and infant characteristics, significant risk factors for idiopathic CTEV in the regression analysis were work status (employed), consanguineous marriage, sex (male), and gestational age (>42 wk). Babies born to first-cousin parents had >4 times the risk of idiopathic CTEV [OR, 4.138, (95% CI, 1.484, 11.538)] and the risk for those born to distant relatives was 2.9 times higher [OR, 2.941, (95% CI, 1.070, 8.087)] than for children of unrelated parents. Consanguineous marriage was significantly associated with an increased risk of idiopathic CTEV. This association remained significant even after adjusting for potential confounding variables. To obtain more accurate results, a population-based screening study with an increased number of cases and controls should be performed in future studies. Case-control study investigating the effect of a patient characteristic on the outcome of disease (level-III).

Consanguineous marriages in the genetic counseling centers of Isfahan and the ethical issues of clinical consultations.

PubMed

Nouri, Narges; Nouri, Nayereh; Tirgar, Samane; Soleimani, Elham; Yazdani, Vida; Zahedi, Farzaneh; Larijani, Bagher

2017-01-01

Consanguineous marriage, which is common in many regions in the world, has absorbed much attention as a causative factor in raising the incidence of genetic diseases. The adverse effects may be attributed to the expression of the genes received from common ancestors and mortality and morbidity of the offspring. Iran has a high rate of consanguineous marriages. In recent years genetic counseling has come to be considered in health care services. This cross-sectional study was conducted in order to determine the prevalence and types of consanguineous marriages in the genetic clinics in Isfahan. We aimed to define the different types of marriages, specific categories of genetic disorders associated with consanguineous marriages, and mode of inheritance in the family tree. We also narratively reviewed the ethical aspects of the issue. The data were collected using a simple questionnaire. A total number of 1535 couples from urban and rural areas formed the study population. The marriages were classified according to the degree of the relationship between couples, including: double cousin, first cousin, first cousin once removed, second cousin and beyond second cousin. The SPSS software version 16 was used for data analysis. Data obtained through genetic counseling offered during a 5-year period revealed that 74.3% had consanguineous relationships, 62.3% were first cousins, 1% were double cousins and 7.8% were second cousins. In addition, 76% of the couples had at least one genetic disease in their family tree. Related ethical issues were also considered in this study, including autonomy and informed decision making, benefit and harm assessment, confidentiality, ethics in research, justice in access to counseling services, financial problems ethics, and the intellectual property of scientific success.

Consanguineous marriages in the genetic counseling centers of Isfahan and the ethical issues of clinical consultations

PubMed Central

Nouri, Narges; Nouri, Nayereh; Tirgar, Samane; Soleimani, Elham; Yazdani, Vida; Zahedi, Farzaneh; Larijani, Bagher

2017-01-01

Consanguineous marriage, which is common in many regions in the world, has absorbed much attention as a causative factor in raising the incidence of genetic diseases. The adverse effects may be attributed to the expression of the genes received from common ancestors and mortality and morbidity of the offspring. Iran has a high rate of consanguineous marriages. In recent years genetic counseling has come to be considered in health care services. This cross-sectional study was conducted in order to determine the prevalence and types of consanguineous marriages in the genetic clinics in Isfahan. We aimed to define the different types of marriages, specific categories of genetic disorders associated with consanguineous marriages, and mode of inheritance in the family tree. We also narratively reviewed the ethical aspects of the issue. The data were collected using a simple questionnaire. A total number of 1535 couples from urban and rural areas formed the study population. The marriages were classified according to the degree of the relationship between couples, including: double cousin, first cousin, first cousin once removed, second cousin and beyond second cousin. The SPSS software version 16 was used for data analysis. Data obtained through genetic counseling offered during a 5-year period revealed that 74.3% had consanguineous relationships, 62.3% were first cousins, 1% were double cousins and 7.8% were second cousins. In addition, 76% of the couples had at least one genetic disease in their family tree. Related ethical issues were also considered in this study, including autonomy and informed decision making, benefit and harm assessment, confidentiality, ethics in research, justice in access to counseling services, financial problems ethics, and the intellectual property of scientific success. PMID:29416832

[Analysis of clinical phenotype and mode of inheritance in retinitis pigmentosa patients with consanguineous marriage].

PubMed

Rong, Wei-ning; Sheng, Xun-lun; Liu, Ya-ni

2012-10-01

To analyse the mode of inheritance and clinical characteristics of retinitis pigmentosa (RP) patients with consanguineous marriage. RP patients were recruited for this study in Ningxia Eye Hospital from September 2009 to July 2011. All patients received complete ophthalmic examination. The mode of inheritance were determined based on family history and marriage history. Clinical features were characterized by complete ophthalmic examinations including visual acuity, macular OCT, visual field and electroretinogram (ERG). A total of 143 individuals with RP (33 families) were recruited. Based on analysis of family history and marriage history, 20 RP families (23 patients) had consanguineous marriage history accounted for 60.6% RP families (16.1% RP patients). There were 4 patients (from 4 families) diagnosed as Usher syndrome. In 20 RP families with consanguineous marriage history, 7 families (35.0%) were Hui ethnicity and 13 families (65%) were Han ethnicity. The marriages of 15 families were between first cousins and 3 families were between second cousins, only 2 families were between half cousins matrimony. Of 23 RP patients, 12 were males and 11 were females. The average age of onset was 11.4 ± 6.8 years and the average age of recruitment was (32.0 ± 13.5) years. The best-corrected visual acuity was less than 0.6 in 78.2% patients. According to the features of the fundus, 13 patients were classical retinitis pigmentosa and 10 patients were retinitis pigmentosa sine pigmento. Visual field examination showed that all patients had varying degrees of peripheral visual field defect. Retinal neuroepithelial layer of macular and peripheral retina became thinner and retinal photoreceptors were disappeared. The average thickness of macular fovea was (186.1 ± 78.7) µm on right eyes and (187.4 ± 76.3) µm on left eyes. The incidence of RP with consanguineous marriages was high in Ningxia Region. The mode of inheritance of RP patients with consanguinity is autosomal recessive. The common marriage pattern of consanguinity is between first cousins. The age of onset is early and the ocular fundus changes of some patients are atypical, this should be paid attention clinically.

Impact of consanguineous marriages and degrees of inbreeding on fertility, child mortality, secondary sex ratio, selection intensity, and genetic load: a cross-sectional study from Northern India.

PubMed

Fareed, Mohd; Kaisar Ahmad, Mir; Azeem Anwar, Malik; Afzal, Mohammad

2017-01-01

The aim of our study was to understand the relationship between consanguineous marriages and reproductive outcomes. A total of 999 families were recruited from five Muslim populations of Jammu region. Family pedigrees were drawn to access the family history and inbreeding status in terms of coefficient of inbreeding (F). Fertility, mortality, secondary sex ratio, selection intensity, and lethal equivalents were measured using standard methods. The significant differences for gross fertility was found to be higher among inbred groups as compared to the unrelated families (P < 0.05) and higher mortality rates were observed among consanguineous families of all populations in comparison with the non-consanguineous family groups. Moreover, the prenatal and postnatal child mortality rates (i.e., U5MR and U18MR) have presented a persuasive increase with an upsurge in the homozygosity level. The mortality rate was found to be maximum among families with the highest value of coefficient of inbreeding (F). The selection intensity (SI) also showed inflations among families with respect to their increasing inbreeding coefficients. The greater values of lethal equivalents per gamete (LEs/gamete) were observed for autosomal inheritance in comparison with sex-linked inheritance. Our conclusive assessment brings out the deleterious consequence of consanguineous marriages on reproductive outcomes.

Socioeconomic, demographic, and geographic variables affecting the diverse degrees of consanguineous marriages in Spain.

PubMed

Fuster, V; Colantonio, S E

2004-02-01

In a population the inbreeding coefficient alpha is determined by the relative incidence of the various degrees of consanguineous marriages--uncle-niece or aunt-nephew (C12), first cousin (C22), first cousin once removed (C23), second cousin (C33)--which may be related to temporal, geographic, demographic, and economic factors. Using published information from Spain corresponding to urban and rural areas, in this article we seek to establish how each specific relationship behaves with respect to geographic, demographic, and socioeconomic factors, to determine differential urban-rural patterns, and to study whether the diverse types of consanguineous matings relate homogeneously to these factors. For this purpose we performed multiple regressions in which the dependent variables were the different degrees of consanguinity previously selected and the independent variables were geographic, demographic, and economic factors. Our results indicate that the various types of consanguineous marriages in Spain are more conditioned by geographic, demographic, and economic variables than by the inbreeding level alpha (the coefficient of determination was between 0.22 and 0.72; the maximum for alpha was 0.35). A regional pattern exists in Spain and corresponds to close and to remote kinship, which may be mainly related to economic and family factors. Close relationships appear to be more associated with economic variables, whereas second-cousin marriages correspond largely to rural areas of the Spanish Central Plateau.

Familial Recurrence of 3MC Syndrome in Consanguineous Families: A Clinical and Molecular Diagnostic Approach With Review of the Literature.

PubMed

Gardner, Olivia K; Haynes, Karla; Schweitzer, Daniela; Johns, Alexis; Magee, William P; Urata, Mark M; Sanchez-Lara, Pedro A

2017-11-01

We report four individuals from two unrelated consanguineous families with 3MC syndrome. In the first family, chromosome microarray data revealed that the two affected sisters, born to first-cousin parents, shared a unique homozygous C-terminal deletion in the COLEC11 gene. Two affected brothers from a second family, also born to first-cousin parents, shared a region of homozygosity that included the second gene known to cause the 3MC syndrome, MASP1. We discuss the diagnostic approach of craniofacial disorders born to consanguineous parents and highlight a literature search and reference a helpful dysmorphology solution powered by FDNA (Facial Dysmorphology Novel Analysis) technology.

Birth prevalence of non-syndromic orofacial clefts in Saudi Arabia and the effects of parental consanguinity

PubMed Central

Sabbagh, Heba J.; Innes, Nicola P.; Sallout, Bahauddin I.; Alamoudi, Najlaa M.; Hamdan, Mustafa A.; Alhamlan, Nasir; Al-Khozami, Amaal I.; Abdulhameed, Fatma D.; Al-Aama, Jumana Y.; Mossey, Peter A.

2015-01-01

Objectives: To describe the characteristics and prevalence of non-syndromic orofacial clefting (NSOFC) and assess the effects of parental consanguinity on NSOFC phenotypes in the 3 main cities of Saudi Arabia. Methods: All infants (114,035) born at 3 referral centers in Riyadh, and 6 hospitals in Jeddah and Madinah between January 2010 and December 2011 were screened. The NSOFC cases (n=133) were identified and data was collected through clinical examination and records, and information on consanguinity through parent interviews. The diagnosis was confirmed by reviewing medical records and contacting the infants’ pediatricians. Control infants (n=233) matched for gender and born in the same hospitals during the same period, were selected. Results: The prevalence of NSOFC was 1.07/1000 births in Riyadh, and 1.17/1000 births overall; cleft lip (CL) was 0.47/1000 births, cleft lip and palate (CLP) was 0.42/1000 births, and cleft palate (CP) was 0.28/1000 births. Cleft palate was significantly associated with consanguinity (p=0.047, odds ratio: 2.5, 95% confidence interval: 1 to 6.46), particularly for first cousin marriages. Conclusion: The birth prevalence of NSOFC in Riyadh alone, and in the 3 main cities of Saudi Arabia were marginally lower than the mean global prevalence. While birth prevalence for CLP was comparable to global figures, the CL:CLP ratio was high, and only CP was significantly associated with consanguinity. PMID:26318465

A prospective study of hepatitis B virus markers in patients with chronic HBV infection from Brazilian families of Western and Asian origin.

PubMed

Carrilho, F J; Ono-Nita, S K; Cardoso, R A; Cancado, E L R; Pinho, J R R; Alves, V A F; Da Silva, L C

2005-09-01

The purpose of the present study was to determine the frequency of hepatitis B virus (HBV) markers in families of HBsAg-positive patients with chronic liver disease. Serum anti-HBc, HBsAg and anti-HBs were determined by enzyme immunoassay and four subpopulations were considered: genetically related (consanguineous) and non-genetically related (non-consanguineous) Asian subjects and genetically related and non-genetically related Western subjects. A total of 165 and 186 relatives of Asian and Western origin were enrolled, respectively. The occurrence of HBsAg and anti-HBs antibodies was significantly higher (P < 0.0001) in family members of Asian origin (81.8%) than in family members of Western origin (36.5%). HBsAg was also more frequent among brothers (79.6 vs 8.5%; P < 0.0001), children (37.9 vs 3.3%; P < 0.0001) and other family members (33.9 vs 16.7%; P < 0.0007) of Asian than Western origin, respectively. No difference between groups was found for anti-HBs, which was more frequently observed in fathers, spouses and other non-genetic relatives. HBV infection was significantly higher in children of Asian than Western mothers (P < 0.0004). In both ethnic groups, the mothers contributed more to their children's infection than the fathers (P < 0.0001). Furthermore, HBsAg was more frequent among consanguineous members and anti-HBs among non-consanguineous members. These results suggest the occurrence of vertical transmission of HBV among consanguineous members and probably horizontal sexual transmission among non-consanguineous members of a family cluster. Thus, the high occurrence of dissemination of HBV infection characterizes family members as a high-risk group that calls for immunoprophylaxis. Finally, the study showed a high familial aggregation rate for both ethnic groups, 18/19 (94.7%) and 23/26 (88.5%) of the Asian and Western origin, respectively.

The prevalence of isolated growth hormone deficiency among children of short stature in Jordan and its relationship with consanguinity.

PubMed

Zayed, Ayman A; Mustafa Ali, Moaath K; Al-Ani, Mohammad A; Momani, Munther S; Yousef, Al-Motassem F

2014-12-01

The prevalence of isolated growth hormone deficiency (IGHD) among short-statured children in Jordan, where consanguineous marriage (CM) is common, is unknown. No studies have investigated the relationship between degrees of consanguinity and IGHD. This study aimed to determine the prevalence of IGHD among short-statured children referred to a university hospital in Jordan and its relationship with different degrees of consanguinity. We conducted a 24-month cross-sectional observational trial at an outpatient tertiary care center in Amman, Jordan. We obtained detailed family histories, medical evaluations and laboratory tests for 94 short-statured children (50 boys and 44 girls aged 6-16 years). Complete and partial GHD were defined as peak GH responses of 5 and 7 μg/l (15 and 21 mIU/l) [IRMA/DiaSorin®], respectively, in both exercise and insulin tolerance tests. GHD was diagnosed in 69·1% of the short children, including 86% (43/50) of the children of consanguineous parents (83·3%, 93·8% and 81·8% of children of first cousins, first cousins once removed and second cousins, respectively) and 50% (20/44) of the children of nonconsanguineous parents (P = 0·039, 0·002 and 0·013, respectively). However, there was no statistically significant difference in the prevalence of small pituitary MRI between GH-deficient children of consanguineous parents and those of nonconsanguineous parents (28·6% vs 13·6%, P = 0·3). The prevalence of IGHD among referred short children in Jordan was exceptionally high and significantly higher in the children of CM. In countries where CM is common, preconception counselling and rigorous surveillance for GHD in short children may be indicated. © 2014 John Wiley & Sons Ltd.

MHC class 2 deficiency and X-linked agammaglobulinaemia in a consanguineous extended family.

PubMed

Broides, A; Shubinsky, G; Parvari, R; Grimbacher, B; Somech, R; Garty, B Z; Levy, J

2009-08-01

Manifestations of immunodeficiency within the same family are presumed to be the same disease. We report a consanguineous extended family where four patients have immunodeficiency, three have X-linked agammaglobulinaemia and one has major histocompatibility complex class 2 deficiency. Within one family, two rare genetic diseases with similar clinical manifestations can occur.

The Effect of Consanguineous Marriage on Reading Disability in the Arab Community

ERIC Educational Resources Information Center

Abu-Rabia, Salim; Maroun, Lateefeh

2005-01-01

The present study examined the effect of consanguineous marriage in the Arab community on reading disabilities of offspring. It examined whether the rate of reading disabilities was higher among offspring of first-cousin parents than offspring of unrelated parents; and whether reading-disabled children of first-cousin parents were more disabled in…

CHANGES IN MARRIAGE PATTERNS AMONG THE ARAB COMMUNITY IN ISRAEL OVER A 60-YEAR PERIOD.

PubMed

Sharkia, Rajech; Mahajnah, Muhammad; Athamny, Esmael; Khatib, Mohammad; Sheikh-Muhammad, Ahmad; Zalan, Abdelnaser

2016-03-01

The aim of this study was to determine the prevalence and trends of various types of consanguineous marriage among the Arab community in Israel over a long time period (1948-2007) by religion and educational level. Data were collected by face-to-face interview of 3173 Arab couples living in Israel in 2007 and 2008. The trend in consanguineous marriages was found to decrease significantly over successive time periods, from 42.5% to 30.9% (p=0.001), and the prevalence of first-cousin and closer marriages decreased, from 23% to 12.7%. Consanguinity was found to be significantly related to religion (p=0.001) and wife's level of education (p=0.028).

Institutional Protocol to Manage Consanguinity Detected by Genetic Testing in Pregnancy in a Minor

PubMed Central

Chen, Laura P.; Beck, Anita E.; Tsuchiya, Karen D.; Chow, Penny M.; Mirzaa, Ghayda M.; Wiester, Rebecca T.

2015-01-01

Single-nucleotide polymorphism arrays and other types of genetic tests have the potential to detect first-degree consanguinity and uncover parental rape in cases of minor teenage pregnancy. We present 2 cases in which genetic testing identified parental rape of a minor teenager. In case 1, single-nucleotide polymorphism array in a patient with multiple developmental abnormalities demonstrated multiple long stretches of homozygosity, revealing parental rape of a teenage mother. In case 2, a vague maternal sexual assault history and diagnosis of Pompe disease by direct gene sequencing identified parental rape of a minor. Given the medical, legal, and ethical implications of such revelations, a protocol was developed at our institution to manage consanguinity identified via genetic testing. PMID:25687148

Associations of recurrent miscarriages with chromosomal abnormalities, thrombophilia allelic polymorphisms and/or consanguinity in Saudi Arabia.

PubMed

Turki, Rola F; Assidi, Mourad; Banni, Huda A; Zahed, Hanan A; Karim, Sajjad; Schulten, Hans-Juergen; Abu-Elmagd, Muhammad; Rouzi, Abdulrahim A; Bajouh, Osama; Jamal, Hassan S; Al-Qahtani, Mohammed H; Abuzenadah, Adel M

2016-10-10

Recurrent pregnancy loss (RPL) or recurrent spontaneous abortion is an obstetric complication that affects couples at reproductive age. Previous reports documented a clear relationship between parents with chromosomal abnormalities and both recurrent miscarriages and infertility. However, limited data is available from the Arabian Peninsula which is known by higher rates of consanguineous marriages. The main goal of this study was to determine the prevalence of chromosomal abnormalities and thrombophilic polymorphisms, and to correlate them with RPL and consanguinity in Saudi Arabia. Cytogenetic analysis of 171 consent patients with RPL was performed by the standard method of 72-h lymphocyte culture and GTG banding. Allelic polymorphisms of three thrombophilic genes (Factor V Leiden, Prothrombin A20210G, MTHFR C677T) were performed using PCR-RFLP (restriction fragment length polymorphism) and gel electrophoresis. Data analysis revealed that 7.6 % of patients were carrier of numerical or structural chromosomal abnormalities. A high rate of translocations (46 %) was associated to increased incidence of RPL. A significant correlation between consanguineous RPL patients and chromosomal abnormalities (P < 0.05) was found. Both Factor V Leiden and Prothrombin A20210G allelic polymorphisms were significantly associated with a higher prevalence of RPL. This study demonstrated a strong association between RPL and the prevalence of chromosomal abnormalities and inherited thrombophilia. Given the high rate of consanguineous marriages in the Saudi population, these results underline the importance of systematic cytogenetic investigation and genetic counseling preferably at the premarital stage or at least during early pregnancy phase through preimplantation genetic diagnosis (PGD).

Consanguinity, human evolution, and complex diseases

PubMed Central

Bittles, A. H.; Black, M. L.

2010-01-01

There is little information on inbreeding during the critical early years of human existence. However, given the small founding group sizes and restricted mate choices it seems inevitable that intrafamilial reproduction occurred and the resultant levels of inbreeding would have been substantial. Currently, couples related as second cousins or closer (F ≥ 0.0156) and their progeny account for an estimated 10.4% of the global population. The highest rates of consanguineous marriage occur in north and sub-Saharan Africa, the Middle East, and west, central, and south Asia. In these regions even couples who regard themselves as unrelated may exhibit high levels of homozygosity, because marriage within clan, tribe, caste, or biraderi boundaries has been a long-established tradition. Mortality in first-cousin progeny is ≈3.5% higher than in nonconsanguineous offspring, although demographic, social, and economic factors can significantly influence the outcome. Improving socioeconomic conditions and better access to health care will impact the effects of consanguinity, with a shift from infant and childhood mortality to extended morbidity. At the same time, a range of primarily social factors, including urbanization, improved female education, and smaller family sizes indicate that the global prevalence of consanguineous unions will decline. This shift in marriage patterns will initially result in decreased homozygosity, accompanied by a reduction in the expression of recessive single-gene disorders. Although the roles of common and rare gene variants in the etiology of complex disease remain contentious, it would be expected that declining consanguinity would also be reflected in reduced prevalence of complex diseases, especially in population isolates. PMID:19805052

Addressing key issues in the consanguinity-related risk of autosomal recessive disorders in consanguineous communities: lessons from a qualitative study of British Pakistanis.

PubMed

Darr, A; Small, N; Ahmad, W I U; Atkin, K; Corry, P; Modell, B

2016-01-01

Currently, there is no consensus regarding services required to help families with consanguineous marriages manage their increased genetic reproductive risk. Genetic services for communities with a preference for consanguineous marriage in the UK remain patchy, often poor. Receiving two disparate explanations of the cause of recessive disorders (cousin marriage and recessive inheritance) leads to confusion among families. Further, the realisation that couples in non-consanguineous relationships have affected children leads to mistrust of professional advice. British Pakistani families at-risk for recessive disorders lack an understanding of recessive disorders and their inheritance. Such an understanding is empowering and can be shared within the extended family to enable informed choice. In a three-site qualitative study of British Pakistanis, we explored family and health professional perspectives on recessively inherited conditions. Our findings suggest, firstly, that family networks hold strong potential for cascading genetic information, making the adoption of a family-centred approach an efficient strategy for this community. However, this is dependent on provision of high-quality and timely information from health care providers. Secondly, families' experience was of ill-coordinated and time-starved services, with few having access to specialist provision from Regional Genetics Services; these perspectives were consistent with health professionals' views of services. Thirdly, we confirm previous findings that genetic information is difficult to communicate and comprehend, further complicated by the need to communicate the relationship between cousin marriage and recessive disorders. A communication tool we developed and piloted is described and offered as a useful resource for communicating complex genetic information.

Inbreeding Depression and IQ in a Study of 72 Countries

ERIC Educational Resources Information Center

Woodley, Michael A.

2009-01-01

In this ecological study, a robust negative correlation of r = - 0.62 (P less than 0.01) is reported between national IQs and consanguinity as measured by the log10 transformed percentage of consanguineous marriages for 72 countries. This correlation is reduced in magnitude, when IQ is controlled for GDP per capita (r = - 0.41, P less than 0.01);…

Thalassemia major and consanguinity in Shiraz city, Iran.

PubMed

Asadi-Pooya, Ali Akbar; Doroudchi, Mehrnoosh

2004-09-05

Beta-thalassemia is among the most common genetic disorders in the world and in Iran, with widespread occurrence. A cross-sectional study on 648 beta-thalassemia patients in Shiraz, Iran was carried out to determine the demography of beta-thalassemia major in Shiraz city, Fars province, Iran and also the rate of consanguinity and the significance of pre-marriage counseling in decreasing familial marriages and consequently preventing this autosomal recessive genetic disease. All interviewed patients had thalassemia major and their age, sex, and the consanguinity between parents were recorded. 40.6% of beta-thalassemia patients were outcomes of first-cousin marriages. Comparison of the percentages of familial marriages (consanguinity) between parents of beta-thalassemia patients and a sample of normal population, revealed a statistically significant difference (p< 0.00001). A nonstatistically significant difference was observed between male (53.5%) and female (46.5%) thalassemia patients. Comparison of data with the situation in 22 years ago revealed a 16.4% decrease in familial marriages among thalassemic families, however, more education and awareness of young women and men about the increased risk of beta-thalassemia after familial marriage through pre-marriage counseling is still necessary.

Affinal and Consanguineal Kin as a Social Support for the Rural Elderly. Paper of the Journal Series of the North Carolina Agricultural Research Service, Raleigh, NC.

ERIC Educational Resources Information Center

Kivett, Vira R.

Although the support network of elderly individuals has received increased attention recently, most research has focused on the parent child relationship without examining other levels of kin interrelations. To examine the help received by rural-transitional older adults from their consanguineous kin (adult children, grandchildren, siblings,…

Increased Probability of Co-Occurrence of Two Rare Diseases in Consanguineous Families and Resolution of a Complex Phenotype by Next Generation Sequencing

PubMed Central

Lal, Dennis; Neubauer, Bernd A.; Toliat, Mohammad R.; Altmüller, Janine; Thiele, Holger; Nürnberg, Peter; Kamrath, Clemens; Schänzer, Anne; Sander, Thomas; Hahn, Andreas; Nothnagel, Michael

2016-01-01

Massively parallel sequencing of whole genomes and exomes has facilitated a direct assessment of causative genetic variation, now enabling the identification of genetic factors involved in rare diseases (RD) with Mendelian inheritance patterns on an almost routine basis. Here, we describe the illustrative case of a single consanguineous family where this strategy suffered from the difficulty to distinguish between two etiologically distinct disorders, namely the co-occurrence of hereditary hypophosphatemic rickets (HRR) and congenital myopathies (CM), by their phenotypic manifestation alone. We used parametric linkage analysis, homozygosity mapping and whole exome-sequencing to identify mutations underlying HRR and CM. We also present an approximate approach for assessing the probability of co-occurrence of two unlinked recessive RD in a single family as a function of the degree of consanguinity and the frequency of the disease-causing alleles. Linkage analysis and homozygosity mapping yielded elusive results when assuming a single RD, but whole-exome sequencing helped to identify two mutations in two genes, namely SLC34A3 and SEPN1, that segregated independently in this family and that have previously been linked to two etiologically different diseases. We assess the increase in chance co-occurrence of rare diseases due to consanguinity, i.e. under circumstances that generally favor linkage mapping of recessive disease, and show that this probability can increase by several orders of magnitudes. We conclude that such potential co-occurrence represents an underestimated risk when analyzing rare or undefined diseases in consanguineous families and should be given more consideration in the clinical and genetic evaluation. PMID:26789268

[Consanguineous marriage and morbi-mortality, short literature review based on an exceptional association: Usher syndrome and Von Recklinghausen neurofibromatosis].

PubMed

Atipo-Tsiba, Pépin-Williams

2016-01-01

Usher syndrome is defined by the association of a progressive or non-progressive congenital sensorineural hearing loss with variable severity and a gradually blinding pigmentary retinopathy. Von Recklinghausen neurofibromatosis or Neurofibromatosis type 1 is the major clinically form of neurofibromatosis which occurs in approximately 90% of cases. Both types of disease are genetic in origin with very low prevalence. The probability of co-occurrence of these diseases in a single individual is exceptional. Inbreeding, as well as all genetic diseases, increases quite significantly the probability of their occurrence. Consanguineous marriages are still widespread in Maghreb and in some regions of the western African. This observation reports an exceptional case of this association in a 40-year-old man of Mauritanian origin born from a consanguineous union.

Attacking al Qaeda’s Operational Centers of Gravity

DTIC Science & Technology

2008-01-01

have allied themselves with al Qaeda.7 The Taliban in Afghanistan have a close relationship with al Qaeda. In Iraq, there are two major insurgent... consanguinity , the ideological affinity between al Qaeda and local insurgents and populations. By designating consanguinity as a decisive point at the...people, materiel, or facilities. Links connect nodes and are behavioral or functional; they could be a command relationship or an ideology. A deci

Consanguinity and primary immunodeficiencies.

PubMed

Al-Herz, Waleed; Aldhekri, Hasan; Barbouche, Mohamed-Ridha; Rezaei, Nima

2014-01-01

Primary immunodeficiencies (PIDs) are a heterogeneous group of genetic disorders caused by defects in the immune system that predispose patients to infections, autoimmune diseases, lymphoproliferation and malignancies. Most PIDs are inherited in an autosomal recessive pattern; therefore, they are more common in areas with high rates of consanguineous marriage. Reports about PIDs from these areas have demonstrated a peculiar prevalence of more severe forms of diseases compared to other regions, and patients born to consanguineous parents have increased rates of morbidity and mortality compared to other patients. Individuals at high risk of having a child with a PID who wish to have a healthy child have limited options, these include prenatal diagnosis and pre-implantation genetic diagnosis. However, these options require a collaborative team of specialists and may not always be implemented due to geographic, religious, financial or social factors. The recent introduction of newborn-screening programs for a number of T and B lymphocyte deficiencies will facilitate early diagnosis and therapeutic interventions, which may include hematopoietic stem cell transplantation and intravenous immunoglobulin treatment. There is a need for the implementation of strategies to increase public awareness of the health risks associated with consanguineous marriage. It should be stressed that genetic counseling should be an important component of the care of patients with PIDs as well as their families. © 2014 S. Karger AG, Basel.

New mutations in BBS genes in small consanguineous families with Bardet-Biedl syndrome: Detection of candidate regions by homozygosity mapping

PubMed Central

Pereiro, Ines; Piñeiro-Gallego, Teresa; Baiget, Montserrat; Borrego, Salud; Ayuso, Carmen; Searby, Charles; Nishimura, Darryl

2010-01-01

Purpose Bardet-Biedl syndrome (BBS, OMIM 209900) is a rare multi-organ disorder in which BBS patients manifest a variable phenotype that includes retinal dystrophy, polydactyly, mental delay, obesity, and also reproductive tract and renal abnormalities. Mutations in 14 genes (BBS1–BBS14) are found in 70% of the patients, indicating that additional mutations in known and new BBS genes remain to be identified. Therefore, the molecular diagnosis of this complex disorder is a challenging task. Methods In this study we show the use of the genome-wide homozygosity mapping strategy in the mutation detection of nine Caucasian BBS families, eight of them consanguineous and one from the same geographic area with no proven consanguinity. Results We identified the disease-causing mutation in six of the families studied, five of which had novel sequence variants in BBS3, BBS6, and BBS12. This is the first null mutation reported in BBS3. Furthermore, this approach defined homozygous candidate regions that could harbor potential candidate genes for BBS in three of the families. Conclusions These findings further underline the importance of homozygosity mapping as a useful technology for diagnosis in small consanguineous families with a complex disease like BBS. PMID:20142850

Severe congenital neutropenia in 2 siblings of consanguineous parents. The role of HAX1 deficiency.

PubMed

Mamishi, S; Esfahani, S A; Parvaneh, N; Diestelhorst, J; Rezaei, N

2009-01-01

Severe congenital neutropenia (SCN) is a rare primary immunodeficiency disease that is characterized by persistent severe neutropenia and severe early-onset bacterial infections. We report the case of 2 siblings with SCN who were the children of consanguineous parents. The HAX1 mutation was identified in both siblings. Both patients suffered from oral ulcers, candidiasis, respiratory tract infections, and diarrhea. A bone marrow biopsy, performed to determine the cause of their persistent severe neutropenia, revealed myeloid maturation arrest; thus confirming the diagnosis of SCN. Granulocyte colony-stimulating factor and prophylactic antibiotics were started. A molecular study revealed a homozygous W44X mutation of the HAX1 gene in both cases. HAX1 deficiency should be considered in any child with severe infections and neutropenia, especially in children of consanguineous parents. Early diagnosis and appropriate treatment could prevent complications in this group of patients.

Consanguineous Iranian Kindreds with Severe Tourette Syndrome

PubMed Central

Motlagh, Maria G.; Seddigh, Arshia; Dashti, Behnoosh; Leckman, James F.; Alaghband-Rad, Javad

2014-01-01

The search for vulnerability genes for Tourette syndrome has been ongoing for nearly three decades. The contribution of recessive loci with reduced penetrance is one possibility that has been difficult to explore. Homo-zygosity mapping has been successfully used to detect recessive loci within populations with high rates of consanguinity. Using this technique, even quite small inbred families can be informative due to autozygosity in which the two alleles at an autosomal locus are identical by descent (i.e., copies of a single ancestral gene). To explore the utility of this approach, we identified 12 consanguineous Iranian families. Remarkably, these families were seen with an unusual natural history characterized by the early onset of vocal tics and coprolalia and frequent comorbidity with obsessive-compulsive disorder. Genotyping the affected and unaffected members of these pedigrees has the potential to identify rare recessive contributions to this disorder. PMID:18785237

A novel founder MYO15A frameshift duplication is the major cause of genetic hearing loss in Oman.

PubMed

Palombo, Flavia; Al-Wardy, Nadia; Ruscone, Guido Alberto Gnecchi; Oppo, Manuela; Kindi, Mohammed Nasser Al; Angius, Andrea; Al Lamki, Khalsa; Girotto, Giorgia; Giangregorio, Tania; Benelli, Matteo; Magi, Alberto; Seri, Marco; Gasparini, Paolo; Cucca, Francesco; Sazzini, Marco; Al Khabori, Mazin; Pippucci, Tommaso; Romeo, Giovanni

2017-02-01

The increased risk for autosomal recessive disorders is one of the most well-known medical implications of consanguinity. In the Sultanate of Oman, a country characterized by one of the highest rates of consanguineous marriages worldwide, prevalence of genetic hearing loss (GHL) is estimated to be 6/10 000. Families of GHL patients have higher consanguinity rates than the general Omani population, indicating a major role for recessive forms. Mutations in GJB2, the most commonly mutated GHL gene, have been sporadically described. We collected 97 DNA samples of GHL probands, affected/unaffected siblings and parents from 26 Omani consanguineous families. Analyzing a first family by whole-exome sequencing, we identified a novel homozygous frameshift duplication (c.1171_1177dupGCCATCT) in MYO15A, the gene linked to the deafness locus DFNB3. This duplication was then found in a total of 8/26 (28%) families, within a 849 kb founder haplotype. Reconstruction of haplotype structure at MYO15A surrounding genomic regions indicated that the founder haplotype branched out in the past two to three centuries from a haplotype present worldwide. The MYO15A duplication emerges as the major cause of GHL in Oman. These findings have major implications for the design of GHL diagnosis and prevention policies in Oman.

Inbreeding and matrimonial structure in a Pyrenean community (Ansó, Huesca, Spain), 1712-1982.

PubMed

Valls, A

1985-03-01

Using data from parish records from 1712 to 1982 in a Spanish Pyrenean village, Ansó, the effects of the raw nuptiality, the types of consanguineous marriages and the rate and evolution of inbreeding on the mating structure have been studied. This structure has been modified in the course of time mostly through the secular variations in the frequency of consanguineous marriages. Recent inbreeding decrease in Ansó is related to the population diminution and cultural changes associated with isolate breakdown.

Consanguinity in Saudi Arabia: a unique opportunity for pediatric kidney research.

PubMed

Kari, Jameela A; Bockenhauer, Detlef; Stanescu, Horia; Gari, Mamdooh; Kleta, Robert; Singh, Ajay K

2014-02-01

Identification of disease-related genes is a critical step in understanding the molecular basis of disease and developing targeted therapies. The genetic study of diseases occurring in the offspring of consanguineous unions is a powerful way to discover new disease genes. Pediatric nephrology provides an excellent example because ∼70% of cases of kidney disease in childhood are congenital with a likely genetic basis. This percentage is likely to be even higher in countries with a high consanguinity rate, such as the Kingdom of Saudi Arabia. However, there are a number of challenges, such as cultural, legal, and religious restrictions, that should be appreciated before carrying out genetic research in a tradition-bound country. In this article, we discuss the background, opportunities, and challenges involved with this unique opportunity to conduct studies of such genetic disorders. Keys to success include collaboration and an understanding of local traditions and laws. Copyright © 2014 National Kidney Foundation, Inc. All rights reserved.

Speech disorders in Israeli Arab children.

PubMed

Jaber, L; Nahmani, A; Shohat, M

1997-10-01

The aim of this work was to study the frequency of speech disorders in Israeli Arab children and its association with parental consanguinity. A questionnaire was sent to the parents of 1,495 Arab children attending kindergarten and the first two grades of the seven primary schools in the town of Taibe. Eight-six percent (1,282 parents) responded. The answers to the questionnaire revealed that 25% of the children reportedly had a speech and language disorder. Of the children identified by their parents as having a speech disorder, 44 were selected randomly for examination by a speech specialist. The disorders noted in this subgroup included errors in articulation (48.0%), poor language (18%), poor voice quality (15.9%); stuttering (13.6%), and other problems (4.5%). Rates of affected children of consanguineous and non-consanguineous marriages were 31% and 22.4%, respectively (p < 0.01). We conclude that speech disorders are an important problem among Israeli Arab schoolchildren. More comprehensive programs are needed to facilitate diagnosis and treatment.

Consanguinity and other marriage market effects of a wealth shock in Bangladesh.

PubMed

Mobarak, Ahmed Mushfiq; Kuhn, Randall; Peters, Christina

2013-10-01

This paper uses a wealth shock from the construction of a flood protection embankment in rural Bangladesh coupled with data on the universe of all 52,000 marriage decisions between 1982 and 1996 to examine changes in marital prospects for households protected by the embankment relative to unprotected households living on the other side of the river. We use difference-in-difference specifications to document that brides from protected households commanded larger dowries, married wealthier households, and became less likely to marry biological relatives. Financial liquidity-constrained households appear to use within-family marriage (in which one can promise ex-post payments) as a form of credit to meet up-front dowry demands, but the resultant wealth shock for households protected by the embankment relaxed this need to marry consanguineously. Our results shed light on the socioeconomic roots of consanguinity, which carries health risks for offspring but can also carry substantial benefits for the families involved.

CONSANGUINITY, GENETICS AND DEFINITIONS OF KINSHIP IN THE UK PAKISTANI POPULATION.

PubMed

Bittles, A H; Small, N A

2016-11-01

Consanguineous marriage is a controversial topic in many Western societies, with attention mainly focused on the health of immigrant communities from Asia and Africa. In the UK consanguinity is especially prevalent in the Pakistani community, which now numbers over 1.1 million. Less attention has been paid to the influence of hereditary population stratification within Pakistani communities, in particular biraderi (literally brotherhood) membership, which denotes male lineages that largely govern marriage partner choice and hence the transmission of disease genes. The various roles played by biraderi and their relationship to other socio-occupational and kinship terms, such as caste, quom and zat, are often overlooked in health-based studies. The interchangeable use of these different kinship terms without rigorous definition can create identity uncertainty and hinders inter-study comparisons. Where feasible, standardization of terminology would be both desirable and beneficial, with biraderi the preferred default term to identify specific social and genetic relationships within the Pakistani diaspora.

Sex linked versus autosomal inbreeding coefficient in close consanguineous marriages in the Basque country and Castile (Spain): genetic implications.

PubMed

Calderón, R; Morales, B; Peña, J A; Delgado, J

1995-10-01

Pedigree structures of 161 uncle/niece-aunt/nephew and 4420 first cousin consanguineous marriages registered during the 19th and 20th centuries in two large and very different Spanish regions have been analysed and their genetic consequences evaluated. The frequencies of the different pedigree subtypes within each degree of relationship were quite similar in both populations despite significant heterogeneity in inbreeding patterns. The mean X-linked inbreeding coefficient (Fx) for each type of cousin mating was calculated and compared to that expected for autosomal genes (F). The effect of genealogical structure on the Fx/F ratio was compared to different cultural populations worldwide. Preferentiality and avoidance of close consanguinity along with specific types of pedigrees are discussed on the basis of premarital migration and sociocultural rules still deeply rooted in certain human groups. By admitting that the observed Fx coefficient is usually higher than F in most human populations some remarks have been made in terms of population genetic risk.

Maximum number of children per sperm donor based on false paternity rate.

PubMed

Sánchez-Castelló, Isabel M; Gonzalvo, María C; Clavero, Ana; López-Regalado, María L; Mozas, Juan; Martínez-Granados, Luis; Navas, Purificación; Castilla, José A

2017-03-01

The aim of this study is to estimate the weight of each relevant factor in such unions of inadvertent consanguinity and to determine a "reasonable" limit for the number of children per donor, matching the probability of inadvertent consanguinity arising from the use of sperm donor in assisted reproduction with that of such a union arising from false paternity. In this study, we applied to Spanish data a mathematical model of consanguineous unions, taking into account the following factors: maximum number of live births/donor, fertility rate, average number of births per donor in a pregnancy, donor success rate, matings per phenotype, number of newborns/year, and number of donors needed in the population/year and births by false paternity. In Spain, the number of inadvertent unions between descendants of the same donor in Spain has been estimated at 0.4/year (one every two and a half years), although this frequency decreases as the reference population increases. On the other hand, the frequency of unions between family members due to false paternity has been estimated at 6.1/year. Thus, only 6% of such unions are due to the use of donor sperm. A total of 25 children per sperm donor are needed to align the probability of inadvertant consanguinity arising from the use of assisted reproduction with that due to false paternity. Therefore, we consider this number to be the maximum "reasonable" number of children born per donor in Spain.

A Mitochondrial DNA A8701G Mutation Associated with Maternally Inherited Hypertension and Dilated Cardiomyopathy in a Chinese Pedigree of a Consanguineous Marriage

PubMed Central

Zhu, Ye; Gu, Xiang; Xu, Chao

2016-01-01

Background: Cardiovascular diseases, including dilated cardiomyopathy (DCM) and hypertension, are the leading cause of death worldwide. The role of mitochondrial DNA (mtDNA) in the pathogenesis of these diseases has not been completely clarified. In this study, we evaluate whether A8701G mutation is associated with maternally inherited hypertension and DCM in a Chinese pedigree of a consanguineous marriage. Methods: Fourteen subjects in a three-generation Han Chinese family with hypertension and DCM, in which consanguineous marriage was present in the parental generation, were interviewed. We divided all the family members into case (7 maternal members) and control group (7 nonmaternal members) for comparison. Clinical evaluations and sequence analysis of mtDNA were obtained from all participants. Frequency differences between maternal and nonmaternal members were tested to locate the disease-associated mutations. Results: The majority of the family members presented with a maternal inheritance of hypertension and DCM. Sequence analysis of mtDNA in this pedigree identified eight mtDNA mutations. Among the mutations identified, there was only one significant mutation: A8701G (P = 0.005), which is a homoplasmic mitochondrial missense mutation in all the matrilineal relatives. There was no clear evidence for any synergistic effects between A8701G and other mutations. Conclusions: A8701G mutation may act as an inherited risk factor for the matrilineal transmission of hypertension and DCM in conjunction with genetic disorders caused by consanguineous marriage. PMID:26831225

Lack of KIF21A mutations in congenital fibrosis of the extraocular muscles type I patients from consanguineous Saudi Arabian families

PubMed Central

Shinwari, Jameela; Omar, Aisha; Al-Sharif, Latifa; Khalil, Dania S.; Alanazi, Mohammed; Al-Amri, Abdullah; Al Tassan, Nada

2011-01-01

Purpose Congenital fibrosis of the extraocular muscles type I (CFEOM1), the most common CFEOM worldwide, is characterized by bilateral ptotic hypotropia, an inability to supraduct above the horizontal midline, horizontal strabismus (typically exotropia), and ophthalmoplegia with abnormal synkinesis. This distinct non-syndromic phenotype is considered autosomal dominant and is virtually always from heterozygous missense mutations in kinesin family member 21A (KIF21A). However, there are occasional KIF21A-negative cases, opening the possibility for a recessive cause. The objective of this study is to explore this possibility by assessing CFEOM1 patients exclusively from consanguineous families, who are the most likely to have recessive cause for their phenotype if a recessive cause exists. Methods Ophthalmic examination and candidate gene direct sequencing (KIF21A, paired-like homeobox 2A [PHOX2A], tubulin beta-3 [TUBB3]) of CFEOM1 patients from consanguineous families referred for counseling from 2005 to 2010. Results All 5 probands had classic CFEOM1 as defined above. Three had siblings with CFEOM. None of the probands had mutations in KIF21A, PHOX2A, or TUBB3. Conclusions The lack of KIF21A mutations in CFEOM1 patients exclusively from consanguineous families, most of whom had siblings with CFEOM, is strong evidence for a recessive form of CFEOM1. Further studies of such families will hopefully uncover the specific locus(loci). PMID:21264235

Royal dynasties as human inbreeding laboratories: the Habsburgs

PubMed Central

Ceballos, F C; Álvarez, G

2013-01-01

The European royal dynasties of the Early Modern Age provide a useful framework for human inbreeding research. In this article, consanguineous marriage, inbreeding depression and the purging of deleterious alleles within a consanguineous population are investigated in the Habsburgs, a royal dynasty with a long history of consanguinity over generations. Genealogical information from a number of historical sources was used to compute kinship and inbreeding coefficients for the Habsburgs. The marriages contracted by the Habsburgs from 1450 to 1750 presented an extremely high mean kinship (0.0628±0.009), which was the result of the matrimonial policy conducted by the dynasty to establish political alliances through marriage. A strong inbreeding depression for both infant and child survival was detected in the progeny of 71 Habsburg marriages in the period 1450–1800. The inbreeding load for child survival experienced a pronounced decrease from 3.98±0.87 in the period 1450–1600 to 0.93±0.62 in the period 1600–1800, but temporal changes in the inbreeding depression for infant survival were not detected. Such a reduction of inbreeding depression for child survival in a relatively small number of generations could be caused by elimination of deleterious alleles of a large effect according with predictions from purging models. The differential purging of the infant and child inbreeding loads suggest that the genetic basis of inbreeding depression was probably very different for infant and child survival in the Habsburg lineage. Our findings provide empirical support that human inbreeding depression for some fitness components might be purged by selection within consanguineous populations. PMID:23572123

Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity.

PubMed

Baris, Hagit N; Barnes-Kedar, Inbal; Toledano, Helen; Halpern, Marisa; Hershkovitz, Dov; Lossos, Alexander; Lerer, Israela; Peretz, Tamar; Kariv, Revital; Cohen, Shlomi; Half, Elizabeth E; Magal, Nurit; Drasinover, Valerie; Wimmer, Katharina; Goldberg, Yael; Bercovich, Dani; Levi, Zohar

2016-03-01

Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1. We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer. In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified. CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis. © 2015 Wiley Periodicals, Inc.

Heterozygote deficits in cyst plant-parasitic nematodes: possible causes and consequences.

PubMed

Montarry, Josselin; Jan, Pierre-Loup; Gracianne, Cecile; Overall, Andrew D J; Bardou-Valette, Sylvie; Olivier, Eric; Fournet, Sylvain; Grenier, Eric; Petit, Eric J

2015-04-01

Deviations of genotypic frequencies from Hardy-Weinberg equilibrium (HWE) expectations could reveal important aspects of the biology of populations. Deviations from HWE due to heterozygote deficits have been recorded for three plant-parasitic nematode species. However, it has never been determined whether the observed deficits were due (i) to the presence of null alleles, (ii) to a high level of consanguinity and/or (iii) to a Wahlund effect. The aim of the present work was, while taking into the possible confounding effect of null alleles, to disentangle consanguinity and Wahlund effect in natural populations of those three economically important cyst nematodes using microsatellite markers: Globodera pallida, G. tabacum and Heterodera schachtii, pests of potato, tobacco and sugar beet, respectively. The results show a consistent pattern of heterozygote deficiency in the three nematode species sampled at the spatial scale of the host plant. We demonstrate that the prevalence of null alleles is weak and that heterozygote deficits do not have a single origin. Our results suggested that it is restricted dispersal that leads to heterozygote deficits through both consanguinity and substructure, which effects can be linked to soil movement, cyst density, and the number of generations per year. We discuss potential implications for the durability of plant resistances that are used to protect crops against parasites in which mating between relatives occur. While consanguineous mating leads to homozygosity at all loci, including loci governing avirulence/virulence, which favours the expression of virulence when recessive, the Wahlund effect is expected to have no particular effect on the adaptation of nematodes to resistances. © 2015 John Wiley & Sons Ltd.

Royal dynasties as human inbreeding laboratories: the Habsburgs.

PubMed

Ceballos, F C; Alvarez, G

2013-08-01

The European royal dynasties of the Early Modern Age provide a useful framework for human inbreeding research. In this article, consanguineous marriage, inbreeding depression and the purging of deleterious alleles within a consanguineous population are investigated in the Habsburgs, a royal dynasty with a long history of consanguinity over generations. Genealogical information from a number of historical sources was used to compute kinship and inbreeding coefficients for the Habsburgs. The marriages contracted by the Habsburgs from 1450 to 1750 presented an extremely high mean kinship (0.0628±0.009), which was the result of the matrimonial policy conducted by the dynasty to establish political alliances through marriage. A strong inbreeding depression for both infant and child survival was detected in the progeny of 71 Habsburg marriages in the period 1450-1800. The inbreeding load for child survival experienced a pronounced decrease from 3.98±0.87 in the period 1450-1600 to 0.93±0.62 in the period 1600-1800, but temporal changes in the inbreeding depression for infant survival were not detected. Such a reduction of inbreeding depression for child survival in a relatively small number of generations could be caused by elimination of deleterious alleles of a large effect according with predictions from purging models. The differential purging of the infant and child inbreeding loads suggest that the genetic basis of inbreeding depression was probably very different for infant and child survival in the Habsburg lineage. Our findings provide empirical support that human inbreeding depression for some fitness components might be purged by selection within consanguineous populations.

HLA sharing among couples appears unrelated to idiopathic recurrent fetal loss in Saudi Arabia.

PubMed

Moghraby, J S; Tamim, H; Anacan, V; Al Khalaf, H; Moghraby, S A

2010-08-01

Recurrent fetal loss (RFL) is a prevalent problem affecting approximately 1% of all women of childbearing age. Many factors can lead to RFL; however, recent studies have indicated the important role of the maternal immune system in this process. The human leukocyte antigens (HLA), HLA-linked genes and regulatory factors play an important role in fetal loss and in fetal development. The current retrospective study was preformed to examine the HLA alleles shared between couples with RFL in Saudi Arabia, using a large cohort of women (having three or more RFL). Specific HLA alleles that could influence this condition, or the number of miscarriages experienced, were expected to be highlighted in this way. A total of 253 consecutive patients who visited the RFL clinic at the King AbdulAziz Medical City, National Guard Hospital in Riyadh were included in this study. They included 54 consanguineous couples, 132 non-consanguineous couples and another 67 couples shared only their tribal origin. Clinical examinations as well as laboratory investigations were carried out on each patient. Class I HLA, HLA-A, HLA-B and HLA-C, and Class II HLA, HLA-DR and HLA-DQ, were typed for each patient and their partner. No relationship was seen between sharing of HLA alleles and the number of RFL experienced by the couples, among neither consanguineous nor non-consanguineous couples. Although the results of this study suggest that HLA sharing is not an indicative factor in RFL, definitive conclusions on this topic must be based on large case-control studies.

Ignoring Intermarker Linkage Disequilibrium Induces False-Positive Evidence of Linkage for Consanguineous Pedigrees when Genotype Data Is Missing for Any Pedigree Member

PubMed Central

Li, Bingshan; Leal, Suzanne M.

2008-01-01

Missing genotype data can increase false-positive evidence for linkage when either parametric or nonparametric analysis is carried out ignoring intermarker linkage disequilibrium (LD). Previously it was demonstrated by Huang et al. [1] that no bias occurs in this situation for affected sib-pairs with unrelated parents when either both parents are genotyped or genotype data is available for two additional unaffected siblings when parental genotypes are missing. However, this is not the case for autosomal recessive consanguineous pedigrees, where missing genotype data for any pedigree member within a consanguinity loop can increase false-positive evidence of linkage. False-positive evidence for linkage is further increased when cryptic consanguinity is present. The amount of false-positive evidence for linkage, and which family members aid in its reduction, is highly dependent on which family members are genotyped. When parental genotype data is available, the false-positive evidence for linkage is usually not as strong as when parental genotype data is unavailable. For a pedigree with an affected proband whose first-cousin parents have been genotyped, further reduction in the false-positive evidence of linkage can be obtained by including genotype data from additional affected siblings of the proband or genotype data from the proband's sibling-grandparents. For the situation, when parental genotypes are unavailable, false-positive evidence for linkage can be reduced by including genotype data from either unaffected siblings of the proband or the proband's married-in-grandparents in the analysis. PMID:18073490

A Qualitative Study on Knowledge and Attitude towards Risk Factors, Early Identification and Intervention of Infant Hearing Loss among Puerperal Mothers- A Short Survey.

PubMed

Dudda, Ravi; Muniyappa, Hanumanth Prasad; Puttaraju, Sahana; Lakshmi, M S

2017-07-01

Maternal active participation and their support are critical for the success of early hearing loss detection program. Erroneous maternal decisions may have large life long consequences on the infant's life. The mothers' knowledge and their attitudes towards infant hearing loss is the basis for their decisions. The present study was done to determine the mothers' knowledge and their attitude towards risk factors of infant hearing loss, its early identification and intervention and also awareness of effect of consanguinity on hearing loss. In this cross-sectional questionnaire survey study, a total of 100 mothers were interviewed using the questionnaire which consisted of three sections namely risk factors, early identification and early intervention of hearing loss. Chi-square test was used to establish relationship between consanguineous and non-consanguineous mother's responses to its effect on hearing loss. A p-value < 0.05 was considered as significant. Mothers' awareness was significantly high for visible causes (ear pain/discharge, head injury and slap to ear) of hearing loss. Positive attitude was seen for importance of screening programs and follow up testing. Moderate level of awareness was found on hazards of consanguinity and benefits of early identification. However, mothers were least aware of neonatal jaundice, NICU admission (>5 days), signs of late-onset and neural hearing loss, management of hearing loss, hearing aid fitting and therapy necessity, which might interfere in early detection and intervention of hearing loss. It is crucial to educate mothers on few risk factors and management of hearing loss to reduce its consequences.

Consanguinity and dysmorphology in Arabs.

PubMed

Al-Gazali, Lihadh; Hamamy, Hanan

2014-01-01

Incidence rates of congenital disorders among the 350 million inhabitants of Arab countries could be influenced via the people's demographic and cultural characteristics. Arabs usually marry at a young age and have large families. They share certain core cultural values and beliefs, with the family accepted as the central structure of society. Consanguineous marriage is favored and respected in most if not all Arab communities, and intrafamilial unions currently account for 20-50% of all marriages. First-cousin unions are especially popular and constitute almost one quarter of all marriages in many Arab countries. Consequently, autosomal recessive (AR) dysmorphic syndromes constitute a considerable proportion of all birth defects among Arabs. Arab geneticists, with their persistent commitment to advancing research, have contributed to the description of a number of rare and new AR syndromes with the identification of novel genes. The collaboration with research teams in high-income countries resulted in a plethora of data on pathogenic variants and their function in causing dysmorphic syndromes. There could still be a considerable number of rare dysmorphic syndromes that prevail among Arabs which are not hitherto described and whose underlying molecular pathologies are not yet defined. Arab countries should thus strive to deploy DNA diagnostics and to build research capability around local priorities. Furthermore, a characterization of the prevailing genetic disorders in each geographic location, together with their mutations, is needed to plan for appropriate screening and testing protocols. An overview of consanguinity in Arab countries and examples of dysmorphology syndromes associated with consanguinity with their available molecular bases will be discussed. © 2014 S. Karger AG, Basel

Clinical and molecular characterization of females affected by X-linked retinoschisis.

PubMed

Staffieri, Sandra E; Rose, Loreto; Chang, Andrew; De Roach, John N; McLaren, Terri L; Mackey, David A; Hewitt, Alex W; Lamey, Tina M

2015-01-01

X-linked retinoschisis (XLRS) is a leading cause of juvenile macular degeneration associated with mutations in the RS1 gene. XLRS has a variable expressivity in males and shows no clinical phenotype in carrier females. Clinical and molecular characterization of male and female individuals affected with XLRS in a consanguineous family. Consanguineous Eastern European-Australian family Four clinically affected and nine unaffected family members were genetically and clinically characterized. Deoxyribonucleic acid (DNA) analysis was conducted by the Australian Inherited Retinal Disease Register and DNA Bank. Clinical and molecular characterization of the causative mutation in a consanguineous family with XLRS. By direct sequencing of the RS1 gene, one pathogenic variant, NM_000330.3: c.304C > T, p. R102W, was identified in all clinically diagnosed individuals analysed. The two females were homozygous for the variant, and the males were hemizygous. Clinical and genetic characterization of affected homozygous females in XLRS affords the rare opportunity to explore the molecular mechanisms of XLRS and the manifestation of these mutations as disease in humans. © 2015 Royal Australian and New Zealand College of Ophthalmologists.

Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases

PubMed Central

Kabir, Firoz; Ullah, Inayat; Ali, Shahbaz; Gottsch, Alexander D.H.; Naeem, Muhammad Asif; Assir, Muhammad Zaman; Khan, Shaheen N.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

2016-01-01

Purpose This study was undertaken to identify causal mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous families. Methods Large consanguineous families were ascertained from the Punjab province of Pakistan. An ophthalmic examination consisting of a fundus evaluation and electroretinography (ERG) was completed, and small aliquots of blood were collected from all participating individuals. Genomic DNA was extracted from white blood cells, and a genome-wide linkage or a locus-specific exclusion analysis was completed with polymorphic short tandem repeats (STRs). Two-point logarithm of odds (LOD) scores were calculated, and all coding exons and exon–intron boundaries of RP1 were sequenced to identify the causal mutation. Results The ophthalmic examination showed that affected individuals in all families manifest cardinal symptoms of RP. Genome-wide scans localized the disease phenotype to chromosome 8q, a region harboring RP1, a gene previously implicated in the pathogenesis of RP. Sanger sequencing identified a homozygous single base deletion in exon 4: c.3697delT (p.S1233Pfs22*), a single base substitution in intron 3: c.787+1G>A (p.I263Nfs8*), a 2 bp duplication in exon 2: c.551_552dupTA (p.Q185Yfs4*) and an 11,117 bp deletion that removes all three coding exons of RP1. These variations segregated with the disease phenotype within the respective families and were not present in ethnically matched control samples. Conclusions These results strongly suggest that these mutations in RP1 are responsible for the retinal phenotype in affected individuals of all four consanguineous families. PMID:27307693

In silico analysis of a disease-causing mutation in PCDH15 gene in a consanguineous Pakistani family with Usher phenotype.

PubMed

Saleha, Shamim; Ajmal, Muhammad; Jamil, Muhammad; Nasir, Muhammad; Hameed, Abdul

2016-01-01

To map Usher phenotype in a consanguineous Pakistani family and identify disease-associated mutation in a causative gene to establish phenotype-genotype correlation. A consanguineous Pakistani family in which Usher phenotype was segregating as an autosomal recessive trait was ascertained. On the basis of results of clinical investigations of affected members of this family disease was diagnosed as Usher syndrome (USH). To identify the locus responsible for the Usher phenotype in this family, genomic DNA from blood sample of each individual was genotyped using microsatellite Short Tandem Repeat (STR) markers for the known Usher syndrome loci. Then direct sequencing was performed to find out disease associated mutations in the candidate gene. By genetic linkage analysis, the USH phenotype of this family was mapped to PCDH15 locus on chromosome 10q21.1. Three different point mutations in exon 11 of PCDH15 were identified and one of them, c.1304A>C was found to be segregating with the disease phenotype in Pakistani family with Usher phenotype. This, c.1304A>C transversion mutation predicts an amino-acid substitution of aspartic acid with an alanine at residue number 435 (p.D435A) of its protein product. Moreover, in silico analysis revealed conservation of aspartic acid at position 435 and predicated this change as pathogenic. The identification of c.1304A>C pathogenic mutation in PCDH15 gene and its association with Usher syndrome in a consanguineous Pakistani family is the first example of a missense mutation of PCDH15 causing USH1 phenotype. In previous reports, it was hypothesized that severe mutations such as truncated protein of PCDH15 led to the Usher I phenotype and that missense variants are mainly responsible for non-syndromic hearing impairment.

Wolcott-Rallison Syndrome Is the Most Common Genetic Cause of Permanent Neonatal Diabetes in Consanguineous Families

PubMed Central

Rubio-Cabezas, Oscar; Patch, Ann-Marie; Minton, Jayne A. L.; Flanagan, Sarah E.; Edghill, Emma L.; Hussain, Khalid; Balafrej, Amina; Deeb, Asma; Buchanan, Charles R.; Jefferson, Ian G.; Mutair, Angham; Hattersley, Andrew T.; Ellard, Sian

2009-01-01

Context and Objective: Mutations in EIF2AK3 cause Wolcott-Rallison syndrome (WRS), a rare recessive disorder characterized by early-onset diabetes, skeletal abnormalities, and liver dysfunction. Although early diagnosis is important for clinical management, genetic testing is generally performed after the full clinical picture develops. We aimed to identify patients with WRS before any other abnormalities apart from diabetes are present and study the overall frequency of WRS among patients with permanent neonatal diabetes. Research Design and Methods: The coding regions of EIF2AK3 were sequenced in 34 probands with infancy-onset diabetes with a clinical phenotype suggestive of WRS (n = 28) or homozygosity at the WRS locus (n = 6). Results: Twenty-five probands (73.5%) were homozygous or compound heterozygous for mutations in EIF2AK3. Twenty of the 26 mutations identified were novel. Whereas a diagnosis of WRS was suspected before genetic testing in 22 probands, three patients with apparently isolated diabetes were diagnosed after identifying a large homozygous region encompassing EIF2AK3. In contrast to nonconsanguineous pedigrees, mutations in EIF2AK3 are the most common known genetic cause of diabetes among patients born to consanguineous parents (24 vs. < 2%). Age at diabetes onset and birth weight might be used to prioritize genetic testing in the latter group. Conclusions: WRS is the most common cause of permanent neonatal diabetes mellitus in consanguineous pedigrees. In addition to testing patients with a definite clinical diagnosis, EIF2AK3 should be tested in patients with isolated neonatal diabetes diagnosed after 3 wk of age from known consanguineous families, isolated populations, or countries in which inbreeding is frequent. PMID:19837917

New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family.

PubMed

Bouali, Nouha; Francou, Bruno; Bouligand, Jérôme; Imanci, Dilek; Dimassi, Sarra; Tosca, Lucie; Zaouali, Monia; Mougou, Soumaya; Young, Jacques; Saad, Ali; Guiochon-Mantel, Anne

2017-10-01

To identify the gene(s) involved in the etiology of premature ovarian insufficiency in a highly consanguineous Tunisian family. Genetic analysis of a large consanguineous family with several affected siblings. University hospital-based cytogenetics and molecular genetics laboratories. A highly consanguineous Tunisian family with several affected siblings born to healthy second-degree cousins. None. Targeted exome sequencing was performed by next-generation sequencing for affected family members. Mutations were validated by Sanger sequencing. Functional experiments were performed to explore the deleterious effects of the identified mutation. DNA damage was induced by increasing mitomycin C (MMC) concentrations on cultured peripheral lymphocytes. Analysis of the next-generation sequencing data revealed a new homozygous missense mutation in the minichromosome maintenance 8 gene (MCM8).This homozygous mutation (c. 482A>C; p.His161Pro) was predicted to be deleterious and segregated with the disease in the family. MCM8 participates in homologous recombination during meiosis and DNA double-stranded break repair by dimerizing with MCM9. Mcm8 knock out results in an early block in follicle development and small gonads. Given this, we tested the chromosomal breakage repair capacity of homozygous and heterozygous MCM8 p.His161Pro mutation on cultured peripheral lymphocytes exposed to increasing MMC concentrations. We found that chromosomal breakage after MMC exposure was significantly higher in cells from homozygously affected individuals than in those from a healthy control. Our findings provide additional support to the view that MCM8 mutations are involved in the primary ovarian insufficiency phenotype. Copyright © 2017 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

A Qualitative Study on Knowledge and Attitude towards Risk Factors, Early Identification and Intervention of Infant Hearing Loss among Puerperal Mothers- A Short Survey

PubMed Central

Dudda, Ravi; Muniyappa, Hanumanth Prasad; Lakshmi, M.S

2017-01-01

Introduction Maternal active participation and their support are critical for the success of early hearing loss detection program. Erroneous maternal decisions may have large life long consequences on the infant’s life. The mothers’ knowledge and their attitudes towards infant hearing loss is the basis for their decisions. Aim The present study was done to determine the mothers’ knowledge and their attitude towards risk factors of infant hearing loss, its early identification and intervention and also awareness of effect of consanguinity on hearing loss. Materials and Methods In this cross-sectional questionnaire survey study, a total of 100 mothers were interviewed using the questionnaire which consisted of three sections namely risk factors, early identification and early intervention of hearing loss. Chi-square test was used to establish relationship between consanguineous and non-consanguineous mother’s responses to its effect on hearing loss. A p-value < 0.05 was considered as significant. Results Mothers’ awareness was significantly high for visible causes (ear pain/discharge, head injury and slap to ear) of hearing loss. Positive attitude was seen for importance of screening programs and follow up testing. Moderate level of awareness was found on hazards of consanguinity and benefits of early identification. However, mothers were least aware of neonatal jaundice, NICU admission (>5 days), signs of late-onset and neural hearing loss, management of hearing loss, hearing aid fitting and therapy necessity, which might interfere in early detection and intervention of hearing loss. Conclusion It is crucial to educate mothers on few risk factors and management of hearing loss to reduce its consequences. PMID:28892940

The Pattern of Female Nuptiality in Oman

PubMed Central

Islam, M. Mazharul; Dorvlo, Atsu S.; Al-Qasmi, Ahmed M.

2013-01-01

Objectives: The purpose of this study was to examine Omani patterns of female nuptiality, including the timing of marriage and determinants of age at a woman’s first marriage. Methods: The study utilised data from the 2000 Oman National Health Survey. Univariate, bivariate, and multivariate statistical methods, including logistic regression analysis, were used for data analysis. Results: One of the most important aspects of the marriage pattern in Oman is the high prevalence of consanguineous marriages, as more than half (52%) of the total marriages in Oman are consanguineous. First cousin unions are the most common type of consanguineous unions, constituting 39% of all marriages and 75% of all consanguineous marriages. About 11% of the marriages are polygynous. Early and universal marriage is still highly prevalent in Oman. Three-quarters (75%) of married women respondents aged 20–44 years were married by age 20, with their median age at their first wedding being 16 years. However, women’s average age upon marriage is gradually increasing. The change is especially apparent in more recent marriages or among younger cohorts of women, and for certain socio-cultural groups. Multivariate analysis identified female education, age cohort, residential status, region of residence, types of marriage, and employment as strong predictors of Omani women’s age at marriage. Conclusion: The growing number of young adults, accompanied by their tendency to delay marriage, may have serious demographic, social, economic, and political ramifications for Oman, highlighting the need to understand the new situation of youth, their unique characteristics, and their interests and demands. Culturally appropriate policies need to be implemented to address the issues and challenges of unmarried young adults. PMID:23573380

Identification of pathogenic gene variants in small families with intellectually disabled siblings by exome sequencing.

PubMed

Schuurs-Hoeijmakers, Janneke H M; Vulto-van Silfhout, Anneke T; Vissers, Lisenka E L M; van de Vondervoort, Ilse I G M; van Bon, Bregje W M; de Ligt, Joep; Gilissen, Christian; Hehir-Kwa, Jayne Y; Neveling, Kornelia; del Rosario, Marisol; Hira, Gausiya; Reitano, Santina; Vitello, Aurelio; Failla, Pinella; Greco, Donatella; Fichera, Marco; Galesi, Ornella; Kleefstra, Tjitske; Greally, Marie T; Ockeloen, Charlotte W; Willemsen, Marjolein H; Bongers, Ernie M H F; Janssen, Irene M; Pfundt, Rolph; Veltman, Joris A; Romano, Corrado; Willemsen, Michèl A; van Bokhoven, Hans; Brunner, Han G; de Vries, Bert B A; de Brouwer, Arjan P M

2013-12-01

Intellectual disability (ID) is a common neurodevelopmental disorder affecting 1-3% of the general population. Mutations in more than 10% of all human genes are considered to be involved in this disorder, although the majority of these genes are still unknown. We investigated 19 small non-consanguineous families with two to five affected siblings in order to identify pathogenic gene variants in known, novel and potential ID candidate genes. Non-consanguineous families have been largely ignored in gene identification studies as small family size precludes prior mapping of the genetic defect. Using exome sequencing, we identified pathogenic mutations in three genes, DDHD2, SLC6A8, and SLC9A6, of which the latter two have previously been implicated in X-linked ID phenotypes. In addition, we identified potentially pathogenic mutations in BCORL1 on the X-chromosome and in MCM3AP, PTPRT, SYNE1, and ZNF528 on autosomes. We show that potentially pathogenic gene variants can be identified in small, non-consanguineous families with as few as two affected siblings, thus emphasising their value in the identification of syndromic and non-syndromic ID genes.

A search for the primary abnormality in adult-onset type II citrullinemia.

PubMed

Kobayashi, K; Shaheen, N; Kumashiro, R; Tanikawa, K; O'Brien, W E; Beaudet, A L; Saheki, T

1993-11-01

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, we show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia. We also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus.

A Homozygous TPO Gene Duplication (c.1184_1187dup4) Causes Congenital Hypothyroidism in Three Siblings Born to a Consanguineous Family

PubMed Central

Cangul, Hakan; Aydin, Banu K.; Bas, Firdevs

2015-01-01

Congenital hypothyroidism (CH) is the most common neonatal endocrine disease, and germ-line mutations in the TPO gene cause the inherited form of the disease. Our aim in this study was to determine the genetic basis of congenital hypothyroidism in three affected children coming from a consanguineous Turkish family. Because CH is usually inherited in autosomal recessive manner in consanguineous/multicase families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the candidate genes. First, we investigated the potential genetic linkage of the family to any known CH locus, using microsatellite markers, and then screened for mutations in linked-gene by conventional sequencing. The family showed potential linkage to the TPO gene and we detected a homozygous duplication (c.1184_1187dup4) in all cases. The mutation segregated with disease status in the family. This study confirms the pathogenicity of the c.1184_1187dup4 mutation in the TPO gene and helps establish a genotype/phenotype correlation associated with this mutation. It also highlights the importance of molecular genetic studies in the definitive diagnosis and accurate classification of CH. PMID:27617131

Dandy–Walker Malformation, Genitourinary Abnormalities, and Intellectual Disability in Two Families

PubMed Central

Gregor, Anne; Gleeson, Joseph G.; Rosti, Rasim Ozgur

2016-01-01

We report on two families, each with documented consanguinity and two affected with overlapping features of Dandy-Walker malformation, genitourinary abnormalities, intellectual disability, and hearing deficit. This phenotype shares similar findings with many well-known syndromes. However, the clinical findings of this syndrome categorize this as a new syndrome as compared with the phenotype of already established syndromes. Due to parental consanguinity, occurrence in siblings of both genders and the absence of manifestations in obligate carrier parents, an autosomal recessive pattern of inheritance is more likely. The authors believe that these families suggest a novel autosomal recessive cerebello–genital syndrome. Array CGH analyses of an affected did not show pathological deletions or duplications. PMID:26109232

Fertility and its relationship with sociocultural factors in Kuwaiti society.

PubMed

Al-Kandari, Y Y

2007-01-01

The aim of this study was to examine the effect of some sociocultural variables on the fertility of Kuwaiti women. A questionnaire was administered to a sample of 7749 married women (aged 15-78 years) selected randomly from 10 primary health care clinics in Kuwait. The fertility rate was 3.58 live births per woman. Fertility was higher among Sunni Muslim women, those of Bedouin ethnicity, and those in a consanguineous marriage (P < 0.001). There was a significant negative relationship between fertility and respondents' educational level, occupation, age at marriage, socioeconomic status and type of marriage (consanguineous or not). There was a positive relationship between fertility and the respondents' age and the family income.

Maximum number of live births per donor in artificial insemination.

PubMed

Wang, Charlotte; Tsai, Miao-Yu; Lee, Mei-Hsien; Huang, Su-Yun; Kao, Chen-Hung; Ho, Hong-Nerng; Hsiao, Chuhsing Kate

2007-05-01

The maximal number of live births (k) per donor was usually determined by cultural and social perspective. It was rarely decided on the basis of scientific evidence or discussed from mathematical or probabilistic viewpoint. To recommend a value for k, we propose three criteria to evaluate its impact on consanguinity and disease incidence due to artificial insemination by donor (AID). The first approach considers the optimization of k under the criterion of fixed tolerable number of consanguineous mating due to AID. The second approach optimizes k under fixed allowable average coefficient of inbreeding. This approach is particularly helpful when assessing the impact on the public, is of interest. The third criterion considers specific inheritance diseases. This approach is useful when evaluating the individual's risk of genetic diseases. When different diseases are considered, this criterion can be easily adopted. All these derivations are based on the assumption of shortage of gamete donors due to great demand and insufficient supply. Our results indicate that strong degree of assortative mating, small population size and insufficient supply in gamete donors will lead to greater risk of consanguinity. Recommendations under other settings are also tabulated for reference. A web site for calculating the limit for live births per donor is available.

High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders.

PubMed

Yavarna, Tarunashree; Al-Dewik, Nader; Al-Mureikhi, Mariam; Ali, Rehab; Al-Mesaifri, Fatma; Mahmoud, Laila; Shahbeck, Noora; Lakhani, Shenela; AlMulla, Mariam; Nawaz, Zafar; Vitazka, Patrik; Alkuraya, Fowzan S; Ben-Omran, Tawfeg

2015-09-01

Clinical exome sequencing (CES) has become an increasingly popular diagnostic tool in patients with heterogeneous genetic disorders, especially in those with neurocognitive phenotypes. Utility of CES in consanguineous populations has not yet been determined on a large scale. A clinical cohort of 149 probands from Qatar with suspected Mendelian, mainly neurocognitive phenotypes, underwent CES from July 2012 to June 2014. Intellectual disability and global developmental delay were the most common clinical presentations but our cohort displayed other phenotypes, such as epilepsy, dysmorphism, microcephaly and other structural brain anomalies and autism. A pathogenic or likely pathogenic mutation, including pathogenic CNVs, was identified in 89 probands for a diagnostic yield of 60%. Consanguinity and positive family history predicted a higher diagnostic yield. In 5% (7/149) of cases, CES implicated novel candidate disease genes (MANF, GJA9, GLG1, COL15A1, SLC35F5, MAGE4, NEUROG1). CES uncovered two coexisting genetic disorders in 4% (6/149) and actionable incidental findings in 2% (3/149) of cases. Average time to diagnosis was reduced from 27 to 5 months. CES, which already has the highest diagnostic yield among all available diagnostic tools in the setting of Mendelian disorders, appears to be particularly helpful diagnostically in the highly consanguineous Middle Eastern population.

A search for the primary abnormality in adult-onset type II citrullinemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kobayashi, Keiko; Shaheen, Nazma; Saheki, Takeyori

1993-11-01

Deficiency of argininosuccinate synthetase (ASS) causes citrullinemia in human beings. Type II citrullinemia is found in most patients with adult-onset citrullinemia in Japan, and ASS deficiency is found specifically in the liver. Previous studies have shown that the decrease of hepatic ASS activity is caused by a decrease in enzyme protein with normal kinetic properties and that there were no apparent abnormalities in the amount, translational activity, and gross structure of hepatic ASS mRNA. In the present work, the authors show by sequencing analysis that there was no mutation in the ASS mRNA from two patients with type II citrullinemia.more » The authors also report RFLP analysis of a consanguineous family with type II citrullinemia, by using three DNA polymorphisms located within the ASS gene locus. In spite of having consanguineous parents, the patient was not a homozygous haplotype for the ASS gene. The RFLP analysis of 16 affected patients from consanguineous parents showed that 5 of 16 patients had the heterozygous pattern for one of the three DNA probes and that the frequency of the heterozygous haplotype was not different from the control frequency. These results suggest that the primary defect of type II citrullinemia is not within the ASS gene locus. 29 refs., 1 fig., 3 tabs.« less

Homozygosity mapping of a third Joubert syndrome locus to 6q23

PubMed Central

Lagier-Tourenne, C; Boltshauser, E; Breivik, N; Gribaa, M; Betard, C; Barbot, C; Koenig, M

2004-01-01

Background: Joubert syndrome (JS) is a recessively inherited disorder characterised by hypotonia at birth and developmental delay, followed by truncal ataxia and cognitive impairment, characteristic neuroimaging findings (cerebellar vermis hypoplasia, "molar tooth sign") and suggestive facial features. JS is clinically heterogeneous with some patients presenting with breathing abnormalities in the neonatal period, oculomotor apraxia, retinal dystrophy, retinal coloboma, ptosis, hexadactyly, and nephronophtisis or cystic dysplastic kidneys. JS is also genetically heterogeneous, with two known loci, on 9q34 (JBTS1) and 11p11-q12 (CORS2), representing only a fraction of cases. Methods: A large consanguineous Joubert family (five affected) was analysed for linkage with a marker set covering the entire genome and 16 smaller families were subsequently tested for candidate loci. Results: We report here the identification of a third locus in 6q23 (JBTS3) from the study of two consanguineous families. LOD score calculation, including the consanguinity loops, gave a maximum value of 4.1 and 2.3 at q = 0 for the two families, respectively. Conclusions: Linkage between the disease and the D6S1620–D6S1699 haplotype spanning a 13.1 cM interval is demonstrated. Genotype-phenotype studies indicate that, unlike CORS2, JBTS3 appears not to be associated with renal dysfunction. PMID:15060101

Consanguineous Marriage as a Risk Factor for Developing Keratoconus

PubMed Central

JAMALI, Hossein; BEIGI, Vahid; SADEGHI-SARVESTANI, Ali

2018-01-01

Heredity plays an important role in keratoconus (KC). Consanguineous marriage (CM) can affect the transmission of recessively inherited conditions. We aimed to investigate the role of consanguineous marriage in the development of KC. This study included two groups: the first group comprised 415 patients who underwent surgery for KC for the first time at Khalili University Hospital (Shiraz, Iran), between 2010 and 2014; the second group comprised 415 healthy individuals who served as age- and sex-matched controls for the patient group. All study subjects were from the Fars province in Iran. CM type was evaluated by a standard checklist in both groups. The mean inbreeding coefficient (α) was evaluated and compared between the two groups. The percentage of parental first-cousin marriages was 35.4% in the patient group and 18.3% in the control group. The mean inbreeding coefficient (α) was 0.0291 in the patient group and 0.0135 in the control group. Patients with KC had a significantly higher mean inbreeding coefficient (α) than controls (T = 8, df = 828, P < 0.001). Our study suggests that CM can play a role in the pathogenesis of KC. As this disease is among the most frequent ocular disorders in our country, CM should be considered by health care systems within their screening programs. PMID:29644240

Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing.

PubMed

Marafie, Makia J; Al-Awadi, Sadiqa; Al-Mosawi, Fatemah; Elshafey, Alaa; Al-Ali, Waleed; Al-Mulla, Fahd

2009-01-01

Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified, other high risk pre-symptomatic carriers could be offered intensive surveillance and management as a preventive measure against cancer development. Here, we present two large highly consanguineous HNPCC-families from Kuwait in whom a founder MSH2 mutation was identified. The relationship between this mutation and cancer expressivity in two large consanguineous families harbouring other genetic defects is discussed. Moreover, we shed light on the challenges pertaining to diagnosis, screening, premarital counselling of couples and prenatal diagnosis of offspring with biallelic MSH2 gene mutation.

[The point-digital interpretation and the choice of the dermatoglyphic patterns on human fingers for diagnostics of consanguineous relationship].

PubMed

Zvyagin, V N; Rakitin, V A; Fomina, E E

The objective of the present study was the development of the point-digital model for the scaless interpretation of the dermatoglyphic papillary patterns on human fingers that would allow to comprehensively describe, in digital terms, the main characteristics of the traits and perform the quantitative assessment of the frequency of their inheritance. A specially developed computer program, D.glyphic. 7-14 was used to mark the dermatoglyphic patterns on the fingerprints obtained from 30 familial triplets (father + mother + child).The values of all the studied traits for kinship diagnostics were found by calculating the ratios of the sums of differences between the traits in the parent-parent pairs to those in the respective parent-child pairs. The algorithms for the point marking of the traits and reading out the digital information about them have been developed. The traditional dermatoglyphic patterns were selected and the novel ones applied for the use in the framework of the point-digital model for the interpretation of the for diagnostics of consanguineous relationship. The present experimental study has demonstrated the high level of inheritance of the selected traits and the possibility to develop the algorithms and computation techniques for the calculation of consanguineous relationship coefficients based on these traits.

X-linked juvenile retinoschisis in a consanguineous family: phenotypic variability and report of a homozygous female patient.

PubMed

Gliem, Martin; Holz, Frank G; Stöhr, Heidi; Weber, Bernhard H F; Charbel Issa, Peter

2014-12-01

To describe the phenotypic variability in a consanguineous family with genetically confirmed X-linked retinoschisis. Five patients, including one homozygous female, were characterized by clinical examination, optical coherence tomography, fundus autofluorescence, mapping of macular pigment optical density, electroretinography, and DNA testing. The 36-year-old male index patient showed a ring of enhanced autofluorescence and outer retinal atrophy on optical coherence tomography. Electroretinography testing revealed a reduced a/b ratio. His mother presented with a central atrophic retina with markedly reduced autofluorescence signal and a surrounding ring of enhanced autofluorescence. The 40-year-old brother of the index patient and his 2 sons showed characteristic signs for X-linked retinoschisis, including retinal schisis and a reduced a/b ratio. Genetic testing revealed a c.293C>A mutation in the RS1 gene in all affected family members while the mother of the index patient was homozygous for this mutation. X-linked retinoschisis can present with a wide phenotypic variability. Here, detailed family history and genetic testing established the diagnosis of X-linked retinoschisis despite striking differences in phenotypic presentation in affected subjects, homozygosity of one affected female, and seemingly dominant inheritance in three subsequent generations because of multiple consanguinity.

A 5-year survey of biopsy proven kidney diseases in Lebanon: significant variation in prevalence of primary glomerular diseases by age, population structure and consanguinity

PubMed Central

Karnib, Hussein H.; Gharavi, Ali G.; Aftimos, Georges; Mahfoud, Ziyad; Saad, Reem; Gemayel, Elias; Masri, Badiaa; Assaad, Shafika; Badr, Kamal F.; Ziyadeh, Fuad N.

2010-01-01

Background. Differences in epidemiology of kidney disease across the Middle East may arise from variations in indication for biopsy, environmental exposure and socio-economic status. The Lebanese population is composed of different ethnicities, with distinct ancestry and religion, enabling comparison of their effect on the prevalence of kidney disease within a confined geographic setting and uniform practices. Here we report 5 years’ detailed epidemiology of renal diseases, based on histological diagnosis, in a sample from three large pathology centres in Lebanon. Methods. Records of renal biopsies analysed at the American University of Beirut Medical Center, Hotel Dieu de France Hospital and the Institut National de Pathologie from January 2003 till December 2007 were retrospectively examined. We recorded the following data for each patient: age, gender, indication for renal biopsy and histopathological diagnosis. Religious affiliation and parents’ consanguinity were recorded when feasible. Results. The mean age at renal biopsy was 36.76 ± 20 years (range 1–84). The most common diagnosis was mesangioproliferative glomerulonephritis (GN; 20%), followed by focal segmental glomerulosclerosis (13.2%). While there were no differences in age, gender or indications for biopsy among different religious affiliations, mesangioproliferative GN was significantly more frequent among Muslims (P = 0.039) and offspring of consanguineous unions (P = 0.036). On the other hand, focal segmental glomerulosclerosis was most prevalent in Christians (P < 0.001). Conclusions. Variation in the distribution of diagnoses between Muslim and Christian groups likely reflects differences in population structure and ancestry. In particular, the increased prevalence of mesangioproliferative GN among offspring of consanguineous unions in Muslims suggests a recessive genetic component to this disease which may be identified via homozygosity mapping. These findings have important implications for formulating renal health policies and designing research studies in this population. PMID:20525974

The frequency of consanguineous marriage in eastern Turkey.

PubMed

Akbayram, S; Sari, N; Akgün, C; Doğan, M; Tuncer, O; Caksen, H; Oner, A F

2009-01-01

The frequency of consanguineous marriage in Eastern Turkey: The rate of consanguineous marriage (CM) varies depended on different factors such as race, characteristics of population, and religion and moral features in different countries. Gene frequency and genetic structure are changed by CMs. The aim of the present study is to assess the prevalence of CM and its effects on miscarriage, stillbirth, congenital malformation and ratio of newborn death. This study was performed in Van region, Eastern Turkey, between September 2005 and April 2006. A total of 650 families from 24 districts chosen in accordance with the number of inhabitants were included in this study. First cousin marriages were accepted as a first degree CMs, sesquialter and second cousin marriages as second degree and marriages between distant relatives were accepted as a third degree CM. Monthly income of the families was classified in accordance with minimum wage determined by government. Of all families, 224 (34.4%) had CM, and 168 (75%) had first-degree consanguinity. A lower CM rate was found in mothers who graduated from secondary school or upgrading (p < 0.01). However, no relationship was found between CM and fathers' education level. While a low CM rate was found in families who had two or less children (p < 0.01), high rate was observed in families who had five or more children. In addition, a high rate of miscarriage, stillbirth and mental-motor retardation was found in families with CM (p < 0.05). The rate of child mortality between the aged 0-2 years was found to be higher in families with CM (p < 0.01). The higher CM rate was observed in families who married due to pressure or insistence of their families than married voluntarily (p < 0.05). Our study showed that CM rate was very high, 34.4%, in our region Eastern Turkey.

The Case for High Resolution Extended 6-Loci HLA Typing for Identifying Related Donors in the Indian Subcontinent.

PubMed

Agarwal, Rajat Kumar; Kumari, Ankita; Sedai, Amit; Parmar, Lalith; Dhanya, Rakesh; Faulkner, Lawrence

2017-09-01

Three-loci low-resolution (LR) or intermediate-resolution HLA typing is generally considered adequate in the related blood and marrow transplantation (BMT) context. However, a single high-resolution (HR) mismatch may have a similar adverse impact on BMT outcome as an LR one. We sought to determine the frequency of mismatches that may go undetected when standard typing (LR or 3-loci HR) is used compared with 6-loci HR typing for related donor compatibility testing, and to assess its impact on relevant BMT outcomes. We analyzed data from a total of 2554 6-loci (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) HR sequence-based typing (full typing [FT]) from 754 patients, 1011 siblings, and 789 parents done at DKMS Germany (www.DKMS.de) between January 1, 2014, and June 21, 2016. We also studied 38 cases in which the family had undergone 3-loci HLA typing (standard typing [ST]). Patients were from India (70%), Pakistan (22%), and Sri Lanka (8%). The IMGT/HLA database (www.ebi.ac.uk/ipd/imgt/hla) was used to tease out nonpermissive DPB1 mismatches. HLA disparity-related outcomes, such as rejection and graft-versus-host disease (GVHD) were assessed in a retrospective matched-pair cohort of 50 patients (25 with ST and 25 with FT) who underwent BMT for severe thalassemia from compatible related donors. We found fully matched (either 12/12 HR matches or with a single permissive DPB1 mismatch) related donors for 285 patients (38%). Of these donors, 89% were siblings and 11% were parents. The likelihood of matching on an individual locus on LR but not on HR was found to be 5%. A total of 9 donors (3%; 7 siblings and 2 parents) who would have been considered a full match by HR typing on A, B, and DRB1 alone were not a match by extended 6-loci HR typing. Five of these 9 donors had a mismatch on C or DQB1, and 4 had a nonpermissive DPB1 mismatch. In this group, 5 donors (56%) belonged to a consanguineous family, in 2 donors (22%) there was no reported consanguinity, and in 2 donors (22%) consanguinity was unknown. We identified 18 donors (6%; 13 siblings and 5 parents) who would have been considered a 12/12 match by LR HLA typing alone but were found not to match on extended HR typing. In this group, 11 donors (61%) were from consanguineous families, 3 donors (17%) had no reported consanguinity, and in 4 donors (22%) consanguinity was unknown. Outcome analysis showed that the actuarial proportion of patients with GVHD was 4% in the FT group compared with 16% in the ST group, with log-rank P = .1952. The ST group included 2 patients with grade III-IV acute GVHD and 1 patient each with moderate and severe chronic GVHD, whereas the FT group only 1 patient with grade III acute GVHD. We conclude that even in the context of related donors, the use of LR and/or 3-loci (A, B, and DRB1) HR HLA typing might result in a sizable risk of missing a clinically relevant mismatch, which may have an adverse impact on transplantation outcomes. In the Indian subcontinent, this observation is not limited to putatively compatible parents or consanguineous families; we recommend full 6-loci HR HLA typing even for matched related BMTs. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Dandy-Walker malformation, genitourinary abnormalities, and intellectual disability in two families.

PubMed

Zaki, Maha S; Masri, Amira; Gregor, Anne; Gleeson, Joseph G; Rosti, Rasim Ozgur

2015-11-01

We report on two families, each with documented consanguinity and two affected with overlapping features of Dandy-Walker malformation, genitourinary abnormalities, intellectual disability, and hearing deficit. This phenotype shares similar findings with many well-known syndromes. However, the clinical findings of this syndrome categorize this as a new syndrome as compared with the phenotype of already established syndromes. Due to parental consanguinity, occurrence in siblings of both genders and the absence of manifestations in obligate carrier parents, an autosomal recessive pattern of inheritance is more likely. The authors believe that these families suggest a novel autosomal recessive cerebello-genital syndrome. Array CGH analyses of an affected did not show pathological deletions or duplications. © 2015 Wiley Periodicals, Inc.

Pentalogy of Cantrell: report of a case with consanguineous parents.

PubMed

Pachajoa, Harry; Barragán, Arelis; Potes, Angela; Torres, Javier; Isaza, Carolina

2010-01-01

Pentalogy of Cantrell is a syndrome evidencing five anomalies: a midline, upper abdominal wall abnormality; lower sternal defect; anterior diaphragmatic defect; diaphragmatic pericardial defect, and congenital abnormalities of the heart. Its prevalence is one in every 65,000 live births and a survival rate that is low if the fall the five defects are present or the gravity of the cardiac anomalies. It may be diagnosed during the first trimester obstetric ultrasound. For postnatal care, emission-computed tomography and magnetic resonance imaging is recommended for a clear definition of the extent of the defect and to design a course of corrective surgery. Herein, a case of pentology of Cantrell is reported for a child offspring of consanguineous parents.

Whole-exome sequencing identifies common and rare variant metabolic QTLs in a Middle Eastern population.

PubMed

Yousri, Noha A; Fakhro, Khalid A; Robay, Amal; Rodriguez-Flores, Juan L; Mohney, Robert P; Zeriri, Hassina; Odeh, Tala; Kader, Sara Abdul; Aldous, Eman K; Thareja, Gaurav; Kumar, Manish; Al-Shakaki, Alya; Chidiac, Omar M; Mohamoud, Yasmin A; Mezey, Jason G; Malek, Joel A; Crystal, Ronald G; Suhre, Karsten

2018-01-23

Metabolomics-genome-wide association studies (mGWAS) have uncovered many metabolic quantitative trait loci (mQTLs) influencing human metabolic individuality, though predominantly in European cohorts. By combining whole-exome sequencing with a high-resolution metabolomics profiling for a highly consanguineous Middle Eastern population, we discover 21 common variant and 12 functional rare variant mQTLs, of which 45% are novel altogether. We fine-map 10 common variant mQTLs to new metabolite ratio associations, and 11 common variant mQTLs to putative protein-altering variants. This is the first work to report common and rare variant mQTLs linked to diseases and/or pharmacological targets in a consanguineous Arab cohort, with wide implications for precision medicine in the Middle East.

48XXYY Syndrome in an Adult with Type 2 Diabetes Mellitus, Unilateral Renal Aplasia, and Pigmentary Retinitis.

PubMed

Zantour, Baha; Sfar, Mohamed Habib; Younes, Samia; Alaya, Wafa; Kamoun, Mahdi; Mkaouar, Emna; Jerbi, Saida

2010-01-01

A 45-year-old male was referred for diabetes mellitus. Clinical examination found a family history of multiple precocious deaths, strong consanguinity, personal history of seizures during childhood, small testicles, small penis, sparse body hair, long arms and legs, dysmorphic features, mental retardation, dysarthria, tremor, and mild gait ataxia. Investigations found pigmentary retinitis, metabolic syndrome, unilateral renal aplasia, and hypergonadotropic hypogonadism, and ruled out mitochondrial cytopathy and leucodystrophy. Karyotype study showed a 48XXYY chromosomal type. Renal aplasia and pigmentary retinitis have not been described in 48XXYY patients. They may be related to the chromosomal sex aneuploidy, or caused by other genetic aberrations in light of the high consanguinity rate in the patient's family.

48XXYY Syndrome in an Adult with Type 2 Diabetes Mellitus, Unilateral Renal Aplasia, and Pigmentary Retinitis

PubMed Central

Zantour, Baha; Sfar, Mohamed Habib; Younes, Samia; Alaya, Wafa; Kamoun, Mahdi; Mkaouar, Emna; Jerbi, Saida

2010-01-01

A 45-year-old male was referred for diabetes mellitus. Clinical examination found a family history of multiple precocious deaths, strong consanguinity, personal history of seizures during childhood, small testicles, small penis, sparse body hair, long arms and legs, dysmorphic features, mental retardation, dysarthria, tremor, and mild gait ataxia. Investigations found pigmentary retinitis, metabolic syndrome, unilateral renal aplasia, and hypergonadotropic hypogonadism, and ruled out mitochondrial cytopathy and leucodystrophy. Karyotype study showed a 48XXYY chromosomal type. Renal aplasia and pigmentary retinitis have not been described in 48XXYY patients. They may be related to the chromosomal sex aneuploidy, or caused by other genetic aberrations in light of the high consanguinity rate in the patient's family. PMID:20827436

Spondyloenchondrodysplasia: a rare cause of short stature.

PubMed

Yeşiltepe-Mutlu, Gül; Ozsu, Elif; Cizmecioğlu, Filiz Mine; Alanay, Yasemin; Hatun, Sükrü

2011-01-01

Skeletal dysplasias (osteochondrodysplasias) are a group of diseases that must be included in the differential diagnosis of disproportionate short stature. History, clinical and radiologic findings and consanguinity are important features to be considered when a specific diagnosis is investigated. Spondyloenchondrodysplasia is a very rare skeletal dysplasia characterized with enchondromas in the long bones and platyspondyly. Manifestation of the disorder may include neurological involvement (spasticity, intracranial calcifications and mental retardation) and immune dysfunction. Herein, we report a 12-year-old boy who admitted to our clinic with short stature, who was born to consanguineous parents. He presented clinical (significant widening of wrists, ankles and knees) and radiologic (enchondromatous lesions in the metaphysis of long bones) features of spondyloenchondrodysplasia but did not yet have neurologic or immunologic involvement.

[Demographic consequences of genetic load: a model of the origin of the incest taboo].

PubMed

Buzin, A Iu

1987-12-01

The prohibition of copulations among near relatives may raise the fitness of population. This effect being irregular and insignificant for a distinct generation, becomes apparent in evolutionary time intervals through the natural selection of populations with incest-taboo. The "characteristic selection time" theta depends on typical population size, genetic damage and the mean rate of population growth. The estimation obtained for theta permit us to assert that the model describes the phenomenon of "socio-cultural selection" in prehistory. The model shows the demographic specificity of small populations. The problem of the number of consanguineous marriages is considered in detail. New explanation for deviation of the observed frequency of consanguineous marriages from classical estimations is proposed.

Usher syndrome in four siblings from a consanguineous family of Pakistani origin.

PubMed

Trop, I; Schloss, M D; Polomeno, R; Der Kaloustian, V

1995-04-01

Usher syndrome is a heterogeneous group of disorders of autosomal recessive inheritance characterized by retinitis pigmentosa and congenital sensorineural hearing loss. Two types are accepted clinically: type I is associated with profound congenital deafness with progressive pigmentary retinopathy and total loss of vestibular function. Type II is a milder form, with moderate-to-profound hearing loss and a milder form of retinitis pigmentosa. Vestibular function is preserved. A total of five loci have been identified as accounting for the two distinct phenotypic presentations. We describe a consanguineous family of Pakistani origin whose four children all are affected with Usher syndrome type I. DNA analysis showed non-linkage to any of the loci already identified as tightly linked to the Usher syndrome type I.

[Juvenile myasthenia gravis in sub-Saharan Africa: a case study of two consanguine sisters born from consanguinity in Togo].

PubMed

Maneh, Nidain; Apetse, Kossivi; Diatewa, Bénédicte Marèbe; Domingo, Sidik Abou-Bakr; Agba, Aidé Isabelle; Ayena, Koffi Didier; Balogou, Koffi Agnon; Balo, Komi Patrice

2017-01-01

Myasthenia gravis is a rare acquired autoimmune pathology causing neuromuscular transmission impairment. Juvenile onset of myasthenia gravis is often characterized by ocular involvement. We report two cases of ocular juvenile myasthenia gravis (JMG) in two siblings. They were two young girls, XA and XB, aged 11 and 9 years, of Malian origin, residing in Togo, born from first-degree of consanguinity presenting to Ophthalmology due to progressive decrease in visual acuity. XA showed visual acuity 8/10 on both eyes while XB showed improvement in visual acuity from 3/10 to 7/10 using a pinhole occluder, suggesting ametropia. XA had a 2-year history of bilateral ptosis lifting the upper eyelid of 7 mm, while XB had a 3-year history of bilateral ptosis with no lifting of the upper eyelid. Ice pack test was strongly positive in both patients. They had Cogan's lid twitch with paresis of the oculomotor nerve without diplopia. The dosage of acetylcholine receptor autoantibodies was normal. The diagnosis of JMG associated with ametropia was suspected. Ametropia was corrected by glasses and a specific treatment with pyridostigmine was initiated, but both patients were lost to follow-up. Autoimmune myasthenia gravis with inaugural ophthalmologic manifestation is rare but it can occur among children living in sub-Saharan Africa. Studies should be conducted to establish the features of this disease.

Mapping autosomal recessive intellectual disability: combined microarray and exome sequencing identifies 26 novel candidate genes in 192 consanguineous families.

PubMed

Harripaul, R; Vasli, N; Mikhailov, A; Rafiq, M A; Mittal, K; Windpassinger, C; Sheikh, T I; Noor, A; Mahmood, H; Downey, S; Johnson, M; Vleuten, K; Bell, L; Ilyas, M; Khan, F S; Khan, V; Moradi, M; Ayaz, M; Naeem, F; Heidari, A; Ahmed, I; Ghadami, S; Agha, Z; Zeinali, S; Qamar, R; Mozhdehipanah, H; John, P; Mir, A; Ansar, M; French, L; Ayub, M; Vincent, J B

2018-04-01

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations (ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7 and USP44), and missense mutations include the first reports of variants in BDNF or TET1 associated with ID. The genes identified also showed overlap with de novo gene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

A novel RLBP1 gene geographical area-related mutation present in a young patient with retinitis punctata albescens.

PubMed

Scimone, Concetta; Donato, Luigi; Esposito, Teresa; Rinaldi, Carmela; D'Angelo, Rosalia; Sidoti, Antonina

2017-08-01

Autosomal recessive forms of retinitis punctata albescens (RPA) have been described. RPA is characterized by progressive retinal degeneration due to alteration in visual cycle and consequent deposit of photopigments in retinal pigment epithelium. Five loci have been linked to RPA onset. Among these, the retinaldehyde-binding protein 1 gene, RLBP1, is the most frequently involved and several founder mutations were reported. We report results of a genetic molecular investigation performed on a large Sicilian family in which appears a young woman with RPA. The proband is in homozygous condition for a novel RLBP1 single-pair deletion, and her healthy parents, both heterozygous, are not consanguineous. Thenovelc.398delC (p.P133Qfs*258) involves the exon 6 and leads to a premature stop codon, resulting in a truncated protein entirely missing of CRAL-TRIO lipid-binding domain. Pedigree analysis showed other non-consanguineous relatives heterozygous for the same mutation in the family. Extension of mutation research in the native town of the proband revealed its presence also in healthy subjects, in a heterozygous condition. A novel RLBP1 truncating mutation was detected in a young girl affected by RPA. Although her parents are not consanguineous, the mutation was observed in a homozygous condition. Being them native of the same small Sicilian town of Fiumedinisi, the hypothesis of a geographical area-related mutation was assessed and confirmed.

Population structure of two black Venezuelan populations studied through their mating structure and other related variables.

PubMed

Castro de Guerra, D; Arvelo, H; Pinto-Cisternas, J

1999-01-01

In order to obtain information about the population structure of two black Venezuelan populations with historical differences both in their origins and development, a variety of variables were utilized, especially on marital structure, including: frequency of surnames, isonymy, population genealogical consanguinity, multiple unions, and marital distances, all of which provided information and isolation, migration, endogamy, consanguinity, and patri-matrifocality. Results showed differences in the extent of isolation and endogamy, as well as differences in population structure, which can be directly related with historical conditions of each population. Results agree with those previously obtained with traditional genetic polymorphisms and with the historical information available. Thus, the usefulness of surnames for inferring about population structure is supported, as well as the usefulness of historical information for explaining genetic diversity.

Search for consanguinity within and among families of patients with trichothiodystrophy associated with xeroderma pigmentosum.

PubMed Central

Nuzzo, F; Zei, G; Stefanini, M; Colognola, R; Santachiara, A S; Lagomarsini, P; Marinoni, S; Salvaneschi, L

1990-01-01

The association of two rare hereditary disorders, trichothiodystrophy (TTD) and xeroderma pigmentosum (XP), was found in four patients from three families, apparently unrelated but living in the same geographical area. In order to test the hypothesis of a common ancestor, consanguinity within and among the families was checked using three different approaches: reconstruction of genealogical trees, typing of blood markers, and surname analysis. The results of the three types of analyses strengthen the hypothesis that, in at least two out of the three families, the genetic defect determining the TTD/XP phenotype is identical by descent, as a consequence of remote inbreeding. This implies that if two mutations are responsible for the two diseases they are at linked loci or affect the same gene. PMID:2308151

The prevalence of attention deficit hyperactivity symptoms in schoolchildren in a highly consanguineous community.

PubMed

Bener, Abdulbari; Al Qahtani, Razna; Teebi, Ahmad S; Bessisso, Mohammed

2008-01-01

The objective of the present study was to find the prevalence of attention deficit hyperactivity (ADH) symptoms in a sample of primary schoolchildren in Qatar and investigate the behaviour of the children with and without ADH symptoms in a highly consanguineous community. A total of 2,500 primary school students, aged 6-12 years, were randomly selected from the government primary schools, and 1,869 students (947 boys and 922 girls) gave consent to participate in this study. An Arabic questionnaire was used to collect the sociodemographic variables and a standardized Arabic version of the Conners' Teacher Rating Scale for ADH symptoms. Of the 947 boys, 158 (16.7%; 95% confidence interval, CI, 14.4-19.2) and of the 922 girls, 50 (5.4%; 95% CI 4.1-7.1) scored above the cut-off (>or=15) for ADH symptoms, thus giving an overall prevalence of 11.1% (95% CI 9.7-12.6). The children who had higher scores for ADH symptoms were in the age group of 6-9 years. Children who had higher scores for ADH symptoms had a poorer school performance than those with lower scores (p = 0.002). Two hundred (96.2%) children with ADH were disobedient, 126 (60.6%) noisy and hyperactive, 76 (36.5%) very cranky, 78 (37.5%) troublesome and 79 (37.9%) nervous. The logistic regression identified socio-economic condition, number of children, school performance and poor relationship between parents as the main contributors to ADH. Although the univariate analysis showed a significant relationship (p = 0.010) between ADH symptoms and consanguineous parents, logistic regression did not support this association (p = 0.075). This suggests that consanguinity has no impact on ADH children. The study revealed that ADH is a common problem among schoolchildren. The children with higher scores for ADH symptoms had a poorer school performance than those with lower scores. A significant difference exists between the behaviour of children with and without ADH. (c) 2008 S. Karger AG, Basel.

Mutations in ALDH1A3 represent a frequent cause of microphthalmia/anophthalmia in consanguineous families.

PubMed

Abouzeid, Hana; Favez, Tatiana; Schmid, Angélique; Agosti, Céline; Youssef, Mohammed; Marzouk, Iman; El Shakankiry, Nihal; Bayoumi, Nader; Munier, Francis L; Schorderet, Daniel F

2014-08-01

Anophthalmia or microphthalmia (A/M), characterized by absent or small eye, can be unilateral or bilateral and represent developmental anomalies due to the mutations in several genes. Recently, mutations in aldehyde dehydrogenase family 1, member A3 (ALDH1A3) also known as retinaldehyde dehydrogenase 3, have been reported to cause A/M. Here, we screened a cohort of 75 patients with A/M and showed that mutations in ALDH1A3 occurred in six families. Based on this series, we estimate that mutations in ALDH1A3 represent a major cause of A/M in consanguineous families, and may be responsible for approximately 10% of the cases. Screening of this gene should be performed in a first line of investigation, together with SOX2. © 2014 WILEY PERIODICALS, INC.

Cervical vertebral fusion (Klippel-Feil) syndrome with consanguineous parents.

PubMed

Juberg, R C; Gershanik, J J

1976-06-01

We describe a female infant with the cervical vertebral fusion (Klippel-Feil) syndrome whom we recognized at birth because of her short neck, restriction of cervical movement, and low posterior hairline. X-ray examination showed anomalies of C1, and between C2-3 and C3-4; thus, we classified her as type II, with variable cervical fusion. At 24 months she was small and manifested hearing deficiency. The mother and father were consanguineous with five common ancestors four generations ago, which resulted in a coefficient of inbreeding equivalent to a second cousin relationship. The parents and grandparents were phenotypically normal, and the parents were radiologically normal. This form of the syndrome has previously been said to be autosomal dominant. Our conclusion of determination by a single autosomal recessive gene is evidence of genetic heterogeneity.

Identification of three novel mutations by studying the molecular genetics of Maple Syrup Urine Disease (MSUD) in the Lebanese population.

PubMed

Tabbouche, Omar; Saker, Amer; Mountain, Harry

2014-01-01

Maple Syrup Urine Disease (MSUD) is a genetically heterogeneous metabolic disorder that is transmitted in an autosomal recessive manner. According to clinical data, MSUD prevalence in Lebanon is expected to be higher than the International prevalence because of consanguineous marriage. Novel mutations are still getting detected by using DNA sequencing for mutation analysis in MSUD patients. In the current study, we have extracted DNA from Lebanese MSUD patients in order to amplify the exonic and flanking intronic regions of the genes implicated in MSUD ( BCKDHA , BCKDHB , and DBT ) and sequenced the resultant amplified products to assess the molecular genetics of MSUD in the Lebanese population studied. All of the mutations identified occurred in the homozygous state, which reflects the high rate of consanguineous marriage in Lebanon. In the current study, we have identified one previously cited mutation and three novel mutations not previously described in the scientific literature. The identified mutations were distributed as follows: three patients (60%) had two nucleotide substitutions in the DBT gene (c.224G>A and c.1430T>G), one patient (20%) had a gross deletion in the BCKDHA gene (c.488_1167+3del), and one patient (20%) had a small deletion in the BCKDHB gene (c.92_102del). The majority of the mutations identified in the Lebanese MSUD patients occurred in the DBT gene. Consanguineous marriage is a major risk factor for the prevalence of MSUD in Lebanon.

A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family

PubMed Central

Sheereen, Atia; Alaamery, Manal; Bawazeer, Shahad; Al Yafee, Yusra; Massadeh, Salam; Eyaid, Wafaa

2017-01-01

Background Autosomal-recessive non-syndromic intellectual disability (ARNS-ID) is an aetiologically heterogeneous disorder. Although little is known about the function of human cereblon (CRBN), its relationship to mild cognitive deficits suggests that it is involved in the basic processes of human memory and learning. Objectives We aim to identify the genetic cause of intellectual disability and self-mutilation in a consanguineous Saudi family with five affected members. Methods Clinical whole-exome sequencing was performed on the proband patient, and Sanger sequencing was done to validate and confirm segregation in other family members. Results A missense variant (c. 1171T>C) in the CRBN gene was identified in five individuals with severe intellectual disability (ID) in a consanguineous Saudi family. The homozygous variant was co-segregating in the family with the phenotype of severe ID, seizures and self-mutilating behaviour. The missense mutation (p.C391R) reported here results in the replacement of a conserved cysteine residue by an arginine in the CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide) domain of CRBN, which contains a zinc-binding site. Conclusions These findings thus contribute to a growing list of ID disorders caused by CRBN mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype–phenotype correlations between CRBN mutations and the aetiology of ARNS-ID. PMID:28143899

The role of vitamin D, obesity and physical exercise in regulation of glycemia in Type 2 Diabetes Mellitus patients.

PubMed

Bener, Abdulbari; Al-Hamaq, Abdulla O A A; Kurtulus, Eda Merve; Abdullatef, Waleed K; Zirie, Mahmoud

The aims of this study were to determine the role of vitamin D, obesity and physical exercise in the regulation of glycemia in Type 2 Diabetes Mellitus patients in a highly consanguineous population. Case and control study. The survey was carried out at the Hamad General Hospital and Primary Health Care (PHC) centers in the State of Qatar. The study was conducted from November 2012 to June 2014 among subjects above 30 years of age. Of the 2224 registered with diagnosed diabetes and free diseases attending Hamad General Hospital and PHC centers agreed and gave their consent to study. Questionnaire included socio-demographic variables, body mass index (BMI), consanguinity, lifestyle habits, family history of diabetes, blood pressure and development of diabetes complications such as retinopathy, nephropathy, and neuropathy were collected at regular intervals throughout the follow-up. Univariate and multivariate statistical analysis were performed. There were statistically significant difference between patients with diabetic and control in terms of ethnicity (p=0.012), level of education (p=0.002), occupation (p<0.001), monthly income (p<0.001), BMI(p=0.024), sport activity (p=0.018), cigarette smoking (p<0.001), consanguinity (p=0.029) and family history of Diabetes Mellitus (p<0.001) and co-morbidity hypertension (p=0.041). Further, the biochemistry values in the studied subjects with T2DM compared to healthy controls and the study revealed that serum Vitamin D, BMI, fasting glucose level, calcium, HbA1c, total cholesterol HDL, LDL, bilirubin, triglycerides, uric acid and blood pressure systolic and diastolic were higher in T2DM compared to their counterparts. Multivariate logistic regression showed that vitamin D deficiency ng/mL, Family History of T2DM, BMI (kg/m 2 ) hypertension, consanguinity, income, mother occupation, ethnicity, educational level and Lack of physical exercise variables were significant predictors of diabetes. In the group of Diabetes Mellitus Type 2 patients, 39.3% as opposed to 51.2% in the control group had vitamin D deficiency, 25(OH) D3 levels≤10ng/ml (p<0.001). In the group of Diabetes Mellitus Type 2 patients, 34.6% as opposed to 37.9% in the control group had vitamin D insufficiency, 25(OH)D3 levels <20ng/ml (p < 0.001). In the group of Diabetes Mellitus Type 2 patients, 22.8% as opposed to 14.2% in the control group had vitamin D sufficiency, 25(OH)D3 levels >30 10ng/ml (p < 0.001). Vitamin D, family history of diabetes, consanguinity marriages' and hereditary gene-environment interactions and physical exercise may also contribute to the current diabetes epidemic in Qatari's Arab populations. Copyright © 2016 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Localization of A Novel Autosomal Recessive Non-Syndromic Hearing Impairment Locus (DFNB38) to 6q26–q27 in a Consanguineous Kindred from Pakistan

PubMed Central

Ansar, Muhammad; Ramzan, Mohammad; Pham, Thanh L.; Yan, Kai; Jamal, Syed Muhammad; Haque, Sayedul; Ahmad, Wasim; Leal, Suzanne M.

2010-01-01

For autosomal recessive nonsyndromic hearing impairment over 30 loci have been mapped and 19 genes have been identified. DFNB38, a novel locus for autosomal recessive nonsyndromic hearing impairment, was localized in a consanguineous Pakistani kindred to 6q26–q27. The affected family members present with profound prelingual sensorineural hearing impairment and use sign language for communications. Linkage was established to microsatellite markers located on chromosome 6q26–q27 (Multipoint lod score 3.6). The genetic region for DFNB38 spans 10.1 cM according to the Marshfield genetic map and is bounded by markers D6S980 and D6S1719. This genetic region corresponds to 3.4 MB on the sequence-based physical map. PMID:12890929

[Genetic isolates and inbreeding customs in three rural municipalities from Honduras].

PubMed

Herrera-Paz, Edwin Francisco

2016-01-01

The isonymic method has been amply used to assess the approximate genetic structure of human communities. The objective of the study was to evaluate the magnitude of genetic isolation and inbreeding customs in 57 communities from three rural municipalities of Honduras using isonymy techniques. The list of 408 different surnames from 20712 voters registered in the national electoral organism, residing in the 57 Honduran communities, was used for this study. For each community, random (IR), non-random (IN), and total (IT) isonymy values were calculated in order to assess inbreeding coefficients FST, FIS and FIT. High consanguinity due to isolation and to endogamous customs was unveiled in many communities. Significant deviation from the exogamous behavior typical of many human populations was observed in the three studied municipalities, when compared to other Honduran populations. The studied communities present high consanguinity due to isolation, ethnic segregation and/or endogamous customs.

Parental consanguineous marriages and clinical response to chemotherapy in locally advanced breast cancer patients.

PubMed

Saadat, Mostafa; Khalili, Maryam; Omidvari, Shahpour; Ansari-Lari, Maryam

2011-03-28

The main aim of the present study was investigating the association between parental consanguinity and clinical response to chemotherapy in females affected with locally advanced breast cancer. A consecutive series of 92 patients were prospectively included in this study. Clinical assessment of treatment was accomplished by comparing initial tumor size with preoperative tumor size using revised RECIST guideline (version 1.1). Clinical response defined as complete response, partial response and no response. The Kaplan-Meier survival analysis were used to evaluate the association of parental marriages (first cousin vs unrelated marriages) and clinical response to chemotherapy (complete and partial response vs no response). Number of courses of chemotherapy was considered as time, in the analysis. Kaplan-Meier analysis revealed that offspring of unrelated marriages had poorer response to chemotherapy (log rank statistic=5.10, df=1, P=0.023). Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

The Decline of Arranged Marriage? Marital Change and Continuity in India

PubMed Central

Allendorf, Keera; Pandian, Roshan K.

2017-01-01

This article evaluates whether arranged marriage declined in India from 1970 to 2012. Specifically, the authors examine trends in spouse choice, the length of time spouses knew each other prior to marriage, intercaste marriage, and consanguineous marriage at the national level, as well as by region, urban residence, and religion/caste. During this period, women were increasingly active in choosing their own husbands, spouses meeting on their wedding day decreased, intercaste marriage rose, and consanguineous marriage fell. However, many of these changes were modest in size and substantial majorities of recent marriages still show the hallmarks of arranged marriage. Further, instead of displacing parents, young women increasingly worked with parents to choose husbands collectively. Rather than unilateral movement towards Western marriage practices, as suggested by theories of family change and found in other Asian contexts, these trends point to a hybridization of customary Western and Indian practices. PMID:28344368

SLC52A2 mutations cause SCABD2 phenotype: A second report.

PubMed

Babanejad, Mojgan; Adeli, Omid Ali; Nikzat, Nooshin; Beheshtian, Maryam; Azarafra, Hakimeh; Sadeghnia, Farnaz; Mohseni, Marzieh; Najmabadi, Hossein; Kahrizi, Kimia

2018-01-01

Autosomal recessive cerebellar ataxias (ARCAs) are a large group of neurodegenerative disorders that manifest mainly in children and young adults. Most ARCAs are heterogeneous with respect to age at onset, severity of disease progression, and frequency of extracerebellar and systemic signs. The phenotype of a consanguineous Iranian family was characterized using clinical testing and pedigree analysis. Whole-exome sequencing was used to identify the disease-causing gene in this family. Using whole exome sequencing (WES), a novel missense mutation in SLC52A2 gene is reported in a consanguineous Iranian family with progressive severe hearing loss, optic atrophy and ataxia. This is the second report of the genotype-phenotype correlation between this syndrome named spinocerebellar ataxia with blindness and deafness type 2 (SCABD2) and SLC52A2 gene. Copyright © 2017 Elsevier B.V. All rights reserved.

Cranial malformations in related white lions (Panthera leo krugeri).

PubMed

Scaglione, F E; Schröder, C; Degiorgi, G; Zeira, O; Bollo, E

2010-11-01

White lions (Panthera leo krugeri) have never been common in the wild, and at present, the greatest population is kept in zoos where they are bred for biological and biodiversity conservation. During the years 2003 to 2008 in a zoological garden in northern Italy, 19 white lions were born to the same parents, who were in turn paternally consanguineous. Out of the 19 lions, 4 (21%) were stillborn, 13 (69%) died within 1 month, and 1 (5%) was euthanatized after 6 months because of difficulty with prehension of food. Six lions (32%) showed malformations involving the head (jaw, tongue, throat, teeth, and cranial bones). One lion (5%) still alive at 30 months revealed an Arnold-Chiari malformation upon submission for neurological evaluation of postural and gait abnormalities. Paternal consanguinity of the parents, along with inbreeding among white lions in general, could account for the high incidence of congenital malformations of the head in this pride of white lions.

Domestic violence in consanguineous marriages - findings from Pakistan Demographic and Health Survey 2012-13.

PubMed

Shaikh, Masood Ali

2016-10-01

Domestic violence is a pandemic and estimated to affect one in three women globally, in their lifetime. Marriages within blood relations in Pakistan are common. In this study a secondary analysis of Pakistan Demographic and Health Survey 2012-13 was done to study the prevalence and profile of domestic violence in the context of consanguineous marriages in Pakistan. Almost 65% of women had some kind of blood relationship with their husbands. Women having a blood relationship with husbands were more likely to report having ever been subjected to marital control behaviours, emotional and physical violence by their husbands, compared to ones without such relationship. However, these associations fail to reach statistical significance; underscoring the ubiquitous nature of marital control and violence. More effective public health education campaigns for just and equal treatment of wives by their husbands to speedily curb the scourge of domestic violence in the country are needed.

The relationship between periodontal status and peripheral levels of neutrophils in two consanguineous siblings with severe congenital neutropenia: case reports.

PubMed

Tözüm, Tolga Fikret; Berker, Ezel; Ersoy, Fügen; Tezcan, Iihan; Sanal, Ozden

2003-03-01

Congenital neutropenia is characterized by a severe reduction in absolute neutrophil counts, resulting in an almost total absence of neutrophils. It is well known that severe neutropenia affects periodontal status. Oral manifestations include ulcerations, gingival desquamation, gingival inflammation, attachment loss, and alveolar bone loss which may result in tooth loss. Treatment with granulocyte-colony stimulating factor (G-CSF) may improve this periodontal condition. This article reports the relationship between periodontal disease status and peripheral neutrophil levels in two consanguineous siblings with severe congenital neutropenia who did not receive routine G-CSF for 2 years prior to examination. Both siblings were given scaling, root planing, and periodontal prophylaxis in regular follow-up visits. This report demonstrates that periodontal therapy supported by adequate oral hygiene may result in restoration of neutrophil counts in siblings with congenital neutropenia.

Domestic violence and consanguineous marriages - perspective from Rawalpindi, Pakistan.

PubMed

Shaikh, M Ali; Kayani, A; Shaikh, I Ali

2014-01-09

Domestic violence is globally endemic and adversely impacts the health and economic well-being of women and society. This study used the standardized and validated assessment instrument "Woman Abuse Screening Tool" to study the prevalence of various forms of domestic violence among married women. The relationship between domestic violence and consanguineous marriage was studied using the chi-squared test. Cumulatively, 1010 married women were interviewed. Emotional abuse was the most commonly reported abuse, reported by 721 (71.4%) women as either often or sometimes, followed by sexual abuse and physical abuse, reported by 527 (52.2%) and 511 (50.6%) respectively. Being married to one's cousin did not protect married women from being abused either emotionally or physically by their husbands; thsi was statistically significant. There is a need for better understanding of the magnitude and scale of domestic violence in Pakistan by using standardized assessment tools for meaningful comparisons across different parts of the country over time.

Exome sequencing and SNP analysis detect novel compound heterozygosity in fatty acid hydroxylase-associated neurodegeneration

PubMed Central

Pierson, Tyler Mark; Simeonov, Dimitre R; Sincan, Murat; Adams, David A; Markello, Thomas; Golas, Gretchen; Fuentes-Fajardo, Karin; Hansen, Nancy F; Cherukuri, Praveen F; Cruz, Pedro; Blackstone, Craig; Tifft, Cynthia; Boerkoel, Cornelius F; Gahl, William A

2012-01-01

Fatty acid hydroxylase-associated neurodegeneration due to fatty acid 2-hydroxylase deficiency presents with a wide range of phenotypes including spastic paraplegia, leukodystrophy, and/or brain iron deposition. All previously described families with this disorder were consanguineous, with homozygous mutations in the probands. We describe a 10-year-old male, from a non-consanguineous family, with progressive spastic paraplegia, dystonia, ataxia, and cognitive decline associated with a sural axonal neuropathy. The use of high-throughput sequencing techniques combined with SNP array analyses revealed a novel paternally derived missense mutation and an overlapping novel maternally derived ∼28-kb genomic deletion in FA2H. This patient provides further insight into the consistent features of this disorder and expands our understanding of its phenotypic presentation. The presence of a sural nerve axonal neuropathy had not been previously associated with this disorder and so may extend the phenotype. PMID:22146942

Variable approaches to genetic counseling for microarray regions of homozygosity associated with parental relatedness.

PubMed

Grote, Lauren; Myers, Melanie; Lovell, Anne; Saal, Howard; Sund, Kristen Lipscomb

2014-01-01

SNP microarrays are capable of detecting regions of homozygosity (ROH) which can suggest parental relatedness. This study was designed to describe pre- and post-test counseling practices of genetics professionals regarding ROH, explore perceived comfort and ethical concerns in the follow-up of such results, demonstrate awareness of laws surrounding duty to report consanguinity and incest, and allow respondents to share their personal experiences with results suggesting a parental relationship. A 35 question survey was administered to 240 genetic counselors and geneticists who had ordered or counseled for SNP microarray. The results are presented using descriptive statistics. There was variation in both pre- and post-test counseling practices of genetics professionals. Twenty-five percent of respondents reported pre-test counseling that ROH can indicate parental relatedness. The most commonly reported ethical concern was disclosure of findings suggesting parental relatedness to parents of the patient; only 48.4% reported disclosing parental relatedness when indicated. Fifty-seven percent felt comfortable receiving results suggesting parental consanguinity while 17% felt comfortable receiving results suggesting parental incest. Twenty percent of respondents were extremely/moderately familiar with the laws about duty to report incest. Personal experiences in post-test counseling included both parental acknowledgement and denial of relatedness. This study highlights the differences in genetics professionals' pre- and post-test counseling practices, comfort, and experiences surrounding parental relatedness suggested by SNP microarray results. It identifies a need for professional organizations to offer guidance to genetics professionals about how to respond to and counsel for molecular results suggesting parental consanguinity or incest. © 2013 Wiley Periodicals, Inc.

[Experience in molecular diagnostic in hereditary neuropathies in a pediatric tertiary hospital].

PubMed

Fernández-Ramos, Joaquín A; López-Laso, Eduardo; Camino-León, Rafael; Gascón-Jiménez, Francisco J; Jiménez-González, M Dolores

2015-12-01

Charcot-Marie-Tooth (CMT) is the most common hereditary sensory motor neuropathy. Advances in molecular diagnosis have increased the diagnostic possibilities of these patients. Retrospective study of 36 pediatric patients diagnosed with CMT in a tertiary center in 2003-2015. We found 16 patients were diagnosed by a duplication in PMP22; two cases were diagnosed of hereditary neuropathy with liability to pressure palsies, one with a point mutation in PMP22; a male with a mild demyelinating phenotype, without family history, was diagnosed with GJB1 mutation; in a patient with a peripheral hypotonia at birth and axonal pattern in EMG by mutation in MFN2; a gypsy patient, with consanguineous family, CMT4D, was identified by a mutation in the gene NDRG1; a patient with multiplex congenital arthrogryposis and vocal cord paralysis, whose mother had a scapular-peroneal syndrome, had a congenital spinal muscular atrophy with mild distal axonal neuropathy by mutation in gene TRPV4; three girls, from a gypsy consanguineous family, with axonal CMT with neuromyotonic discharges were diagnosed by a mutation in the gene HINT1; twelve patients haven't molecular diagnosis currently. CMT1A predominated in our series (44%), as previous studies. We emphasize the description of a patient with a mutation in TRPV4 recently described as a cause of CMT2C and three cases, of gypsy consanguineous family, with the same mutation in HINT1 gene, recently described as a cause of axonal neuropathy with neuromyotonia, autosomal recessive (AR-CMT2). The proportion of patients without molecular diagnosis is similar to main European series.

Organ donation consanguinity or universality.

PubMed

Kishore, R R

1996-01-01

1. Neither the "Diseased Persons" nor the "Genetic Relations" provide an answer to "trading" in human body parts. 2. Live human body constitutes a vital source of supply of organs and tissues and the possibilities of optimum utilisation should be explored. 3. There is no scope for dogmatic postures and open-mindedness should be the approach while dealing with the issue of Organ Transplantation. 4. Society owes a duty to save the file of a dying man and in the event of failure to do so, it is absolutely immoral to interfere with his own arrangements by making unrealistic laws. No immorality is involved if an individual disposes of his spare body parts for a valid consideration to a needy person. 5. The scarcity needs to be urgently overcome otherwise unwarranted trade and crime are liable to thrive. 6. Families are not unconnected or antagonistic fragments of humanity. After thousands of years of continuous efforts the individuals on this earth have attained the stage of organic and functional integration. Atomisation of society on the basis of consanguineous proximities amounts to reversing this holistic trend. Organ transplantation is a functional expression of a highly evolved pursuit with inherent and intimate interaction in the form of organic exchange at the individual level, independent of consanguineous inducements or motivations. As such there is absolutely no scope for restricting organ donations by strangers. 7. Commercialisation should be curbed by making the enforcement agencies more efficient and not by depriving a needy person of his genuine requirements. Legislative craftsmanship lies in providing an answer without curtailing the freedom of the people.

Efficiency of allogeneic hematopoietic SCT from HLA fully-matched non-sibling relatives: a new prospect of exploiting extended family search.

PubMed

Hamidieh, A A; Dehaghi, M Ostadali; Paragomi, P; Navaei, S; Jalali, A; Eslami, G Ghazizadeh; Behfar, M; Ghavamzadeh, A

2015-04-01

The best donors for hematopoietic SCT (HSCT) are fully-matched siblings. In patients without fully-matched siblings, HLA registries or cord blood banks are alternative strategies with some restrictions. Owing to the high rate of consanguineous marriage in our country, between 2006 and 2013, extended family searches were undertaken in Hematology-Oncology Research Center and Stem Cell Transplantation (HORCSCT), Tehran, Iran, in 523 HSCT candidates with parental consanguinity and no available HLA identical sibling. Fully-matched other-relative donors were found for 109 cases. We retrospectively studied the HSCT outcome in these patients. Median time to neutrophil engraftment was 13 days (range: 9-31days). In 83 patients, full chimerism and in 17 patients, mixed chimerism was achieved. Acute GvHD (aGvHD) grade II-IV appeared in 36 patients (33%). The frequency of aGvHD development in various familial subgroups was NS. Five patients expired before day+100. In the surviving 104 cases, chronic GvHD developed in 20 patients (19.2%). The distantly related subgroup had significantly a higher rate of cGvHD (P=0.04). The 2-year OS and disease-free survival (DFS) were 76.7±4.5% and 71.7±4.7%, respectively. No significant difference in OS (P=0.30) and DFS (P=0.80) was unraveled between various familial relationships. Our considerable rate of fully-matched non-sibling family members and the favorable outcome support the rationale for extended family search in regions where consanguineous marriage is widely practiced.

Socio-demographic and consanguinity risk factors associated with low birthweight.

PubMed

Bener, Abdulbari; Saleh, Najah Mohammed; Salameh, Khalil Mohd Khalil; Basha, Basma; Joseph, Sharen; Al Buz, Rama

2013-05-01

To examine socio-demographic and biological risk factors associated with mothers giving birth to a low birthweight newborn among Arab women in Qatar. The case-control study was conducted at two main tertiary hospitals in Qatar in which participants were prospectively identified from January 2010 to April 2011. Data were collected by survey on maternal ethnicity, age, education, socioeconomic status, body mass index, consanguinity and gestational age. A total of 16,500 newborns were screened for low birthweight. A total of 863 mothers of low birthweight cases and an equal number of mothers of normal-weight babies were studied. Qatari mothers were found to be 1.2 times as likely to have a low birthweight (< 2500g) newborn compared to other Arab women (p < 0.057). Mothers with a primary school education were 1.6 times as likely as university educated mothers to have a low birthweight newborn (p < 0.006). Likewise, obese mothers were 1.5 times as likely as their normal-weight counterparts (p < 0.009). Consanguineous couples who were first-degree cousins were 1.9 times as likely as non-related couples to have a low birthweight newborn (p < 0.001). Newborns with a gestational age of < 37 weeks were 19.6 times as likely as those > or = 37 weeks to have a low birthweight (p < 0.001). The majority of the risk factors associated with low birthweight were modifiable. Health education campaigns need to target the most vulnerable groups to reduce the rates of low birthweight among Arabs in Qatar.

Genomic Runs of Homozygosity Record Population History and Consanguinity

PubMed Central

Kirin, Mirna; McQuillan, Ruth; Franklin, Christopher S.; Campbell, Harry; McKeigue, Paul M.; Wilson, James F.

2010-01-01

The human genome is characterised by many runs of homozygous genotypes, where identical haplotypes were inherited from each parent. The length of each run is determined partly by the number of generations since the common ancestor: offspring of cousin marriages have long runs of homozygosity (ROH), while the numerous shorter tracts relate to shared ancestry tens and hundreds of generations ago. Human populations have experienced a wide range of demographic histories and hold diverse cultural attitudes to consanguinity. In a global population dataset, genome-wide analysis of long and shorter ROH allows categorisation of the mainly indigenous populations sampled here into four major groups in which the majority of the population are inferred to have: (a) recent parental relatedness (south and west Asians); (b) shared parental ancestry arising hundreds to thousands of years ago through long term isolation and restricted effective population size (Ne), but little recent inbreeding (Oceanians); (c) both ancient and recent parental relatedness (Native Americans); and (d) only the background level of shared ancestry relating to continental Ne (predominantly urban Europeans and East Asians; lowest of all in sub-Saharan African agriculturalists), and the occasional cryptically inbred individual. Moreover, individuals can be positioned along axes representing this demographic historic space. Long runs of homozygosity are therefore a globally widespread and under-appreciated characteristic of our genomes, which record past consanguinity and population isolation and provide a distinctive record of the demographic history of an individual's ancestors. Individual ROH measures will also allow quantification of the disease risk arising from polygenic recessive effects. PMID:21085596

A SIGMAR1 splice-site mutation causes distal hereditary motor neuropathy.

PubMed

Li, Xiaobo; Hu, Zhengmao; Liu, Lei; Xie, Yongzhi; Zhan, Yajing; Zi, Xiaohong; Wang, Junling; Wu, Lixiang; Xia, Kun; Tang, Beisha; Zhang, Ruxu

2015-06-16

To identify the underlying genetic cause in a consanguineous Chinese family segregating distal hereditary motor neuropathy (dHMN) in an autosomal recessive pattern. We used whole-exome sequencing and homozygosity mapping to detect the genetic variant in 2 affected individuals of the consanguineous Chinese family with dHMN. RNA analysis of peripheral blood leukocytes and immunofluorescence and immunoblotting of stable cell lines were performed to support the pathogenicity of the identified mutation. We identified 3 shared novel homozygous variants in 3 shared homozygous regions of the affected individuals. Sequencing of these 3 variants in family members revealed the c.151+1G>T mutation in SIGMAR1 gene, which located in homozygous region spanning approximately 5.3 Mb at chromosome 9p13.1-p13.3, segregated with the dHMN phenotype. The mutation causes an alternative splicing event and generates a transcript variant with an in-frame deletion of 60 base pairs in exon 1 (c.92_151del), and results in an internally shortened protein σ1R(31_50del). The proteasomal inhibitor treatment increased the intracellular amount of σ1R(31_50del) and led to the formation of nuclear aggregates. Stable expressing σ1R(31_50del) induced endoplasmic reticulum stress and enhanced apoptosis. The homozygous c.151+1G>T mutation in SIGMAR1 caused a novel form of autosomal recessive dHMN in a Chinese consanguineous family. Endoplasmic reticulum stress may have a role in the pathogenesis of dHMN. © 2015 American Academy of Neurology.

Tuberous sclerosis complex: neonatal deaths in three of four children of consanguineous, non-expressing parents.

PubMed Central

Ruggieri, M; Carbonara, C; Magro, G; Migone, N; Grasso, S; Tinè, A; Pavone, L; Gomez, M R

1997-01-01

We describe here four sibs, born to consanguineous, healthy, asymptomatic parents. Three of these infants had a rapidly fatal course in the neonatal period; death was attributed to congestive heart failure with radiographic evidence of cardiomegaly in all of them. Necropsy was done in only one of them and showed the typical findings of tuberous sclerosis complex (TSC) in the central nervous system (CNS), kidneys, heart, and liver. The fourth sib, currently 2 years old, also has typical signs of TSC, namely hypomelanotic skin macules and calcified subependymal nodules. Both parents and a living maternal grandmother had appropriate examination, which included skin inspection under Wood's lamp, dental examination, fundoscopy, echocardiography, abdominal and renal ultrasound, and head CT and MRI scans, and no signs of TSC were found in either parent or in the only living grandmother. By history alone there is no other relative with signs or symptoms suggestive of TSC. Linkage analysis and loss of heterozygosity (LOH) investigations on a variety of lesions obtained from postmortem and tissue or blood specimens from all available family members studied failed to identify a microdeletion in the chromosomal regions where TSC genes are located. It is very unusual that in a single TSC family there were three consecutive neonatal deaths, and very likely that all had cardiac rhabdomyomas. Moreover, to the best of our knowledge, there are no previous reports of TSC families with more than one affected sib, unusually severe manifestations of the disease, and completely normal, consanguineous parents. Images PMID:9132502

APOA5 Q97X mutation identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family.

PubMed

Dussaillant, Catalina; Serrano, Valentina; Maiz, Alberto; Eyheramendy, Susana; Cataldo, Luis Rodrigo; Chavez, Matías; Smalley, Susan V; Fuentes, Marcela; Rigotti, Attilio; Rubio, Lorena; Lagos, Carlos F; Martinez, José Alfredo; Santos, José Luis

2012-11-15

Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family.

Colorectal Cancer Mortality in Relation to Glucose - 6 - Phosphate Dehydrogenase Deficiency and Consanguinity in Sardinia: A Spatial Correlation Analysis

PubMed

Pes, Giovanni Mario; Bassotti, Gabrio; Dore, Maria Pina

2017-09-27

Background: Colorectal cancer (CRC) is one of the most diffuse malignancy in the world. In Southern Europe, the incidence and prevalence are lower than in most Western countries, although some hot spots of increased risk are emerging. In Sardinia, the cancer rate has risen steeply in the last years. Among risk factors for CRC, genomic homozygosity has been postulated. Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been hypothesized to decrease CRC risk. In Sardinians, this disorder has a frequency of 12-24% due to selection by past malaria. In this study the relationship between mortality for CRC, homozygosity and G6PD deficiency was analysed using spatial analysis. Methods: The spatial association between CRC mortality and G6PD deficiency and homozygosity was assessed in the 377 municipalities of the island using ordinary least squares regression and geographically weighted regression. Results: A consanguinity index, available across all municipalities, was used as a proxy for homozygosity. A significant inverse correlation was found between CRC mortality and G6PD deficiency (ρ = ‒0.216; p = 0.002) whereas no association was found for consanguinity (ρ = ‒0.077; p = 0.498). The geographical map of CRC mortality showed a significant clustering in mountain areas compared to the population living in lowlands, whereas hot spot areas of G6PD deficiency were observed on the south-western side of Sardinia. Conclusions: These results indicate that G6PD deficiency might contribute to reduce colon carcinogenesis, and is in line with in vitro and in vivo studies. Creative Commons Attribution License

Family relationship, water contact and occurrence of Buruli ulcer in Benin.

PubMed

Sopoh, Ghislain Emmanuel; Barogui, Yves Thierry; Johnson, Roch Christian; Dossou, Ange Dodji; Makoutodé, Michel; Anagonou, Sévérin Y; Kestens, Luc; Portaels, Françoise

2010-07-13

Mycobacterium ulcerans disease (Buruli ulcer) is the most widespread mycobacterial disease in the world after leprosy and tuberculosis. How M. ulcerans is introduced into the skin of humans remains unclear, but it appears that individuals living in the same environment may have different susceptibilities. This study aims to determine whether frequent contacts with natural water sources, family relationship or the practice of consanguineous marriages are associated with the occurrence of Buruli ulcer (BU). Case control study. Department of Atlantique, Benin. BU-confirmed cases that were diagnosed and followed up at the BU detection and treatment center (CDTUB) of Allada (Department of the Atlantique, Benin) during the period from January 1st, 2006, to June 30th, 2008, with three matched controls (persons who had no signs or symptoms of active or inactive BU) for age, gender and village of residence per case. Contact with natural water sources, BU history in the family and the practice of consanguineous marriages. A total of 416 participants were included in this study, including 104 cases and 312 controls. BU history in the family (p<0.001), adjusted by daily contact with a natural water source (p = 0.007), was significantly associated with higher odds of having BU (OR; 95% CI = 5.5; 3.0-10.0). The practice of consanguineous marriage was not associated with the occurrence of BU (p = 0.40). Mendelian disorders could explain this finding, which may influence individual susceptibility by impairing immunity. This study suggests that a combination of genetic factors and behavioral risk factors may increase the susceptibility for developing BU.

Primary Immunodeficiency Diseases in Highly Consanguineous Populations from Middle East and North Africa: Epidemiology, Diagnosis, and Care

PubMed Central

Al-Mousa, Hamoud; Al-Saud, Bandar

2017-01-01

Middle East and North Africa region (MENA)1 populations are of different ethnic origins. Consanguineous marriages are common practice with an overall incidence ranging between 20 and 50%. Primary immunodeficiency diseases (PIDs) are a group of heterogeneous genetic disorders caused by defects in the immune system that predisposes patients to recurrent infections, autoimmune diseases, and malignancies. PIDs are more common in areas with high rates of consanguineous marriage since most have an autosomal recessive mode of inheritance. Studies of PIDs in the region had contributed into the discovery and the understanding of several novel immunodeficiency disorders. Few MENA countries have established national registries that helped in estimating the prevalence and defining common PID phenotypes. Available reports from those registries suggest a predominance of combined immunodeficiency disorders in comparison to antibody deficiencies seen in other populations. Access to a comprehensive clinical immunology management services is limited in most MENA countries. Few countries had established advanced clinical immunology service, capable to provide extensive genetic testing and stem cell transplantation for various immunodeficiency disorders. Newborn screening for PIDs is an essential need in this population considering the high incidence of illness and can be implemented and incorporated into existing newborn screening programs in some MENA countries. Increased awareness, subspecialty training in clinical immunology, and establishing collaborating research centers are necessary to improve patient care. In this review, we highlight some of the available epidemiological data, challenges in establishing diagnosis, and available therapy for PID patients in the region. PMID:28694805

A missense mutation in the CRBN gene that segregates with intellectual disability and self-mutilating behaviour in a consanguineous Saudi family.

PubMed

Sheereen, Atia; Alaamery, Manal; Bawazeer, Shahad; Al Yafee, Yusra; Massadeh, Salam; Eyaid, Wafaa

2017-04-01

Autosomal-recessive non-syndromic intellectual disability (ARNS-ID) is an aetiologically heterogeneous disorder. Although little is known about the function of human cereblon (CRBN), its relationship to mild cognitive deficits suggests that it is involved in the basic processes of human memory and learning. We aim to identify the genetic cause of intellectual disability and self-mutilation in a consanguineous Saudi family with five affected members. Clinical whole-exome sequencing was performed on the proband patient, and Sanger sequencing was done to validate and confirm segregation in other family members. A missense variant (c. 1171T>C) in the CRBN gene was identified in five individuals with severe intellectual disability (ID) in a consanguineous Saudi family. The homozygous variant was co-segregating in the family with the phenotype of severe ID, seizures and self-mutilating behaviour. The missense mutation (p.C391R) reported here results in the replacement of a conserved cysteine residue by an arginine in the CULT (cereblon domain of unknown activity, binding cellular ligands and thalidomide) domain of CRBN, which contains a zinc-binding site. These findings thus contribute to a growing list of ID disorders caused by CRBN mutations, broaden the spectrum of phenotypes attributable to ARNS-ID and provide new insight into genotype-phenotype correlations between CRBN mutations and the aetiology of ARNS-ID. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Age-standardized Incidence Rates for Leukemia Associated with Consanguineous Marriages in 68 Countries, an Ecological Study

PubMed Central

Saadat, Mostafa

2015-01-01

Consanguineous marriage that defines as a union between biologically related persons has a variety of known deleterious correlations with factors that affect public health within human populations. To investigate the association between the mean of inbreeding coefficient (α) and incidence of leukemia, the present ecological study on 68 countries was carried out. Statistical analysis showed that the age-standardized incidence rate of leukemia positively correlated with log10GNI per capita (r=0.699, df=66, P<0.001) and negatively correlated with log10α (r=−0.609, df=66, P<0.001). Controlling log10GNI per capita, a significant negative correlation between log10α and the age-standardized incidence rate of leukemia was observed (r=−0.392, df=65, P=0.001). The countries were stratified according to their annual GNI per capita, low and high-income countries with GNI per capita less than and more than 10,000$, respectively. Statistical analysis showed that in high-income countries, after controlling for log10GNI per capita, the correlation between the age-standardized incidence rate of leukemia and log10α was still significant (r=−0.600, df=36, P<0.001). It should be noted that there was no significant association between the age-standardized mortality rate due to leukemia and log10α (P>0.05). The present finding indicates that the rate of leukemia, age-standardized for incidence, is lower in countries with a high prevalence of consanguineous marriages. PMID:25960855

APOA5 Q97X Mutation Identified through homozygosity mapping causes severe hypertriglyceridemia in a Chilean consanguineous family

PubMed Central

2012-01-01

Background Severe hypertriglyceridemia (HTG) has been linked to defects in LPL, APOC2, APOA5, LMF1 and GBIHBP1 genes. However, a number of severe HTG cases are probably caused by as yet unidentified mutations. Very high triglyceride plasma levels (>112 mmol/L at diagnosis) were found in two sisters of a Chilean consanguineous family, which is strongly suggestive of a recessive highly penetrant mutation. The aim of this study was to determine the genetic locus responsible for the severe HTG in this family. Methods We carried out a genome-wide linkage study with nearly 300,000 biallelic markers (Illumina Human CytoSNP-12 panel). Using the homozygosity mapping strategy, we searched for chromosome regions with excess of homozygous genotypes in the affected cases compared to non-affected relatives. Results A large homozygous segment was found in the long arm of chromosome 11, with more than 2,500 consecutive homozygous SNP shared by the proband with her affected sister, and containing the APOA5/A4/C3/A1 cluster. Direct sequencing of the APOA5 gene revealed a known homozygous nonsense Q97X mutation (p.Gln97Ter) found in both affected sisters but not in non-affected relatives nor in a sample of unrelated controls. Conclusion The Q97X mutation of the APOA5 gene in homozygous status is responsible for the severe hypertriglyceridemia in this family. We have shown that homozygosity mapping correctly pinpointed the genomic region containing the gene responsible for severe hypertriglyceridemia in this consanguineous Chilean family. PMID:23151256

Incidence, types, geographical distribution, and risk factors of congenital anomalies in Al-Ramadi Maternity and Children's Teaching Hospital, Western Iraq.

PubMed

Al-Ani, Zaid R; Al-Haj, Shaker A; Al-Ani, Muhammad M; Al-Dulaimy, Khamees M; Al-Maraie, Ayad Kh; Al-Ubaidi, Belal Kh

2012-09-01

To study the incidence, types, geographical distribution, and risk factors of congenital anomalies (CAs) in a teaching hospital. A total of 5864 neonates were examined for CAs between October 2010 and October 2011 in Al-Ramadi Maternity and Children's Teaching Hospital, Al-Ramadi, Western Iraq. Data include: neonate's name, gender, weight, and type of CAs, mother's age, residence, education, parity, consanguinity, smoking, illness, drugs, and ultrasound (U/S) results, father's age and smoking, and family recurrence of CAs. For every case, 2 controls were selected. Types and incidence of CAs was calculated. Odds ratio and confidence interval was utilized for risk factors evaluation. Overall CA incidences were 40.5/1000 for total births, 40.8/1000 live births, and 270.0/1000 for stillbirths. Twenty percent of CAs was found as multiple, 80% single, 63.8% major, and 36.2% minor. The cardiovascular system was found most affected, followed by genito-urinary system. Low birth weight, male gender, maternal smoking, consanguinity, parity, and CAs family recurrence were found to be significant risk factors, and oligohydramnios, polyhydramnios, and positive CAs by U/S, found as significant co-factors associated with CAs, while parental age, and maternal education were not considered risk factors. Although the incidence of CAs was lower than the Al-Fallujah rate, it is still higher than many developed and developing countries. Amniotic fluid volume changes in U/S may hide an ominous CA, and maternal smoking exposure during pregnancy and consanguinity may expose the family to a congenitally anomalous delivery.

Nonsyndromic retinitis pigmentosa is highly prevalent in the Jerusalem region with a high frequency of founder mutations.

PubMed

Sharon, Dror; Banin, Eyal

2015-01-01

Nonsyndromic retinitis pigmentosa (RP) is the most common inherited retinal degeneration, and prevalence of the disease has been reported in populations of American and European origin with a relatively low consanguinity rate. Our aim was to determine the prevalence of nonsyndromic RP in the Jerusalem region, which has a population of about 1 million individuals with a high rate of consanguinity. The patients' clinical data included eye exam findings (visual acuity, anterior segment, and funduscopy) as well as electroretinographic (ERG) testing results under scotopic and photopic conditions. Mutation analysis on a subgroup of patients was performed mainly with candidate gene analysis and homozygosity mapping. We evaluated the medical records of patients with degenerative retinal diseases residing in the Jerusalem region who were examined over the past 20 years in a large tertiary medical center. A total of 453 individuals affected with nonsyndromic RP were diagnosed at our center, according to funduscopic findings and ERG testing. Based on the estimated population size of 945,000 individuals who reside in the vicinity of Jerusalem, the prevalence of nonsyndromic RP in this region is 1:2,086. The prevalence of RP was higher among Arab Muslims (1:1,798) compared to Jews (1:2,230), mainly due to consanguineous marriages that are more common in the Arab Muslim population. To identify the genetic causes of RP in our cohort, we recruited 383 patients from 183 different families for genetic analysis: 70 with autosomal recessive (AR) inheritance, 15 with autosomal dominant, 86 isolate cases, and 12 with an X-linked inheritance pattern. In 64 (35%) of the families, we identified the genetic cause of the disease, and we revised the inheritance pattern of 20 isolate cases to the AR pattern; 49% of the families in our cohort had AR inheritance. Interestingly, in 42 (66%) of the genetically identified families, the cause of disease was a founder mutation. Previous studies showed an approximate prevalence of 1:5,260 on average for nonsyndromic RP in American and European populations. We show that the prevalence in the vicinity of Jerusalem is two-and-a-half times higher due to a high rate of consanguinity and highly prevalent founder mutations within the historically semi-isolated subpopulations we serve.

Nonsyndromic retinitis pigmentosa is highly prevalent in the Jerusalem region with a high frequency of founder mutations

PubMed Central

Banin, Eyal

2015-01-01

Purpose Nonsyndromic retinitis pigmentosa (RP) is the most common inherited retinal degeneration, and prevalence of the disease has been reported in populations of American and European origin with a relatively low consanguinity rate. Our aim was to determine the prevalence of nonsyndromic RP in the Jerusalem region, which has a population of about 1 million individuals with a high rate of consanguinity. Methods The patients’ clinical data included eye exam findings (visual acuity, anterior segment, and funduscopy) as well as electroretinographic (ERG) testing results under scotopic and photopic conditions. Mutation analysis on a subgroup of patients was performed mainly with candidate gene analysis and homozygosity mapping. Results We evaluated the medical records of patients with degenerative retinal diseases residing in the Jerusalem region who were examined over the past 20 years in a large tertiary medical center. A total of 453 individuals affected with nonsyndromic RP were diagnosed at our center, according to funduscopic findings and ERG testing. Based on the estimated population size of 945,000 individuals who reside in the vicinity of Jerusalem, the prevalence of nonsyndromic RP in this region is 1:2,086. The prevalence of RP was higher among Arab Muslims (1:1,798) compared to Jews (1:2,230), mainly due to consanguineous marriages that are more common in the Arab Muslim population. To identify the genetic causes of RP in our cohort, we recruited 383 patients from 183 different families for genetic analysis: 70 with autosomal recessive (AR) inheritance, 15 with autosomal dominant, 86 isolate cases, and 12 with an X-linked inheritance pattern. In 64 (35%) of the families, we identified the genetic cause of the disease, and we revised the inheritance pattern of 20 isolate cases to the AR pattern; 49% of the families in our cohort had AR inheritance. Interestingly, in 42 (66%) of the genetically identified families, the cause of disease was a founder mutation. Conclusions Previous studies showed an approximate prevalence of 1:5,260 on average for nonsyndromic RP in American and European populations. We show that the prevalence in the vicinity of Jerusalem is two-and-a-half times higher due to a high rate of consanguinity and highly prevalent founder mutations within the historically semi-isolated subpopulations we serve. PMID:26261414

Short stature, brachydactyly, and Peters' anomaly (Peters'-plus syndrome): confirmation of autosomal recessive inheritance.

PubMed Central

de Almeida, J C; Reis, D F; Llerena Júnior, J; Barbosa Neto, J; Pontes, R L; Middleton, S; Telles, L F

1991-01-01

Two sibs with a phenotype characterised by short stature, brachydactyly, and ocular anomalies (Peters' anomaly) are reported (Peters'-plus syndrome). The consanguinity is in agreement with the proposed autosomal recessive inheritance. Images PMID:1856836

Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening

PubMed Central

Chen, Jianjun; Wang, Qiwei; Cabrera, Patricia E.; Zhong, Zilin; Sun, Wenmin; Jiao, Xiaodong; Chen, Yabin; Govindarajan, Gowthaman; Naeem, Muhammad Asif; Khan, Shaheen N.; Ali, Muhammad Hassaan; Assir, Muhammad Zaman; Rahman, Fawad Ur; Qazi, Zaheeruddin A.; Riazuddin, Sheikh; Akram, Javed; Riazuddin, S. Amer; Hejtmancik, J. Fielding

2017-01-01

Purpose To identify the genetic origins of autosomal recessive congenital cataracts (arCC) in the Pakistani population. Methods Based on the hypothesis that most arCC patients in consanguineous families in the Punjab areas of Pakistan should be homozygous for causative mutations, affected individuals were screened for homozygosity of nearby highly informative microsatellite markers and then screened for pathogenic mutations by DNA sequencing. A total of 83 unmapped consanguineous families were screened for mutations in 33 known candidate genes. Results Patients in 32 arCC families were homozygous for markers near at least 1 of the 33 known CC genes. Sequencing the included genes revealed homozygous cosegregating sequence changes in 10 families, 2 of which had the same variation. These included five missense, one nonsense, two frame shift, and one splice site mutations, eight of which were novel, in EPHA2, FOXE3, FYCO1, TDRD7, MIP, GALK1, and CRYBA4. Conclusions The above results confirm the usefulness of homozygosity mapping for identifying genetic defects underlying autosomal recessive disorders in consanguineous families. In our ongoing study of arCC in Pakistan, including 83 arCC families that underwent homozygosity mapping, 3 mapped using genome-wide linkage analysis in unpublished data, and 30 previously reported families, mutations were detected in approximately 37.1% (43/116) of all families studied, suggesting that additional genes might be responsible in the remaining families. The most commonly mutated gene was FYCO1 (14%), followed by CRYBB3 (5.2%), GALK1 (3.5%), and EPHA2 (2.6%). This provides the first comprehensive description of the genetic architecture of arCC in the Pakistani population. PMID:28418495

Incidence of cleft Lip and palate in the state of Andhra Pradesh, South India

PubMed Central

Reddy, Srinivas Gosla; Reddy, Rajgopal R.; Bronkhorst, Ewald M.; Prasad, Rajendra; Ettema, Anke M.; Sailer, Hermann F.; Bergé, Stefaan J.

2010-01-01

Objective: To assess the incidence of cleft lip and palate defects in the state of Andhra Pradesh, India. Design Setting: The study was conducted in 2001 in the state of Andhra Pradesh, India. The state has a population of 76 million. Three districts, Cuddapah, Medak and Krishna, were identified for this study owing to their diversity. They were urban, semi-urban and rural, respectively. Literacy rates and consanguinity of the parents was elicited and was compared to national averages to find correlations to cleft births. Type and side of cleft were recorded to compare with other studies around the world and other parts of India. Results: The birth rate of clefts was found to be 1.09 for every 1000 live births. This study found that 65% of the children born with clefts were males. The distribution of the type of cleft showed 33% had CL, 64% had CLP, 2% had CP and 1% had rare craniofacial clefts. Unilateral cleft lips were found in 79% of the patients. Of the unilateral cleft lips 64% were left sided. There was a significant correlation of children with clefts being born to parents who shared a consanguineous relationship and those who were illiterate with the odds ratio between 5.25 and 7.21 for consanguinity and between 1.55 and 5.85 for illiteracy, respectively. Conclusion: The birth rate of clefts was found to be comparable with other Asian studies, but lower than found in other studies in Caucasian populations and higher than in African populations. The incidence was found to be similar to other studies done in other parts of India. The distribution over the various types of cleft was comparable to that found in other studies. PMID:21217978

A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family.

PubMed

Audo, Isabelle; Bujakowska, Kinga; Mohand-Saïd, Saddek; Tronche, Sophie; Lancelot, Marie-Elise; Antonio, Aline; Germain, Aurore; Lonjou, Christine; Carpentier, Wassila; Sahel, José-Alain; Bhattacharya, Shomi; Zeitz, Christina

2011-01-01

To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition. A detailed ophthalmic and auditory examination was performed on a Portuguese patient with severe autosomal recessive rod-cone dystrophy. Known genetic defects were excluded by performing autosomal recessive retinitis pigmentosa (arRP) genotyping microarray analysis and by Sanger sequencing of the coding exons and flanking intronic regions of eyes shut homolog-drosophila (EYS) and chromosome 2 open reading frame 71 (C2orf71). Subsequently, genome-wide homozygosity mapping was performed in DNA samples from available family members using a 700K single nucleotide polymorphism (SNP) microarray. Candidate genes present in the significantly large homozygous regions were screened for mutations using Sanger sequencing. The largest homozygous region (~11 Mb) in the affected family members was mapped to chromosome 9, which harbors deafness, autosomal recessive 31 (DFNB31; a gene previously associated with Usher syndrome). Mutation analysis of DFNB31 in the index patient identified a novel one-base-pair deletion (c.737delC), which is predicted to lead to a truncated protein (p.Pro246HisfsX13) and co-segregated with the disease in the family. Ophthalmic examination of the index patient and the affected siblings showed severe rod-cone dystrophy. Pure tone audiometry revealed a moderate hearing loss in the index patient, whereas the affected siblings were reported with more profound and early onset hearing impairment. We report a novel truncating mutation in DFNB31 associated with severe rod-cone dystrophy and varying degrees of hearing impairment in a consanguineous family of Portuguese origin. This is the second report of DFNB31 implication in Usher type 2.

Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia

PubMed Central

Makrythanasis, Periklis; Kato, Mitsuhiro; Zaki, Maha S.; Saitsu, Hirotomo; Nakamura, Kazuyuki; Santoni, Federico A.; Miyatake, Satoko; Nakashima, Mitsuko; Issa, Mahmoud Y.; Guipponi, Michel; Letourneau, Audrey; Logan, Clare V.; Roberts, Nicola; Parry, David A.; Johnson, Colin A.; Matsumoto, Naomichi; Hamamy, Hanan; Sheridan, Eamonn; Kinoshita, Taroh; Antonarakis, Stylianos E.; Murakami, Yoshiko

2016-01-01

Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors >150 various proteins to the cell surface. At least 27 genes are involved in biosynthesis and transport of GPI-anchored proteins (GPI-APs). To date, mutations in 13 of these genes are known to cause inherited GPI deficiencies (IGDs), and all are inherited as recessive traits. IGDs mainly manifest as intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms are caused by the decreased surface expression of GPI-APs or by structural abnormalities of GPI. Here, we present five affected individuals (from two consanguineous families from Egypt and Pakistan and one non-consanguineous family from Japan) who show intellectual disability, hypotonia, and early-onset seizures. We identified pathogenic variants in PIGG, a gene in the GPI pathway. In the consanguineous families, homozygous variants c.928C>T (p.Gln310∗) and c.2261+1G>C were found, whereas the Japanese individual was compound heterozygous for c.2005C>T (p.Arg669Cys) and a 2.4 Mb deletion involving PIGG. PIGG is the enzyme that modifies the second mannose with ethanolamine phosphate, which is removed soon after GPI is attached to the protein. Physiological significance of this transient modification has been unclear. Using B lymphoblasts from affected individuals of the Egyptian and Japanese families, we revealed that PIGG activity was almost completely abolished; however, the GPI-APs had normal surface levels and normal structure, indicating that the pathogenesis of PIGG deficiency is not yet fully understood. The discovery of pathogenic variants in PIGG expands the spectrum of IGDs and further enhances our understanding of this etiopathogenic class of intellectual disability. PMID:26996948

Prevalence and risk factors for neurological disorders in children aged 6 months to 2 years in northern India.

PubMed

Kumar, Rashmi; Bhave, Anupama; Bhargava, Roli; Agarwal, Girdhar G

2013-04-01

To study prevalence and risk factors for neurological disorders--epilepsy, global developmental delay, and motor, vision, and hearing defects--in children aged 6 months to 2 years in northern India. A two-stage community survey for neurological disorders was conducted in rural and urban areas of Lucknow. After initial screening with a new instrument, the Lucknow Neurodevelopment Screen, screen positives and a random proportion of screen negatives were validated using predefined criteria. Prevalence was calculated by weighted estimates. Demographic, socio-economic, and medical risk factors were compared between validated children who were positive and negative for neurological disorders by univariate and logistic regression analysis. Of 4801 children screened (mean age [SD] 15.32mo [5.96]; 2542 males, 2259 females), 196 were positive; 190 screen positives and 269 screen negatives were validated. Prevalence of neurological disorders was 27.92 per 1000 (weighted 95% confidence interval 12.24-43.60). Significant risk factors (p≤0.01) for neurological disorders were higher age in months (p=0.010), lower mean number of appliances in the household (p=0.001), consanguineous marriage of parents (p=0.010), family history of neurological disorder (p=0.001), and infants born exceptionally small (parental description; p=0.009). On logistic regression, the final model included age (p=0.0193), number of appliances (p=0.0161), delayed cry at birth (p=0.0270), postneonatal meningoencephalitis (p=0.0549), and consanguinity (p=0.0801). Perinatal factors, lower socio-economic status, and consanguinity emerged as predictors of neurological disorders. These factors are largely modifiable. © The Authors. Developmental Medicine & Child Neurology © 2013 Mac Keith Press.

Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia.

PubMed

Makrythanasis, Periklis; Kato, Mitsuhiro; Zaki, Maha S; Saitsu, Hirotomo; Nakamura, Kazuyuki; Santoni, Federico A; Miyatake, Satoko; Nakashima, Mitsuko; Issa, Mahmoud Y; Guipponi, Michel; Letourneau, Audrey; Logan, Clare V; Roberts, Nicola; Parry, David A; Johnson, Colin A; Matsumoto, Naomichi; Hamamy, Hanan; Sheridan, Eamonn; Kinoshita, Taroh; Antonarakis, Stylianos E; Murakami, Yoshiko

2016-04-07

Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors >150 various proteins to the cell surface. At least 27 genes are involved in biosynthesis and transport of GPI-anchored proteins (GPI-APs). To date, mutations in 13 of these genes are known to cause inherited GPI deficiencies (IGDs), and all are inherited as recessive traits. IGDs mainly manifest as intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms are caused by the decreased surface expression of GPI-APs or by structural abnormalities of GPI. Here, we present five affected individuals (from two consanguineous families from Egypt and Pakistan and one non-consanguineous family from Japan) who show intellectual disability, hypotonia, and early-onset seizures. We identified pathogenic variants in PIGG, a gene in the GPI pathway. In the consanguineous families, homozygous variants c.928C>T (p.Gln310(∗)) and c.2261+1G>C were found, whereas the Japanese individual was compound heterozygous for c.2005C>T (p.Arg669Cys) and a 2.4 Mb deletion involving PIGG. PIGG is the enzyme that modifies the second mannose with ethanolamine phosphate, which is removed soon after GPI is attached to the protein. Physiological significance of this transient modification has been unclear. Using B lymphoblasts from affected individuals of the Egyptian and Japanese families, we revealed that PIGG activity was almost completely abolished; however, the GPI-APs had normal surface levels and normal structure, indicating that the pathogenesis of PIGG deficiency is not yet fully understood. The discovery of pathogenic variants in PIGG expands the spectrum of IGDs and further enhances our understanding of this etiopathogenic class of intellectual disability. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Hereditary ectodermal dysplasia: A retrospective study

PubMed Central

More, Chandramani B.; Bhavsar, Khusbhu; Joshi, Jigar; Varma, Saurabh N.; Tailor, Mansi

2013-01-01

Background: Ectodermal dysplasia (ED) is a group of rare, inherited disorders characterized by sparse hair, missing teeth and inability to sweat. Objective: To review and analyze cases of ED with an emphasis on clinical manifestations and parent's marriage history. Methodology: The present retrospective study was conducted by assessing the clinical records of nineteen cases of ED, available in the archives of the department; for age, gender, family history of consanguineous marriage and clinical manifestations. Results: It was observed that ED was more prevalent in males, with a ratio of 1.7:1. The hypohydrotic type was more common (78.95%) than hydrotic type (21.05%). The marriage history of parents revealed that 66.67% had consanguineous marriage and had 68.42% offspring's affected with ED; whereas 33.33% had history of non-consanguineous marriage and had 31.58% offspring's affected with ED. The clinical manifestations observed were- dry skin(94.74%); scaly skin(42.11%); sparse hair on scalp, eyebrows and eyelashes(100%); frontal bossing(63.18%); saddle nose (57.89%); hypertelorism (47.37%); nail abnormality(52.63%); normal sweat glands(21.05%); abnormal sweat glands(78.95%); hypoplastic maxilla(52.63%); protuberant lips (57.89%); palmo-plantar keratosis(21.05%); wrinkled & hyper pigmented facial skin(84.21%); partial anodontia(94.74%); conical shaped teeth(84.21%); high arched palate(68.42%); thin alveolar bone(100.00%); taurodontism(21.05%) and cleft lip & cleft palate(05.26%). The number of teeth present in all the cases ranged from 0 to 19. Conclusion: ED patients suffer from social problems and poor psychological and physiological development as a result of unacceptable esthetics and abnormal function of orofacial structures. Oral rehabilitation thus becomes mandatory, although it is often difficult; particularly in pediatric patients. PMID:24082749

Risk factors for maternal anaemia and low birth weight in pregnant women living in rural India: a prospective cohort study.

PubMed

Ahankari, A S; Myles, P R; Dixit, J V; Tata, L J; Fogarty, A W

2017-10-01

The aim of this prospective study was to estimate the prevalence and risk factors for maternal anaemia and low birth weight (LBW) in pregnant women living in Maharashtra state, India. This is a prospective study. Women between 3 and 5 months of pregnancy were recruited from 34 villages based in Maharashtra state. Baseline data collection, anthropometric measurements and blood investigations were performed. Participants were followed-up to record birth weight. In total, 303 women were eligible, and 287 (95%) provided data. 77% were anaemic, defined as haemoglobin less than 11.0 g/dl at the time of recruitment, with a mean corpuscular volume of 80.5 fl/cell (standard deviation: 7.22, range: 53.4-93.8). The increased risk of anaemia was seen in women with consanguineous marriages (odds ratio [OR]: 2.41, 95% confidence interval [CI]: 1.16-5.01, P = 0.01) after adjustment for potential confounding factors. Postdelivery data from full-term singleton live births demonstrated a 7% prevalence of LBW. Consanguineous marriage was a major risk factor for LBW (OR: 4.10, 95% CI: 1.25-13.41, P = 0.02). The presence of maternal anaemia during 3-5 months of pregnancy was associated with lower risk of LBW (unadjusted OR: 0.34, 95% CI: 0.13-0.92, P = 0.03). About 30% of our study participants were in a consanguineous marriage, which was identified as a potentially avoidable risk factor for both anaemia and LBW. Copyright © 2017 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

Genetic assessment and folate receptor autoantibodies in infantile-onset cerebral folate deficiency (CFD) syndrome.

PubMed

Ramaekers, V Th; Segers, K; Sequeira, J M; Koenig, M; Van Maldergem, L; Bours, V; Kornak, U; Quadros, E V

2018-05-01

Cerebral folate deficiency (CFD) syndromes are defined as neuro-psychiatric conditions with low CSF folate and attributed to different causes such as autoantibodies against the folate receptor-alpha (FR) protein that can block folate transport across the choroid plexus, FOLR1 gene mutations or mitochondrial disorders. High-dose folinic acid treatment restores many neurologic deficits. Among 36 patients from 33 families the infantile-onset CFD syndrome was diagnosed based on typical clinical features and low CSF folate. All parents were healthy. Three families had 2 affected siblings, while parents from 4 families were first cousins. We analysed serum FR autoantibodies and the FOLR1 and FOLR2 genes. Among three consanguineous families homozygosity mapping attempted to identify a monogenetic cause. Whole exome sequencing (WES) was performed in the fourth consanguineous family, where two siblings also suffered from polyneuropathy as an atypical finding. Boys (72%) outnumbered girls (28%). Most patients (89%) had serum FR autoantibodies fluctuating over 5-6 weeks. Two children had a genetic FOLR1 variant without pathological significance. Homozygosity mapping failed to detect a single autosomal recessive gene. WES revealed an autosomal recessive polynucleotide kinase 3´phosphatase (PNKP) gene abnormality in the siblings with polyneuropathy. Infantile-onset CFD was characterized by serum FR autoantibodies as its predominant pathology whereas pathogenic FOLR1 gene mutations were absent. Homozygosity mapping excluded autosomal recessive inheritance of any single responsible gene. WES in one consanguineous family identified a PNKP gene abnormality that explained the polyneuropathy and also its contribution to the infantile CFD syndrome because the PNKP gene plays a dual role in both neurodevelopment and immune-regulatory function. Further research for candidate genes predisposing to FRα-autoimmunity is suggested to include X-chromosomal and non-coding DNA regions. Copyright © 2018 Elsevier Inc. All rights reserved.

Whole-exome sequencing identifies novel homozygous mutation in NPAS2 in family with nonobstructive azoospermia.

PubMed

Ramasamy, Ranjith; Bakırcıoğlu, M Emre; Cengiz, Cenk; Karaca, Ender; Scovell, Jason; Jhangiani, Shalini N; Akdemir, Zeynep C; Bainbridge, Matthew; Yu, Yao; Huff, Chad; Gibbs, Richard A; Lupski, James R; Lamb, Dolores J

2015-08-01

To investigate the genetic cause of nonobstructive azoospermia (NOA) in a consanguineous Turkish family through homozygosity mapping followed by targeted exon/whole-exome sequencing to identify genetic variations. Whole-exome sequencing (WES). Research laboratory. Two siblings in a consanguineous family with NOA. Validating all variants passing filter criteria with Sanger sequencing to confirm familial segregation and absence in the control population. Discovery of a mutation that could potentially cause NOA. A novel nonsynonymous mutation in the neuronal PAS-2 domain (NPAS2) was identified in a consanguineous family from Turkey. This mutation in exon 14 (chr2: 101592000 C>G) of NPAS2 is likely a disease-causing mutation as it is predicted to be damaging, it is a novel variant, and it segregates with the disease. Family segregation of the variants showed the presence of the homozygous mutation in the three brothers with NOA and a heterozygous mutation in the mother as well as one brother and one sister who were both fertile. The mutation is not found in the single-nucleotide polymorphism database, the 1000 Genomes Project, the Baylor College of Medicine cohort of 500 Turkish patients (not a population-specific polymorphism), or the matching 50 fertile controls. With the use of WES we identified a novel homozygous mutation in NPAS2 as a likely disease-causing variant in a Turkish family diagnosed with NOA. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases for which conventional genetic approaches have previously failed to find a molecular diagnosis. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Temporal variation in the mating structure of Sanday, Orkney Islands.

PubMed

Brennan, E R; Relethford, J H

1983-01-01

Pedigree and vital statistics data from the population of Sanday, Orkney Islands, Scotland, were used to assess temporal changes in population structure. Secular trends in patterns of mate choice were analysed for three separate birth cohorts of spouses: 1855-1884, 1885-1924 and 1925-1964. The degree to which mating was random or assortative with respect to both genealogical and geographic distance was determined by comparing average characteristics of all potential mates of married males with those of actual wives. We integrated this procedure, originally developed by Dyke (1971), into a three-fold investigation of population structure: (1) comparison of random and non-random components of relatedness as measured from pedigree data; (2) an analysis of marital distance distributions for actual and potential mates of married males; and (3) the relationship between genealogical relatedness and geographic distance. As population size decreased from 1881 to the present, total kinship and spatial distances between spouses increased. Whereas the random component of relatedness increased over time, consanguinity avoidance was sufficient to decrease the total coefficient of kinship over time. Part of the increase in consanguinity avoidance was associated with isolate breakdown, as distances between island-born spouses, as well as the total amount of off-island migration, increased from the mid-nineteenth century to the present. Mate choice was influenced by geographic distance for all time periods, although this effect diminished over time. Since decreases in population size, concomitant with increases in consanguinity avoidance and community exogamy, have probably occurred quite frequently in small human populations, as well as in rural Western communities in the past century, observed secular trends illustrate the potential for change in population structure characteristic of isolate breakdown.

Inbreeding in Southeastern Spain : The Impact of Geography and Demography on Marital Mobility and Marital Distance Patterns (1900-1969).

PubMed

Calderón, R; Hernández, C L; García-Varela, G; Masciarelli, D; Cuesta, P

2018-03-01

In this paper, the structure of a southeastern Spanish population was studied for the first time with respect to its inbreeding patterns and its relationship with demographic and geographic factors. Data on consanguineous marriages (up to second cousins) from 1900 to 1969 were taken from ecclesiastic dispensations. Our results confirm that the patterns and trends of inbreeding in the study area are consistent with those previously observed in most non-Cantabrian Spanish populations. The rate of consanguineous marriages was apparently stable between 1900 and 1935 and then sharply decreased since 1940, which coincides with industrialization in Spain. A marked departure from Hardy-Weinberg expectations (0.25) in the ratio of first cousin (M22) to second cousin (M33) marriages in the study population (0.88) was observed. The high levels of endogamy (>80%) and its significant steadiness throughout the twentieth century is noteworthy. Accordingly, our results show that exogamous marriages were not only poorly represented but also that this reduced mobility (<6 km) suggests that the choice of a mate was preferentially local. We found higher mobility in M22 with respect to M33 cousin mating. The relationships between population size and consanguinity rates and inbreeding fit power-law distributions. A significant positive correlation was observed between inbreeding and elevation. Many Spanish populations have experienced a prolonged and considerable isolation across generations, which has led to high proportions of historical and local endogamy that is associated, in general, with high [Formula: see text] values. Thus, assessing genomic inbreeding using runs of homozygosity (ROH) in current Spanish populations could be an additional pertinent strategy for obtaining a more refined perspective regarding the population history inferred from the extent and frequency of ROH regions.

Clinical and molecular effect on offspring of a marriage of consanguineous spinocerebellar ataxia type 7 mutation carriers: a family case report

PubMed Central

Magaña, Jonathan J; Tapia-Guerrero, Yessica S; Velázquez-Pérez, Luis; Cruz-Mariño, Tania; Cerecedo-Zapata, Cesar M; Gómez, Rocío; Murillo-Melo, Nadia M; González-Piña, Rigoberto; Hernández-Hernández, Oscar; Cisneros, Bulmaro

2014-01-01

Spinocerebellar ataxia type 7 (SCA7) is a genetic disorder characterized by degeneration of the cerebellum, brainstem, and retina that is caused by abnormal expansion of a CAG repeat located in the ATXN7 gene encoding sequence on chromosome 3p21.1. Although SCA7 is an uncommon autosomal dominant ataxia, we previously found increased prevalence of the disease in a Southeastern Mexican population. In this study, we described to our knowledge for the first time a marriage of consanguineous SCA7 mutation carriers and their offspring effect. We characterized a severely affected infantile-onset female patient whose parents and two siblings exhibited no symptoms of the disease at time of diagnosis. A comprehensive clinical analysis of the proband showed a progressive cerebellar syndrome, including gait ataxia, movement disorders, and saccadic movements, as well as hyperreflexia, visual deterioration, urinary and cardiovascular dysfunction, and impaired nerve conduction. The SCA7 mutation was detected in the proband patient. Subsequently, genetic examination using four ATXN7 gene-linked markers (three centromeric microsatellite markers [D3S1228, D3S1287, and D3S3635] and an intragenic Single Nucleotide Polymorphism [SNP-3145G/A]) revealed that the proband descends from a couple of consanguineous SCA7 mutation carriers. Genotyping analysis demonstrated that all offspring inherited only one mutant allele, and that the severe infantile-onset phenotype is caused by germinal expansion (from 37 to 72 CAG repeats) of the paternal mutant allele. Interestingly, the couple also referred a miscarriage. Finally, we found no CAA interruptions in the ATXN7 gene CAG repeats tract in this family, which might explain, at least in part, the triplet instability in the proband. PMID:25664129

A Proper Perspective on the Twin Deficits

DTIC Science & Technology

1989-05-01

deficit twins, the relation between them, and their consanguine parentage. The trade deficit or, to be more accurate, the current account deficit, is...In general, there is a small negative, but statistically significant, relationship between the size of the federal deficit in one year and the

Diencephalic-Mesencephalic Junction Dysplasia: A Novel Recessive Brain Malformation

ERIC Educational Resources Information Center

Zaki, Maha S.; Saleem, Sahar N.; Dobyns, William B.; Barkovich, A. James; Bartsch, Hauke; Dale, Anders M.; Ashtari, Manzar; Akizu, Naiara; Gleeson, Joseph G.; Grijalvo-Perez, Ana Maria

2012-01-01

We describe six cases from three unrelated consanguineous Egyptian families with a novel characteristic brain malformation at the level of the diencephalic-mesencephalic junction. Brain magnetic resonance imaging demonstrated a dysplasia of the diencephalic-mesencephalic junction with a characteristic "butterfly"-like contour of the…

Retinal detachment and cataract, facial dysmorphism, generalized osteoporosis, immobile spine and platyspondyly in a consanguinous kindred--a possible new syndrome.

PubMed

Schmidt, H; Rudolph, G; Hergersberg, M; Schneider, K; Moradi, S; Meitinger, T

2001-02-01

We report on a consanguineous family with 6 children (out of 7) affected by a spondylo-ocular syndrome. Clinical features include cataract, loss of vision due to retinal detachment, facial dysmorphism, facial hypotonia, normal height with disproportional short trunk, immobile spine with thorakal kyphosis and reduced lumbal lordosis. On ophthalmological examination of the index patient, a dense cataract and complete retinal detachment could be detected on the right eye. On the left eye, an absent lens nucleus was found, but no retinal detachment. On radiological examination, there was generalized moderate osteoporosis; the spine showed marked platyspondyly and the bone age was advanced. On laboratory investigations, a normal excretion of amino acids, mucopolysaccharides and oligosaccharides could be found. The phenotypical spectrum observed in the 6 affected individuals was rather uniform. The karyotype was normal in all affected children. This hitherto undescribed combination of oculo-skeletal symptoms shows most resemblance with connective tissue disorders, suggesting a range of candidate genes for mutation analysis.

Microcephalic osteodysplastic primordial dwarfism Taybi-Linder type: report of four cases and review of the literature.

PubMed

Sigaudy, S; Toutain, A; Moncla, A; Fredouille, C; Bourlière, B; Ayme, S; Philip, N

1998-10-30

Microcephalic and osteodysplastic primordial dwarfism (MODP) types I, II, and III were defined by Majewski et al. in 1982. This group of syndromes was characterized by intrauterine growth retardation, microcephaly, and typical facial appearance with prominent nose and micrognathia. Type II was clearly different, both clinically and radiologically, whereas types I and III shared manifestations. Distinction between the latter two was established on the basis of subtle radiological differences. In 1967, Taybi and Linder described another syndrome with microcephalic congenital dwarfism. There is a consensus that MODP type I and III and Taybi-Linder cephaloskeletal dysplasia represent the same disorder. We report on four patients with MODP type Taybi-Linder syndromes, two of whom were born to unrelated but consanguineous parents, while the other two were sibs. Second-trimester prenatal detection by ultrasonography was possible in one case. Consanguinity in two cases and recurrence among sibs are consistent with autosomal recessive inheritance.

Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery.

PubMed

Scott, Eric M; Halees, Anason; Itan, Yuval; Spencer, Emily G; He, Yupeng; Azab, Mostafa Abdellateef; Gabriel, Stacey B; Belkadi, Aziz; Boisson, Bertrand; Abel, Laurent; Clark, Andrew G; Alkuraya, Fowzan S; Casanova, Jean-Laurent; Gleeson, Joseph G

2016-09-01

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Persian Gulf region, North Africa, and Central Asia, has resulted in an elevated burden of recessive disease. Here we generated a whole-exome GME variome from 1,111 unrelated subjects. We detected substantial diversity and admixture in continental and subregional populations, corresponding to several ancient founder populations with little evidence of bottlenecks. Measured consanguinity rates were an order of magnitude above those in other sampled populations, and the GME population exhibited an increased burden of runs of homozygosity (ROHs) but showed no evidence for reduced burden of deleterious variation due to classically theorized 'genetic purging'. Applying this database to unsolved recessive conditions in the GME population reduced the number of potential disease-causing variants by four- to sevenfold. These results show variegated genetic architecture in GME populations and support future human genetic discoveries in Mendelian and population genetics.

Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery

PubMed Central

Scott, Eric M.; Halees, Anason; Itan, Yuval; Spencer, Emily G.; He, Yupeng; Azab, Mostafa Abdellateef; Gabriel, Stacey B.; Belkadi, Aziz; Boisson, Bertrand; Abel, Laurent; Clark, Andrew G.; Alkuraya, Fowzan S.; Casanova, Jean-Laurent; Gleeson, Joseph G.

2016-01-01

The Greater Middle East (GME) has been a central hub of human migration and population admixture. The tradition of consanguinity, variably practiced in the Gulf region, North Africa, and Central Asia 1–3, has resulted in an elevated burden of recessive disease4. Here we generated a whole exome GME variome from 1,111 unrelated subjects. We detected substantial diversity from sub-geographies, continental and subregional admixture, several ancient founder populations with little evidence of bottlenecks. Measured consanguinity was an order-of-magnitude above that of other sampled populations, and included an increased burden of runs of homozygosity (ROH), but no evidence for reduced burden of deleterious variation due to classically theorized ‘genetic purging’. Applying this database to unsolved GME recessive conditions reduced the number of potential disease-causing variants by 4–7-fold. These results reveal the variegated GME genetic architecture and support future human genetic discoveries in Mendelian and population genetics. PMID:27428751

Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes.

PubMed

Prasad, M K; Laouina, S; El Alloussi, M; Dollfus, H; Bloch-Zupan, A

2016-12-01

Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis. © International & American Associations for Dental Research 2016.

Spatial analysis of the aptitude to late maternity on the island of Sardinia.

PubMed

Tentoni, Stefania; Lisa, Antonella; Fiorani, Ornella; Lipsi, Rosa Maria; Caselli, Graziella; Astolfi, Paola

2012-05-01

This study examines local heterogeneity in the aptitude of Sardinian mothers towards late reproduction, and explores its temporal persistence and association with both post-reproductive longevity and propensity to consanguineous marriage. Data on women's fertility from 1961 and birth records for 1980-1996 from Vital Statistics were analysed by means of the following indicators: the incidence of old mothers at last childbirth, female mortality (1980-2001) at 80 years of age and over and the proportion of consanguineous marriages (1930-1969). A variable kernel-smoothing method was used to create interpretable representations of the true spatial structure of the indicators, and to highlight areas of higher than expected intensity. In particular, an area of reproductive and post-reproductive longevity was identified where the traits combine with a higher tendency to relatedness. Intriguingly, this area corresponds approximately to the geographically and historically well defined central-eastern zone, which was the refuge of Sardinians during past invasions, and overlaps the Ogliastra region, which has been widely studied for its genetic homogeneity.

The Use of Dynamic Segment Scoring for Language-Independent Question Answering

DTIC Science & Technology

2001-01-01

initial window with one sentence is compared to scores corre- his/PRONOUN brother/ CONSANGUINITY like/SIMILARITY his/PRONOUN call/NOMENCLATURE he/PRONOUN...the query processing mod- ule. Using the differences between index numbers to specify phys- ical distance relationships among query keywords, we can

Splice-site mutations identified in PDE6A responsible for retinitis pigmentosa in consanguineous Pakistani families

PubMed Central

Khan, Shahid Y.; Ali, Shahbaz; Naeem, Muhammad Asif; Khan, Shaheen N.; Husnain, Tayyab; Butt, Nadeem H.; Qazi, Zaheeruddin A.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

2015-01-01

Purpose This study was conducted to localize and identify causal mutations associated with autosomal recessive retinitis pigmentosa (RP) in consanguineous familial cases of Pakistani origin. Methods Ophthalmic examinations that included funduscopy and electroretinography (ERG) were performed to confirm the affectation status. Blood samples were collected from all participating individuals, and genomic DNA was extracted. A genome-wide scan was performed, and two-point logarithm of odds (LOD) scores were calculated. Sanger sequencing was performed to identify the causative variants. Subsequently, we performed whole exome sequencing to rule out the possibility of a second causal variant within the linkage interval. Sequence conservation was performed with alignment analyses of PDE6A orthologs, and in silico splicing analysis was completed with Human Splicing Finder version 2.4.1. Results A large multigenerational consanguineous family diagnosed with early-onset RP was ascertained. An ophthalmic clinical examination consisting of fundus photography and electroretinography confirmed the diagnosis of RP. A genome-wide scan was performed, and suggestive two-point LOD scores were observed with markers on chromosome 5q. Haplotype analyses identified the region; however, the region did not segregate with the disease phenotype in the family. Subsequently, we performed a second genome-wide scan that excluded the entire genome except the chromosome 5q region harboring PDE6A. Next-generation whole exome sequencing identified a splice acceptor site mutation in intron 16: c.2028–1G>A, which was completely conserved in PDE6A orthologs and was absent in ethnically matched 350 control chromosomes, the 1000 Genomes database, and the NHLBI Exome Sequencing Project. Subsequently, we investigated our entire cohort of RP familial cases and identified a second family who harbored a splice acceptor site mutation in intron 10: c.1408–2A>G. In silico analysis suggested that these mutations will result in the elimination of wild-type splice acceptor sites that would result in either skipping of the respective exon or the creation of a new cryptic splice acceptor site; both possibilities would result in retinal photoreceptor cells that lack PDE6A wild-type protein. Conclusions we report two splice acceptor site variations in PDE6A in consanguineous Pakistani families who manifested cardinal symptoms of RP. Taken together with our previously published work, our data suggest that mutations in PDE6A account for about 2% of the total genetic load of RP in our cohort and possibly in the Pakistani population as well. PMID:26321862

Anophthalmia-Waardenburg syndrome: a report of three cases.

PubMed

Suyugül, Z; Seven, M; Hacihanefioğlu, S; Kartal, A; Suyugül, N; Cenani, A

1996-04-24

We report on 2 Turkish families with children who had bilateral anophthalmia, upper and lower limb abnormalities, mental retardation and consanguineous parents. We have evaluated the 2 cases in the first family and the only case in the second as anophthalmia-Waardenburg syndrome. This is an extremely rare autosomal recessive syndrome.

Cutaneous features associated with microcephalic osteodysplastic primordial dwarfism type II.

PubMed

Webber, Naomi; O'Toole, Edel A; Paige, David G; Rosser, Elisabeth

2008-01-01

We present an 18-month-old Pakistani girl who had short stature, craniofacial dysmorphism, and multiple café-au-lait spots. After consultation with the geneticists, microcephalic osteodysplastic primordial dwarfism type II was diagnosed (MIM210720). The presence of consanguinity in reported families is suggestive of autosomal recessive inheritance.

Benign cephalic histiocytosis

PubMed Central

Samson, Joan F.; Libu, Gnanaseelan Kanakamma; Philip, Mariam; Simi, Puthenveedu Salahudeen

2013-01-01

A one and a half year old girl born of a non-consanguineous marriage presented with multiple asymptomatic erythematous to hyperpigmented and skin colored papules on both cheeks slowly increasing in number of 1 year duration. On the basis of clinical, histopathological, and immunohistochemistry findings, a diagnosis of benign cephalic histiocytosis was made. PMID:24350010

Mongolism, Ciba Foundation Study Group Number 25.

ERIC Educational Resources Information Center

Wolstenholme, G. E. W., Ed.; Porter, Ruth, Ed.

Resulting from a 1-day conference on mongolism, the book contains research studies and discussion summaries. Papers include "Parental Age, Live-Birth Order, and Pregnancy-Free Interval in Down's Syndrome in Japan" by E. Matsunaga, "Consanguineous Marriages and Mongolism" by H. Foressman and H. O. Akesson, "Correlation of Dermal Patterns on…

Correlation of WAIS IQ in 10 Pairs of Brothers.

ERIC Educational Resources Information Center

Matarazzo, Joseph D.; And Others

1978-01-01

Pairs of brothers were individually examined with Wechsler Adult Intelligence Scale some 10 months apart by an experienced clinical psychologist unaware of the consanguineous relationship. Correlation of .42 for Full Scale IQ is consistent with median correlation reported by Erlenmeyer-Kimling and Jarvik in their 1963 literature review.…

Cryptorchidism due to chromosome 5q inversion duplication.

PubMed

Dutta, M K; Gundgurthi, A; Garg, M K; Pakhetr, R

2013-12-01

We present a 15 year old boy who was born out of a non consanguineous marriage, and presented with bilateral cryptorchidism, mental retardation, facial dysmorphism, hypergonadotrophic hypogonadism with failure of anatomical and biochemical localisation of testes. Karyotype analysis showed 46 XY with inverted duplication on chromosome 5q22-31.

Validating the Mexican American Intergenerational Caregiving Model

ERIC Educational Resources Information Center

Escandon, Socorro

2011-01-01

The purpose of this study was to substantiate and further develop a previously formulated conceptual model of Role Acceptance in Mexican American family caregivers by exploring the theoretical strengths of the model. The sample consisted of women older than 21 years of age who self-identified as Hispanic, were related through consanguinal or…

A novel mutation in PGAP2 gene causes developmental delay, intellectual disability, epilepsy and microcephaly in consanguineous Saudi family.

PubMed

Naseer, Muhammad Imran; Rasool, Mahmood; Jan, Mohammed M; Chaudhary, Adeel G; Pushparaj, Peter Natesan; Abuzenadah, Adel M; Al-Qahtani, Mohammad H

2016-12-15

PGAP2 (Post-GPI Attachment to Proteins 2) gene is involved in lipid remodeling steps of Glycosylphosphatidylinositol (GPI)-anchor maturation. At the surface of the cell this gene is required for proper expression of GPI-anchored proteins. Hyperphosphatasia with mental retardation syndrome-3 is an autosomal recessive disorder usually characterized by severe mental retardation. Mutations in the PGAP2 gene cause hyperphosphatasia mental retardation syndrome-3. We have identified a large consanguineous family from Saudi origin segregating developmental delay, intellectual disability, epilepsy and microcephaly. Whole exome sequencing with 100× coverage was performed on two affected siblings of the family. Data analysis in the patient revealed a novel missense mutation c.191C>T in PGAP2 gene resulting in Alanine to Valine substitution (Ala64Val). The mutation was reconfirmed and validated by subsequent Sanger sequencing method. The mutation was ruled out in 100 unrelated healthy controls. We suggest that this pathogenic mutation disrupts the proper function of the gene proteins resulting in the disease state. Copyright © 2016 Elsevier B.V. All rights reserved.

Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity

PubMed Central

Lopez-Herrera, Gabriela; Tampella, Giacomo; Pan-Hammarström, Qiang; Herholz, Peer; Trujillo-Vargas, Claudia M.; Phadwal, Kanchan; Simon, Anna Katharina; Moutschen, Michel; Etzioni, Amos; Mory, Adi; Srugo, Izhak; Melamed, Doron; Hultenby, Kjell; Liu, Chonghai; Baronio, Manuela; Vitali, Massimiliano; Philippet, Pierre; Dideberg, Vinciane; Aghamohammadi, Asghar; Rezaei, Nima; Enright, Victoria; Du, Likun; Salzer, Ulrich; Eibel, Hermann; Pfeifer, Dietmar; Veelken, Hendrik; Stauss, Hans; Lougaris, Vassilios; Plebani, Alessandro; Gertz, E. Michael; Schäffer, Alejandro A.; Hammarström, Lennart; Grimbacher, Bodo

2012-01-01

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity. PMID:22608502

Two siblings with early infantile myoclonic encephalopathy due to mutation in the gene encoding mitochondrial glutamate/H+ symporter SLC25A22.

PubMed

Cohen, Rony; Basel-Vanagaite, Lina; Goldberg-Stern, Hadassah; Halevy, Ayelet; Shuper, Avinoam; Feingold-Zadok, Michal; Behar, Doron M; Straussberg, Rachel

2014-11-01

To characterize a new subset of early myoclonic encephalopathy usually associated with metabolic etiologies with a new genetic entity. We describe two siblings with early myoclonic encephalopathy born to consanguineous parents of Arab Muslim origin from Israel. We used homozygosity mapping and candidate gene sequencing to reveal the genetic basis of the myoclonic syndrome. We found a rare missense mutation in the gene encoding one of the two mitochondrial glutamate/H symporters, SLC25A22. The phenotype of early myoclonic encephalopathy was first linked to the same mutation in 2005 in patients of the same ethnicity as our family. Owing to the devastating nature of this encephalopathy, we focus attention on its clinical history, epileptic semiology, distinct electroencephalography features, and genetic basis. We provide the evidence that an integrated diagnostic strategy combining homozygosity mapping with candidate gene sequencing is efficient in consanguineous families with highly heterogeneous autosomal recessive diseases. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Preconception health status of Iraqi women after trade embargo.

PubMed

Abbas, Wafa Abdul Karim; Azar, Najood G; Haddad, Linda G; Umlauf, Mary Grace

2008-01-01

To describe the preconception health status of Iraqi women in 2001 following the trade embargo imposed on Iraq beginning in 1991 and only partially removed in 1996. A descriptive cross-sectional prevalence study. 500 Iraqi women at a premarital clinic in Baghdad in 2001. Women were surveyed for age, area of residence, menstrual history, household crowding, consanguinity, and a family history of congenital problems. Clinical findings regarding height, weight, and hemoglobin level were included in the data. Almost one third of the women were below the age of 20 and the majority were between 20 and 25 years of age. More than half of the women in this study had an intermediate-level education or less and lived in very crowded housing. Most of the women were anemic and reported a delay in menarche, suggesting malnutrition. Most of the women were planning consanguineous unions even though many reported congenital conditions in their family of origin. Young Iraqi women who endured embargo needed, and continue to need, aggressive preventive health services to recoup health gains lost during the 1990s and to address prevention of common congenital disorders.

Severe congenital neutropenia in two siblings related to HAX1 mutation without neurodevelopmental disorders.

PubMed

Patiroglu, T; Gungor, H Eke; Triot, A; Unal, E

2013-01-01

Severe congenital neutropenia (SCN) is a rare primary myelopoiesis disorder, characterized by reduced absolute neutrophil counts from birth, increased susceptibility to recurrent and life-threatening infections, and a preleukemic predisposition. Herein, we describe two siblings with SCN born from consanguineous parents who were referred for complaints of recurrent cutaneous infections, gingivitis, purulent otitis media, and both lower and upper respiratory tract infections. Bone marrow aspiration of one patient demonstrated a maturation arrest in the myeloid lineage at the promyelocyte-myelocyte stages. Genetic analysis revealed a homozygous mutation in exon 2 c.130-131insA; p.W44X in the HAX1 gene. Although identical mutations were detected in both siblings, there was a clear discrepancy between the clinical course of the brother, who eventually required granulocyte colony stimulating factor (G-CSF) therapy, and the sister, who did not. Although SCN is a rare disorder, the early onset of recurrent infections and severe neutropenia, especially in children born from consanguineous parents, should always raise suspicion and warrant further evaluation.

A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome.

PubMed

Vilain, C; Rens, C; Aeby, A; Balériaux, D; Van Bogaert, P; Remiche, G; Smet, J; Van Coster, R; Abramowicz, M; Pirson, I

2012-09-01

Although deficiency of complex I of the mitochondrial respiratory chain is a frequent cause of encephalopathy in children, only a few mutations have been reported in each of its subunits. In the absence of families large enough for conclusive segregation analysis and of robust functional testing, it is difficult to unequivocally show the causality of the observed mutations and to delineate genotype-phenotype correlations, making additional observations necessary. We observed two consanguineous siblings with an early-onset encephalopathy, medulla, brainstem and mesencephalon lesions on brain magnetic resonance imaging and death before 8 months of age, caused by a complex I deficiency. We used a homozygosity mapping approach and identified a missense mutation in the NDUFV1 gene. The mutation, p.Arg386His, affects a highly conserved residue, contiguous to a cysteine residue known to coordinate an Fe ion. This observation adds to our understanding of complex I deficiency disease. It validates the important role of Arg386 and therefore supports the current molecular model of iron-sulfur clusters in NDUFV1. © 2011 John Wiley & Sons A/S.

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients.

PubMed

Ben-Mustapha, Imen; Agrebi, Nourhen; Barbouche, Mohamed-Ridha

2018-03-01

Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning. ©2017 Society for Leukocyte Biology.

Further Validation of the SIGMAR1 c.151+1G>T Mutation as Cause of Distal Hereditary Motor Neuropathy

PubMed Central

Lee, Jessica J. Y.; Drögemoller, Britt; Shyr, Casper; Tarailo-Graovac, Maja; Eydoux, Patrice; Ross, Colin J.; Wasserman, Wyeth W.; Björnson, Bruce; Wu, John K.

2016-01-01

Distal hereditary motor neuropathies represent a group of rare genetic disorders characterized by progressive distal motor weakness without sensory loss. Their genetic heterogeneity is high and thus eligible for diagnostic whole exome sequencing. The authors report successful application of whole exome sequencing in diagnosing a second consanguineous family with distal hereditary motor neuropathy due to a homozygous c.151+1G>T variant in SIGMAR1. This variant was recently proposed as causal for the same condition in a consanguineous Chinese family. Compared to this family, the Afghan ethnic origin of our patient is distinct, yet the features are identical, validating the SIGMAR1 deficiency phenotype: progressive muscle wasting/weakness in lower and upper limbs without sensory loss. Rapid disease progression during adolescent growth is similar and may be due to SIGMAR1’s role in regulating axon elongation and tau phosphorylation. Finally, the authors conclude that SIGMAR1 deficiency should be added to the differential diagnosis of distal hereditary motor neuropathies. PMID:28503617

HomSI: a homozygous stretch identifier from next-generation sequencing data.

PubMed

Görmez, Zeliha; Bakir-Gungor, Burcu; Sagiroglu, Mahmut Samil

2014-02-01

In consanguineous families, as a result of inheriting the same genomic segments through both parents, the individuals have stretches of their genomes that are homozygous. This situation leads to the prevalence of recessive diseases among the members of these families. Homozygosity mapping is based on this observation, and in consanguineous families, several recessive disease genes have been discovered with the help of this technique. The researchers typically use single nucleotide polymorphism arrays to determine the homozygous regions and then search for the disease gene by sequencing the genes within this candidate disease loci. Recently, the advent of next-generation sequencing enables the concurrent identification of homozygous regions and the detection of mutations relevant for diagnosis, using data from a single sequencing experiment. In this respect, we have developed a novel tool that identifies homozygous regions using deep sequence data. Using *.vcf (variant call format) files as an input file, our program identifies the majority of homozygous regions found by microarray single nucleotide polymorphism genotype data. HomSI software is freely available at www.igbam.bilgem.tubitak.gov.tr/softwares/HomSI, with an online manual.

Variable pathogenicity of exon 43del (FAA) in four Fanconi anaemia patients within a consanguineous family.

PubMed

Koc, A; Pronk, J C; Alikasifoglu, M; Joenje, H; Altay, C

1999-01-01

Four Fanconi anaemia group A (FAA) patients within two related consanguineous families are presented: the propositus (male, 13 years, transplanted at age 10), and his three cousins (one male, 8 years, and two female newborns). Assignment of the patients to FAA was based on the functional complementation analysis by somatic cell hybridization and confirmed by mutation screening showing a homozygous deletion of exon 43 (4267-4404del) in the FAA gene to be present in all four patients. The newborn patients had been diagnosed prenatally by DNA analysis. In spite of identical molecular pathology and close familial relationship the clinical phenotypes of the four patients were not concordant. Discordant symptoms included birthweight, pigmentation abnormalities, skeletal, renal and genital abnormalities, whereas microcephaly and possibly the haematological course were concordant. Differences in environmental conditions and/or genetic make-up along with chance effects during development may explain discordant phenotypes despite identical molecular pathology in these patients. However, our results do not rule out the possibility that the exon 43del mutation may have prognostic value for the haematological course of the disease.

Sequence variants in four genes underlying Bardet-Biedl syndrome in consanguineous families

PubMed Central

Ullah, Asmat; Umair, Muhammad; Yousaf, Maryam; Khan, Sher Alam; Nazim-ud-din, Muhammad; Shah, Khadim; Ahmad, Farooq; Azeem, Zahid; Ali, Ghazanfar; Alhaddad, Bader; Rafique, Afzal; Jan, Abid; Haack, Tobias B.; Strom, Tim M.; Meitinger, Thomas; Ghous, Tahseen

2017-01-01

Purpose To investigate the molecular basis of Bardet-Biedl syndrome (BBS) in five consanguineous families of Pakistani origin. Methods Linkage in two families (A and B) was established to BBS7 on chromosome 4q27, in family C to BBS8 on chromosome 14q32.1, and in family D to BBS10 on chromosome 12q21.2. Family E was investigated directly with exome sequence analysis. Results Sanger sequencing revealed two novel mutations and three previously reported mutations in the BBS genes. These mutations include two deletions (c.580_582delGCA, c.1592_1597delTTCCAG) in the BBS7 gene, a missense mutation (p.Gln449His) in the BBS8 gene, a frameshift mutation (c.271_272insT) in the BBS10 gene, and a nonsense mutation (p.Ser40*) in the MKKS (BBS6) gene. Conclusions Two novel mutations and three previously reported variants, identified in the present study, further extend the body of evidence implicating BBS6, BBS7, BBS8, and BBS10 in causing BBS. PMID:28761321

Enhancing health literacy through co-design: development of culturally appropriate materials on genetic risk and customary consanguineous marriage.

PubMed

Ali, Parveen Azam; Salway, Sarah; Such, Elizabeth; Dearden, Andrew; Willox, Matt

2018-04-12

AimTo develop a simple health literacy intervention aimed at supporting informed reproductive choice among members of UK communities practising customary consanguineous marriage. The contribution of 'health literacy' to reducing health inequalities and improving primary health-care efficiency is increasingly recognised. Enhancing genetic literacy has received particular attention recently. Consanguineous marriage is customarily practised among some UK minority ethnic communities and carries some increased risk of recessive genetic disorders among offspring compared with unions among unrelated partners. The need to enhance genetic literacy on this issue has been highlighted, but no national response has ensued. Instead, a range of undocumented local responses are emerging. Important knowledge gaps remain regarding how the development and implementation of culturally appropriate, effective and sustainable responses can be achieved. Our co-design approach involved active participation by local people. Initial insight generation employed six focus group discussions and 14 individual interviews to describe current understandings and information needs. A total of 11 personas (heuristic narrative portraits of community 'segments') resulted; four participatory workshops provided further understanding of: preferred information channels; feasible information conveyance; and responses to existing materials. Prototype information resources were then developed and feedback gathered via two workshops. Following further refinement, final feedback from health-care professionals and community members ensured accuracy and appropriateness.FindingsThe project demonstrated the utility of co-design for addressing an issue often considered complex and sensitive. With careful planning and orchestration, active participation by diverse community members was achieved. Key learning included: the importance of establishing trusting and respectful relationships; responding to diversity within the community; and engendering a creative and enjoyable experience. The resultant materials were heavily shaped by local involvement. Evaluative work is now needed to assess impacts on knowledge and service uptake. Longer term sustainability will depend on whether innovative community-level work is accompanied by broader strategy including investment in services and professional development.

They aren't all first cousins: Bedouin marriage and health policies in Lebanon.

PubMed

Mansour, Nisrine; Chatty, Dawn; El-Kak, Faysal; Yassin, Nasser

2014-01-01

Fertility and consanguineous marriages among the Bedouin tribes of the Middle East have long generated interest particularly around health outcomes and social relations. In particular, Bedouin in Lebanon have increasingly embraced the Lebanese national bio-medical health system in the past two decades, while Lebanese policy-makers' responses continue to be minimal and ill-informed. This paper investigates the mismatch between policy-makers' formulations of Bedouin consanguineous marriages and the Bedouins's actual reproductive practices and discusses the implications of these formulations on the Bedouins's access to health services. The findings are drawn from the data collected as part of the Bedouin Health Project, an EU-funded five-year study (2005-2010), aiming at assessing access to reproductive and child health care among the Bedouin in Lebanon. The data was collected from 6 clusters representing the main Bedouin informal and unrecognized settlements in the Bekaa Valley of Lebanon. The data consists of 111 socioeconomic questionnaires with Bedouin women users of local public, private, and nongovernmental reproductive and child health-focused clinics, in addition to 40 in-depth interviews with Bedouin women across the clusters and 17 semi-structured interviews with policy-makers. The findings suggest a gap between the perceptions of policy-makers and the incidence of consanguineous marriages and reproductive practices among the Bedouin. While there was no national data available for the Bedouin populations, policy-makers relied on a constructed 'Bedouin reproductive profile' that portrayed them as 'a problematic health group'. The national policy formulation of the Bedouin reproductive profile has an exclusionary impact on the Bedouin population as they are ignored from any targeted health policies or provided with politically motivated palliative care provision. These findings highlight the importance of addressing stereotyping and discrimination among health practitioners and policy-makers, as a crucial part of improving the overall marriage and reproductive health practices of the Bedouin.

Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity.

PubMed

Saleheen, Danish; Natarajan, Pradeep; Armean, Irina M; Zhao, Wei; Rasheed, Asif; Khetarpal, Sumeet A; Won, Hong-Hee; Karczewski, Konrad J; O'Donnell-Luria, Anne H; Samocha, Kaitlin E; Weisburd, Benjamin; Gupta, Namrata; Zaidi, Mozzam; Samuel, Maria; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Ishaq, Madiha; Akhtar, Saba; Trindade, Kevin; Mucksavage, Megan; Qamar, Nadeem; Zaman, Khan Shah; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Hayyat Mallick, Nadeem; Ishaq, Mohammad; Rasheed, Syed Zahed; Memon, Fazal-Ur-Rehman; Mahmood, Khalid; Ahmed, Naveeduddin; Do, Ron; Krauss, Ronald M; MacArthur, Daniel G; Gabriel, Stacey; Lander, Eric S; Daly, Mark J; Frossard, Philippe; Danesh, John; Rader, Daniel J; Kathiresan, Sekar

2017-04-12

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.

Mutational analysis of AGXT gene in Libyan children with primary hyperoxaluria type 1 at Tripoli Children Hospital.

PubMed

Rhuma, Naziha R; Fituri, Omar A; Sabei, Laila T

2018-01-01

Primary hyperoxaluria type 1 (PH1) is an inborn error of glyoxylate metabolism. It results from genetic mutation of the AGXT gene. The study objective was to verify the clinical and epidemiological patterns of PH1 in Libyan children at Tripoli Children Hospital confirmed by AGXT gene mutation. A descriptive case series study of 53 children with PH1 diagnosed between 1994 and 2015 was carried out in the Nephrology Unit at Tripoli Children Hospital. Diagnosis of PH1 was based on the clinical presentation (renal stones or nephrocalcinosis), positive family history of PH1, and high 24 h urinary oxalate. Sampling for AGXT gene mutation was collected from April 2012 to December. 2015. Among the 53 children included, males composed of 62.3% of patients. Their age at presentation ranged between two months and 20 years with a mean age of 55.4 ± 48 months. The parents of 81.1% of these patients had positive consanguinity. Forty (75.5%) patients were from South West (mountain area), and 16 (40%) of them were from Yefrin. The most common mutation found in this study was c.731T>C (p.lle244thr) seen in 32 (71%) of children, and interestingly, among these patients, 87.1% were homozygous in gene typing, 86.2% had positive history of consanguinity, 71.4% were from South West (mountain area), 96.6% had family history of PH1, and 20% presented with impaired renal function. The patients with this mutation were younger at presentation than that with other genes, and it was more prevalent among boys (61.3%). Thus, the most common gene mutation found in Libyan children with PH1 was c.731T>C (p.lle244thr) and this is more likely due to the strong genetic pooling caused by the high consanguinity rate which requires an extensive genetic counseling.

Genetic heterogeneity and consanguinity lead to a “double hit”: Homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa

PubMed Central

Goldenberg-Cohen, Nitza; Banin, Eyal; Zalzstein, Yael; Cohen, Ben; Rotenstreich, Ygal; Rizel, Leah; Basel-Vanagaite, Lina

2013-01-01

Purpose Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. Methods The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. Results The family was found to segregate novel mutations of two different genes: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. Conclusions This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient. PMID:23882135

Genetic heterogeneity and consanguinity lead to a "double hit": homozygous mutations of MYO7A and PDE6B in a patient with retinitis pigmentosa.

PubMed

Goldenberg-Cohen, Nitza; Banin, Eyal; Zalzstein, Yael; Cohen, Ben; Rotenstreich, Ygal; Rizel, Leah; Basel-Vanagaite, Lina; Ben-Yosef, Tamar

2013-01-01

Retinitis pigmentosa (RP), the most genetically heterogeneous disorder in humans, actually represents a group of pigmentary retinopathies characterized by night blindness followed by visual-field loss. RP can appear as either syndromic or nonsyndromic. One of the most common forms of syndromic RP is Usher syndrome, characterized by the combination of RP, hearing loss, and vestibular dysfunction. The underlying cause of the appearance of syndromic and nonsyndromic RP in three siblings from a consanguineous Israeli Muslim Arab family was studied with whole-genome homozygosity mapping followed by whole exome sequencing. THE FAMILY WAS FOUND TO SEGREGATE NOVEL MUTATIONS OF TWO DIFFERENT GENES: myosin VIIA (MYO7A), which causes type 1 Usher syndrome, and phosphodiesterase 6B, cyclic guanosine monophosphate-specific, rod, beta (PDE6B), which causes nonsyndromic RP. One affected child was homozygous for both mutations. Since the retinal phenotype seen in this patient results from overlapping pathologies, one might expect to find severe retinal degeneration. Indeed, he was diagnosed with RP based on an abnormal electroretinogram (ERG) at a young age (9 months). However, this early diagnosis may be biased, as two of his older siblings had already been diagnosed, leading to increased awareness. At the age of 32 months, he had relatively good vision with normal visual fields. Further testing of visual function and structure at different ages in the three siblings is needed to determine whether the two RP-causing genes mutated in this youngest sibling confer increased disease severity. This report further supports the genetic heterogeneity of RP, and demonstrates how consanguinity could increase intrafamilial clustering of multiple hereditary diseases. Moreover, this report provides a unique opportunity to study the clinical implications of the coexistence of pathogenic mutations in two RP-causative genes in a human patient.

Loss-of-function mutations in the thyrotropin receptor gene as a major determinant of hyperthyrotropinemia in a consanguineous community.

PubMed

Tenenbaum-Rakover, Yardena; Grasberger, Helmut; Mamanasiri, Sunee; Ringkananont, Usanee; Montanelli, Lucia; Barkoff, Marla S; Dahood, Ahmad Mahameed-Hag; Refetoff, Samuel

2009-05-01

Resistance to TSH (RTSH) is a condition of impaired responsiveness of the thyroid gland to TSH, characterized by elevated serum TSH, low or normal thyroid hormone levels, and hypoplastic or normal-sized thyroid gland. The aim of the study was to evaluate the clinical course and the genotype-phenotype relationship of RTSH caused by two different TSH receptor (TSHR) gene mutations in a consanguineous population. We conducted a clinical and genetic investigation of 46 members of an extended family and 163 individuals living in the same town. In vitro functional studies of the mutant TSHRs were also performed. Two TSHR gene mutations (P68S and L653V) were identified in 33 subjects occurring as homozygous L653V (five subjects), heterozygous L653V (20 subjects), heterozygous P68S (four subjects), and compound heterozygous L653V/P68S (four subjects). With the exception of one individual with concomitant autoimmune thyroid disease, all homozygotes and compound heterozygotes presented with compensated RTSH (high TSH with free T(4) and T(3) in the normal range). Only nine of 24 heterozygotes had mild hyperthyrotropinemia. The L653V mutation resulted in a higher serum TSH concentration and showed a more severe in vitro abnormality than P68S. Haplotype analysis predicted a founder of the L653V six to seven generations earlier, whereas the P68S is older. Cross-sectional and prospective longitudinal studies indicate that TSH and T(4) concentrations remain stable over time. High frequency hyperthyrotropinemia in an Israeli Arab-Muslim consanguineous community is attributed to two inactivating TSHR gene mutations. Concordant genotype-phenotype was demonstrated clinically and by in vitro functional analysis. Retrospective and prospective studies indicate that in the absence of concomitant autoimmune thyroid disease, elevated TSH levels reflect stable compensated RTSH.

Roberts-SC Phocomelia Syndrome (Pseudothalidomide Syndrome): A Case Report.

PubMed

Keypour, Farideh; Naghi, Ilana; Behnam, Babak

2013-03-01

A 39-year-old pregnant woman at 38 weeks of gestation was referred with labor pain to a hospital. She had consanguinity with her husband. A female newborn had multiple craniofacial anomalies and phocomelia in right upper limb. The disease locus was assigned to chromosome17q21. Four days later, infant died of cardiopulmonary arrest.

Roberts-SC Phocomelia Syndrome (Pseudothalidomide Syndrome): A Case Report

PubMed Central

Naghi, Ilana; Behnam, Babak

2013-01-01

A 39-year-old pregnant woman at 38 weeks of gestation was referred with labor pain to a hospital. She had consanguinity with her husband. A female newborn had multiple craniofacial anomalies and phocomelia in right upper limb. The disease locus was assigned to chromosome17q21. Four days later, infant died of cardiopulmonary arrest. PMID:24971102

Numerical Sensitivity of Trajectories Across Conformational Energy Hypersurfaces from Geometry Optimized Molecular Orbital Calculations: AM1, MNDO, and MINDO/3

DTIC Science & Technology

1988-01-01

relationship studies, it became corn- surfaces are being traversed, the molecule monly believed that compounds with higher h can go along different paths on...1975). AMPAC, and consanguineous programs 15. W. Thiel, Quantum Chem. Prog. Exchange Cata- should be done with the tightest available log, 11, 353

From "New Genetics" to Everyday Knowledge: Ideas about How Genetic Diseases Are Transmitted in Two Large Brazilian Families

ERIC Educational Resources Information Center

Santos, Silvana; Bizzo, Nelio

2005-01-01

This study focuses on everyday or lay understandings of inheritance. In the northeastern Brazil, 100 individuals were interviewed in order to describe how they explain the origin of genetic disorders affecting their relatives for several generations. There were involved 60 individuals from a large consanguineous family with many members affected…

Kindler syndrome: report of two cases.

PubMed

Mendes, Luciana; Nogueira, Lisiane; Vilasboas, Virginia; Talhari, Carolina; Talhari, Sinésio; Santos, Mônica

2012-01-01

Kindler syndrome is a rare autosomal recessive genodermatosis characterized by trauma-induced blisters, progressive poikiloderma and varying degrees of photosensitivity. In 2003, loss-of-function mutations were identified in the gene KIND1 mapped to chromosome 20p12.3. In this paper, we report Kindler syndrome in two children born to consanguineous parents presenting acral blistering, photosensitivity, poikiloderma, cutaneous atrophy and periodontitis.

Diagnostic Yield of Chromosomal Microarray Analysis in a Cohort of Patients with Autism Spectrum Disorders from a Highly Consanguineous Population

ERIC Educational Resources Information Center

Al-Mamari, Watfa; Al-Saegh, Abeer; Al-Kindy, Adila; Bruwer, Zandre; Al-Murshedi, Fathiya; Al-Thihli, Khalid

2015-01-01

Autism Spectrum Disorders are a complicated group of disorders characterized with heterogeneous genetic etiologies. The genetic investigations for this group of disorders have expanded considerably over the past decade. In our study we designed a tired approach and studied the diagnostic yield of chromosomal microarray analysis on patients…

[Oral mucosa analog allografts in non-consanguineous rats].

PubMed

González, Luis; Padrón, Karla; Salmen, Siham; Jerez, Elsy; Dávila, Lorena; Solórzano, Eduvigis

2017-01-24

Although there are therapeutic options for the treatment of oral mucosa defects, the need for functional, anatomical and aesthetically similar substitutes persists, as well as for solutions to reduce autologous grafts morbidity. To determine clinical and histological compatibility of equivalent oral mucosa allografts generated through tissue engineering in non-consanguineous rats. We used a sample of oral mucosa from Sprague Dawley rats to obtain a fibroblast culture and a keratinocytes and fibroblasts co-culture. In both cases, we used a commercial collagen membrane as "scaffold". After ten weeks of culture, we grafted the resulting membranes into four Wistar rats. The first phase of the study was the development of the oral mucosa equivalents generated by tissue engineering. Then, we implanted them in immunocompetent Wistar rats, and finallywe evaluated the clinical and histological features of the allografts. In vivo evaluation of mucosal substitutes showed a correct integration of artificial oral mucosa in immunocompetent hosts, with an increase in periodontal biotype and the creation of a zone with increased keratinization. Histologically, the tissue was similar to the control oral mucosa sample with no inflammatory reaction nor clinical or histological rejection signs. The equivalent oral mucosa allografts generated by tissue engineering showed clinical and histological compatibility.

Consanguinity and recurrence risk of stillbirth and infant death.

PubMed Central

Stoltenberg, C; Magnus, P; Skrondal, A; Lie, R T

1999-01-01

OBJECTIVES: The aim of this study was to estimate the recurrence risk for stillbirth and infant death and compare results for offspring of first-cousin parents with results for offspring of unrelated parents. METHODS: The study population consisted of all single births with a previous sibling born in Norway between 1967 and 1994. Altogether, 629,888 births were to unrelated parents, and 3466 births were to parents who were first cousins. The risk of stillbirth and infant death was estimated for subsequent siblings contingent on parental consanguinity and survival of the previous sibling. RESULTS: For unrelated parents, the risk of early death (stillbirth plus infant death) for the subsequent sibling was 17 of 1000 if the previous child survived and 67 of 1000 if the previous child died before 1 year of age. For parents who were first cousins, the risk of early death for the subsequent sibling was 29 of 1000 if the previous child survived and 116 of 1000 if the previous child died. CONCLUSIONS: The risk of recurrence of stillbirth and infant death is higher for offspring of first-cousin parents compared with offspring of unrelated parents. PMID:10191794

The effect of religious, cultural and social identity on population genetic structure among Muslims in Pakistan.

PubMed

Hussain, R

2005-01-01

Knowledge of historical demography and contemporary social stratification can be valuable in understanding disease patterns, including genetic disorders, especially in communities that have a high prevalence of endogamous and/or consanguineous marriages. This paper provides a background to the religious, historical and socio-cultural factors that have helped define the bounds of endogamy for Muslims in undivided India and more specifically since the creation of Pakistan. The preference for endogamous marriage is based on the clan-oriented nature of the society, which values and actively seeks similarities in social group identity based on several factors, including religious, sectarian, ethnic, and tribal/clan affiliation. Religious affiliation is itself multi-layered and includes religious considerations other than being Muslim, such as sectarian identity (e.g. Shia or Sunni, etc.) and religious orientation within the sect (Isnashari, Ismaili, Ahmedi, etc.). Both ethnic affiliation (e.g. Sindhi, Baloch, Punjabi, etc.) and membership of specific biraderis or zat/quoms are additional integral components of social identity. Within the bounds of endogamy defined by the above parameters, close consanguineous unions are preferential due to a congruence of key features of group- and individual-level background factors.

A rare association--amelogenesis imperfecta, platispondyly and bicytopenia: a case report.

PubMed

Laouina, Samir; El Alaoui, Siham Chafai; Amezian, Rachida; Al Bouzidi, Abderrahmane; Sefiani, Abdelaziz; El Alloussi, Mustapha

2015-10-28

Amelogenesis imperfecta is an inherited disease characterized by generalized structural abnormalities of the enamel on all teeth, including both primary and permanent dentition. To the best of our knowledge, this is the first case report of a rare association of amelogenesis imperfecta, platyspondyly, and bicytopenia. A 5-year-old Moroccan boy was examined in the Centre for Dental Consultation and Treatment, Faculty of Dentistry, Rabat. He was a child of consanguineous parents (first degree). The child failed to thrive (-4 standard deviation score) and displayed delayed overall development. A dental examination revealed a hypoplastic amelogenesis imperfecta with a bacterial biofilm deposit on tooth surfaces. A complete blood count revealed bicytopenia (normocytic-normochromic anemia with thrombocytopenia). A radiographic examination of the spinal column showed a deviation of the spine in the frontal plane in the form of thoracolumbar scoliosis. The interpedicular distance was not expanded; but a mild platyspondyly exists, especially pronounced in T11 and T12. No other family members presented amelogenesis imperfecta, bicytopenia, or platyspondyly. The consanguineous marriage suggested an autosomal recessive mode of inheritance. Further studies are necessary to clarify the genetic defect producing this syndrome, and the symptomatic associations of amelogenesis imperfecta, platyspondyly and bicytopenia.

Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity.

PubMed

Dehghani, Mohammad Reza; Mehrjardi, Mohammad Yahya Vahidi; Dilaver, Nafi; Tajamolian, Masoud; Enayati, Samaneh; Ebrahimi, Pirooz; Amoli, Mahsa M; Farooqi, Sadaf; Maroofian, Reza

2018-03-12

Congenital Leptin receptor (LEPR) deficiency is a rare genetic cause of early-onset morbid obesity characterised by severe early onset obesity, major hyperphagia, hypogonadotropic hypogonadism and immune and neuroendocrine/metabolic dysfunction. We identified a homozygous loss-of-function mutation, NM_002303.5:c.464 T > G; p.(Tyr155*), in the LEPR in an extended consanguineous family with multiple individuals affected by early-onset severe obesity and hyperphagia. Interestingly, the LEPR-deficient adult females have extremely high body mass index (BMI) with hypogonadal infertility, the BMI of the affected males began to decline around the onset of puberty (13-15 years) with fertility being preserved. These findings lead to the speculation that LEPR deficiency may have a gender-specific effect on the regulation of body weight. In order to elucidate gender-specific effects of LEPR deficiency on reproduction further investigations are needed. The limitations of this study are that our conclusion is based on observations of two males and two females. Further LEPR deficient males and females are required for comparison in order to support this finding more confidently. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Epidemiological characteristics of Hirschsprung's disease (HSCR): Results of a case series of fifty patients from Bangladesh.

PubMed

Karim, Anwarul; Akter, Mastura; Aziz, Tasmiah T; Hoque, Mozammel; Chowdhury, Tanvir K; Imam, Md Sharif; Walid, Adnan; Kabir, Mahfuzul; So, Manting; Lam, Wai Yee; Tang, Clara Sm; Wong, Kenneth K; Tam, Paul K; Garcia-Barcelo, Merce; Banu, Tahmina

2018-01-31

The epidemiology of Hirschsprung's disease (HSCR) in Bangladesh has never been studied. The aim of this study was to determine the epidemiological characteristics of HSCR in Bangladesh. Data from fifty patients were collected prospectively from two hospitals in Chittagong, Bangladesh. The rate of consanguinity (16%) among parents of HSCR patients was higher than that of the general population (10%). Maternal age at the time of birth of the affected child was ≤30years in all cases except one. No association was found between parents' occupation and HSCR. No patient was born preterm and only three patients (6%) had low birth weight. Nine patients (18%) had associated anomalies. We found coexistence of bilateral accessory tragi and ankyloglossia in one patient, and coexistence of rectal duplication cyst in another. Neither anomaly had been previously reported in HSCR patients. Our study suggests that consanguinity might increase the risk of HSCR whereas advanced maternal age does not. HSCR patients were found more likely to born at term and with normal birth weight. The coexistence of HSCR with previously unreported anomalies highlights the diversity of conditions that can co-occur with HSCR. IV. Copyright © 2018. Published by Elsevier Inc.

Between acculturation and ambivalence: knowledge of genetics and attitudes towards genetic testing in a consanguineous bedouin community.

PubMed

Raz, Aviad E; Atar, Marcela; Rodnay, Maya; Shoham-Vardi, Ilana; Carmi, Rivka

2003-01-01

The Bedouins of the Negev (Southern part of Israel) are a community at increased risk for genetic diseases and congenital anomalies as a result of frequent consanguinity (particularly patrilateral parallel-cousin marriage) and underutilization of prenatal genetic tests due to a Muslim ban on abortion. To assess the knowledge and attitudes of Bedouin schoolchildren and their teachers towards a community-based, premarital carrier-matching program aimed at reducing the prevalence at birth of genetic diseases. A questionnaire was presented to 61 teachers and 40 schoolchildren as part of guided interaction in small groups, conducted in Bedouin schools between 1999 and 2001. Susceptibility as well as knowledge of genetics were found to correlate with a positive attitude towards the genetics program among both teachers and pupils. However, pupils had a lower knowledge index as compared to teachers, and their attitudes were slightly less positive. The difference between teachers and pupils is discussed in the context of the latter's acculturation, which contradicts tradition and parental authority and can generate ambivalence. Attitudes are further discussed in the context of the Health Belief Model and the complex interplay of tradition, Islam, cousin marriage and biomedicine. Copyright 2003 S. Karger AG, Basel

Poikiloderma with Neutropenia in Morocco: a Report of Four Cases.

PubMed

Aglaguel, Ayoub; Abdelghaffar, Houria; Ailal, Fatima; Habti, Norddine; Hesse, Sebastian; Kohistani, Naschla; Klein, Christoph; Bousfiha, Ahmed Aziz

2017-05-01

Poikiloderma with Neutropenia (PN) is inherited genodermatosis which results from a biallelic mutation in the USB1 gene (U Six Biogenesis 1). PN, first described in Navajo Native Americans, is characterized by early onset poikiloderma, pachyonychia, palmo-plantar hyperkeratosis, and permanent neutropenia. This condition results in frequent respiratory tract infections during infancy and childhood. From 2011 to 2013, four cases of PN were diagnosed in Morocco. In this paper, we report the first four cases of PN diagnosed in Morocco, out of three unrelated consanguinous families. We investigated the genetic, immunological, and clinical features of four Moroccan patients with PN from three unrelated consanguinous families. Mean age at onset was 3 months and mean age at diagnosis was 7.5 years. The diagnosis of these PN patients was made based on clinical features and confirmed by molecular analysis for three cases. We identified two undescribed homozygous mutations in the USB1 gene: c.609 + 1G>A in two siblings and c.518 T>G(p.(Leu173Arg)) in the other case. This report confirms the clinical and genetic identity of Poikiloderma with Neutropenia syndrome.

Risk factors for congenital anomaly in a multiethnic birth cohort: an analysis of the Born in Bradford study.

PubMed

Sheridan, Eamonn; Wright, John; Small, Neil; Corry, Peter C; Oddie, Sam; Whibley, Catherine; Petherick, Emily S; Malik, Teena; Pawson, Nicole; McKinney, Patricia A; Parslow, Roger C

2013-10-19

Congenital anomalies are a leading cause of infant death and disability and their incidence varies between ethnic groups in the UK. Rates of infant death are highest in children of Pakistani origin, and congenital anomalies are the most common cause of death in children younger than 12 in this ethnic group. We investigated the incidence of congenital anomalies in a large multiethnic birth cohort to identify the causes of the excess of congenital anomalies in this community. We obtained questionnaire data from the mothers of children with one or more anomalies from the Born in Bradford study, a prospective birth cohort study of 13,776 babies and their families in which recruitment was undertaken between 2007 and 2011. Details of anomalies were prospectively reported to the study and we cross checked these details against medical records. We linked data for anomalies to maternal questionnaire and clinical data gathered as part of the Born in Bradford study. We calculated univariate and multivariate risk ratios (RRs) with 95% CIs for various maternal risk factors. Of 11,396 babies for whom questionnaire data were available, 386 (3%) had a congenital anomaly. Rates for congenital anomaly were 305·74 per 10,000 livebirths, compared with a national rate of 165·90 per 10,000. The risk was greater for mothers of Pakistani origin than for those of white British origin (univariate RR 1·96, 95% CI 1·56-2·46). Overall, 2013 (18%) babies were the offspring of first-cousin unions. These babies were mainly of Pakistani origin--1922 (37%) of 5127 babies of Pakistani origin had parents in first-cousin unions. Consanguinity was associated with a doubling of risk for congenital anomaly (multivariate RR 2·19, 95% CI 1·67-2·85); we noted no association with increasing deprivation. 31% of all anomalies in children of Pakistani origin could be attributed to consanguinity. We noted a similar increase in risk for mothers of white British origin older than 34 years (multivariate RR 1·83, 95% CI 1·14-3·00). Maternal education to degree level was protective (0·53, 95% CI 0·38-0·75), irrespective of ethnic origin. Consanguinity is a major risk factor for congenital anomaly. The risk remains even after adjustment for deprivation, and accounts for almost a third of anomalies in babies of Pakistani origin. High levels of educational attainment are associated with reduced risk in all ethnic groups. Our findings will be valuable in health promotion and public health, and to those commissioning antenatal, paediatric, and clinical genetic services. Sensitive advice about the risks should be provided to communities at increased risk, and to couples in consanguineous unions, to assist in reproductive decision making. National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care programme. Copyright © 2013 Elsevier Ltd. All rights reserved.

Severe myopia with unusual retinal anomalies and Dandy-Walker sequence in two sibs. A distinct new neuro-ocular disorder.

PubMed

de Crecchio, Giuseppe; Cennamo, Gilda; de Leeuw, Nicole; Ventruto, Maria Luisa; Lonardo, Maria Concetta; Friso, Patrizia; Ventruto, Valerio

2013-12-01

We have observed a male and a female, sibs of non-consanguineous parents, affected by severe myopia with characteristic retinal defects and Dandy-Walker variant. The peculiarity of the retinopathy consists of pathological myopia with anomalous vitreal fenestrated membranes in the retinal periphery. We suppose that these associations may configure a new genetic syndrome.

JPRS Report, East Asia, Southeast Asia.

DTIC Science & Technology

1988-12-14

for a woman called Cory. Not to be overlooked as possible contributors to the presidential woe are those who take advantage of their consanguine ...the southwest has become one of peace and friendship with a rapidly growing bilateral relationship and with more and more border crossings. Cashing...adjusting agricultural production relationships to local realities, making more capital available for investment, giving attention to building a water

JPRS Report, China

DTIC Science & Technology

1989-07-06

harboring suspicions about neighboring states. Singa- pore’s Premier Lee Kuan Yew has pointed out many times that relationships between his country and...and blackmail in general are some corrupt phenomena emerging politically. The feudal ties of consanguinity and favoritism in some places are even... relationship and the giving of gifts in the distribution of materials and sale of products. Chen Shifu, deputy director of the Nantou District

HLA-D: The T Cell Perspective

DTIC Science & Technology

1985-01-01

offspring of consanguineous marriage, in which case the cells are almost always homosygous for all HLA-region products; in other cases, HTCs are...story. Certain relationships exist between the class II serologically defined (I&) and T lymphocyte defined (Dw/LD) specificities. One speaks of one...DRwI4 specificities; in addition, certain of the DRI-DRwl4 specificities are supertypic to the various Dw specificities. The relationships of these

Salient Mainstream and Hispanic Values in a Navy Training Environment: An Anthropological Description.

DTIC Science & Technology

1982-08-01

nature of personal relationships , over the neutral or depersonalized organizational contacts. They felt that other individuals were more readily...be more in consonance with Anglo/mainstream interactive behavior; it places less im- portance on consanguineally or afinally ascribed connections, and...Triandis notes that values are "conceptions of relationships among abstract categories (e.g., humans, nature, time) which have strong affective components

Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity

PubMed Central

Saleheen, Danish; Natarajan, Pradeep; Armean, Irina M.; Zhao, Wei; Rasheed, Asif; Khetarpal, Sumeet; Won, Hong-Hee; Karczewski, Konrad J.; O’Donnell-Luria, Anne H.; Samocha, Kaitlin E.; Weisburd, Benjamin; Gupta, Namrata; Zaidi, Mozzam; Samuel, Maria; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Ishaq, Madiha; Akhtar, Saba; Trindade, Kevin; Mucksavage, Megan; Qamar, Nadeem; Zaman, Khan Shah; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Mallick, Nadeem Hayyat; Ishaq, Mohammad; Rasheed, Syed Zahed; Memon, Fazal-ur-Rehman; Mahmood, Khalid; Ahmed, Naveeduddin; Do, Ron; Krauss, Ronald M.; MacArthur, Daniel G.; Gabriel, Stacey; Lander, Eric S.; Daly, Mark J.; Frossard, Philippe; Danesh, John; Rader, Daniel J.; Kathiresan, Sekar

2017-01-01

A major goal of biomedicine is to understand the function of every gene in the human genome.1 Loss-of-function (LoF) mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such ‘human knockouts’ can provide insight into gene function. Consanguineous unions are more likely to result in offspring who carry LoF mutations in a homozygous state. In Pakistan, consanguinity rates are notably high.2 Here, we sequenced the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS) designed to understand the determinants of cardiometabolic diseases in South Asians.3 We identified individuals carrying predicted LoF (pLoF) mutations in the homozygous state, and performed phenotypic analysis involving >200 biochemical and disease traits. We enumerated 49,138 rare (<1 % minor allele frequency) pLoF mutations. These pLoF mutations are predicted to knock out 1,317 genes in at least one participant. Homozygosity for pLoF mutations at PLAG27 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signaling. Finally, APOC3 is a gene which retards clearance of plasma triglyceride-rich lipoproteins and where heterozygous deficiency confers protection against coronary heart disease.4,5 In Pakistan, we now observe APOC3 homozygous pLoF carriers; we recalled these knockout humans and challenged with an oral fat load. Compared with wild-type family members, APOC3 knockouts displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a ‘human knockout project’, a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans. PMID:28406212

Distinct mutations with different inheritance mode caused similar retinal dystrophies in one family: a demonstration of the importance of genetic annotations in complicated pedigrees.

PubMed

Chen, Xue; Sheng, Xunlun; Liu, Yani; Li, Zili; Sun, Xiantao; Jiang, Chao; Qi, Rui; Yuan, Shiqin; Wang, Xuhui; Zhou, Ge; Zhen, Yanyan; Xie, Ping; Liu, Qinghuai; Yan, Biao; Zhao, Chen

2018-05-29

Retinitis pigmentosa (RP) is the most common form of inherited retinal dystrophy presenting remarkable genetic heterogeneity. Genetic annotations would help with better clinical assessments and benefit gene therapy, and therefore should be recommended for RP patients. This report reveals the disease causing mutations in two RP pedigrees with confusing inheritance patterns using whole exome sequencing (WES). Twenty-five participants including eight patients from two families were recruited and received comprehensive ophthalmic evaluations. WES was applied for mutation identification. Bioinformatics annotations, intrafamilial co-segregation tests, and in silico analyses were subsequently conducted for mutation verification. All patients were clinically diagnosed with RP. The first family included two siblings born to parents with consanguineous marriage; however, no potential pathogenic variant was found shared by both patients. Further analysis revealed that the female patient carried a recurrent homozygous C8ORF37 p.W185*, while the male patient had hemizygous OFD1 p.T120A. The second family was found to segregate mutations in two genes, TULP1 and RP1. Two patients born to consanguineous marriage carried homozygous TULP1 p.R419W, while a recurrent heterozygous RP1 p.L762Yfs*17 was found in another four patients presenting an autosomal dominant inheritance pattern. Crystal structural analysis further indicated that the substitution from arginine to tryptophan at the highly conserved residue 419 of TULP1 could lead to the elimination of two hydrogen bonds between residue 419 and residues V488 and S534. All four genes, including C8ORF37, OFD1, TULP1 and RP1, have been previously implicated in RP etiology. Our study demonstrates the coexistence of diverse inheritance modes and mutations affecting distinct disease causing genes in two RP families with consanguineous marriage. Our data provide novel insights into assessments of complicated pedigrees, reinforce the genetic complexity of RP, and highlight the need for extensive molecular evaluations in such challenging families with diverse inheritance modes and mutations.

Junctional epidermolysis bullosa in the Middle East: clinical and genetic studies in a series of consanguineous families.

PubMed

Nakano, Aoi; Lestringant, Gilles G; Paperna, Tamar; Bergman, Reuven; Gershoni, Ruth; Frossard, Philippe; Kanaan, Moien; Meneguzzi, Guerrino; Richard, Gabriele; Pfendner, Ellen; Uitto, Jouni; Pulkkinen, Leena; Sprecher, Eli

2002-04-01

Junctional epidermolysis bullosa (JEB) is a group of inherited blistering diseases characterized by epidermal-dermal separation resulting from mutations that affect the function of critical components of the basement membrane zone. This group of autosomal recessive diseases is especially prevalent in regions where consanguinity is common, such as the Middle East. However, the clinical and genetic epidemiology of JEB in this region remains largely unexplored. The aim of the present study was to assess a series of consanguineous JEB families originating from the Middle East. We identified 7 families referred to us between 1998 and 1999 and originating from the United Arab Emirates, Saudi Arabia, Sudan, Yemen, and Israel. Histologic, immunofluorescence, and electron microscopy studies were performed to direct the subsequent molecular analysis. DNA obtained from all family members was amplified by means of polymerase chain reaction and analyzed by conformation-sensitive gel electrophoresis with subsequent direct sequencing. In 6 families presenting with the clinical and histologic features distinctive for JEB, mutations in genes encoding 1 of the 3 subunit polypeptides of laminin-5 were identified. Two families each had mutations in LAMB3, 2 in LAMA3, and 2 in LAMC2. Out of 7 distinct mutations, 5 were novel and 2 were recurrent. No relationship was found between the presence of nonsense/frameshift mutations in laminin-5 genes and perinatal mortality, contradicting a major genotype-phenotype correlation previously reported in the European and US literature. Similarly, none of the recurrent LAMB3 hot spot mutations previously described in other populations was found in our series. Finally, in a family with the clinical diagnosis of generalized atrophic benign epidermolysis bullosa, a homozygous non-sense mutation in Col17A1 gene (encoding the BPAG2 antigen) was identified. The present report suggests (1) the existence of a unique spectrum of mutations in the Middle East populations and (2) the need for the implementation of a diagnostic strategy tailored to the genetic features of JEB in this region.

Application of a high-throughput genotyping method for loci exclusion in non-consanguineous Australian pedigrees with autosomal recessive retinitis pigmentosa

PubMed Central

Paterson, Rachel L.; McLaren, Terri L.; Hewitt, Alex W.; Hoffmann, Ling; Lamey, Tina M.

2012-01-01

Purpose Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. Methods DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. Results Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (p<0.0001). Subsequent DNA sequencing resulted in identification of the likely disease-causing gene as CRB1 in one family (c.2548 G>A) and USH2A in two families (c.2276 G>T). Conclusions This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the genetic characterization of arRP in a non-consanguineous population; however, this method is effective only when DNA samples are available from more than one affected individual. PMID:22876132

Application of a high-throughput genotyping method for loci exclusion in non-consanguineous Australian pedigrees with autosomal recessive retinitis pigmentosa.

PubMed

Paterson, Rachel L; De Roach, John N; McLaren, Terri L; Hewitt, Alex W; Hoffmann, Ling; Lamey, Tina M

2012-01-01

Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (p<0.0001). Subsequent DNA sequencing resulted in identification of the likely disease-causing gene as CRB1 in one family (c.2548 G>A) and USH2A in two families (c.2276 G>T). This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the genetic characterization of arRP in a non-consanguineous population; however, this method is effective only when DNA samples are available from more than one affected individual.

Dental findings and treatment in consanguinity associated congenital chronic familial neutropenia.

PubMed

Buduneli, Nurcan; Cogulu, Dilsah; Kardesler, Levent; Kütükçüler, Necil

2006-01-01

The purpose of this report is to describe dental findings and treatment of an 11-year old male patient and a 5-year old female patient, children of first cousins, suffering from severe benign congenital chronic familial neutropenia. This case report emphazises the importance of differential diagnosis of immunodeficiencies including congenital chronic familial neutropenia in the background of severe periodontal diseases and/or diffuse carious lesions in children.

Development of Genetic Therapies for the Hemidesmosol Subtypes of Junction Epidermolysis Bullosa

DTIC Science & Technology

2003-11-01

Aita, V.M. and Christiano, A.M. (2001) Structural Analysis Reflects the Evolutionary Relationship between the Desmocollin Gene Family Mambers. Exp...Christiano, A.M. and Zlotogorski, A. (2003) Atrichia With Papular Lesions In Non Consanguineous Families. J. Invest. Dermatol. (in press). 36 %9 172...phenotype-genotype correlations in this disorder as well as the relationship between the skin, the musculoskeletal and the nervous systems. The Ogna Variant

Korean Affairs Report.

DTIC Science & Technology

1985-06-25

the military dictatorship be overthrown» Also, they branded and denounced U.S.-South Korean relations as a shameful relationship between master and...34 "Let us overthrow the military dictatorship," "U.S.-South Korean relations are a shameful and unacceptable relationship of master and servants...Seoul. But, we have something to say concerning Seoul: Seoul is on the same land as the North. The people there are our consanguineous compatriots

Voices Crying in the Wilderness: A Comparison of Pro-Boers and Anti- Imperialists, 1899-1902

DTIC Science & Technology

1991-05-01

subordinate relationship to the national office. Its activities remained the same, however, and it continued to dominate the direction of the movement...repugnant, yet mutually exclusive, options confronted Blacks. First, an obvious consanguinity figuratively linked Filipinos and Blacks. Soldiers calling...more than a reaction to arbitrary military despotism. For some time the basic relationship between the home .:ountry and some colonies, the "white

Novel C8orf37 mutations cause retinitis pigmentosa in consanguineous families of Pakistani origin

PubMed Central

Ravesh, Zeinab; El Asrag, Mohammed E.; Weisschuh, Nicole; McKibbin, Martin; Reuter, Peggy; Watson, Christopher M.; Baumann, Britta; Poulter, James A.; Sajid, Sundus; Panagiotou, Evangelia S.; O’Sullivan, James; Abdelhamed, Zakia; Bonin, Michael; Soltanifar, Mehdi; Black, Graeme C.M.; Din, Muhammad Amin-ud; Toomes, Carmel; Ansar, Muhammad; Inglehearn, Chris F.; Wissinger, Bernd

2015-01-01

Purpose To investigate the molecular basis of retinitis pigmentosa in two consanguineous families of Pakistani origin with multiple affected members. Methods Homozygosity mapping and Sanger sequencing of candidate genes were performed in one family while the other was analyzed with whole exome next-generation sequencing. A minigene splicing assay was used to confirm the splicing defects. Results In family MA48, a novel homozygous nucleotide substitution in C8orf37, c.244–2A>C, that disrupted the consensus splice acceptor site of exon 3 was found. The minigene splicing assay revealed that this mutation activated a cryptic splice site within exon 3, causing a 22 bp deletion in the transcript that is predicted to lead to a frameshift followed by premature protein truncation. In family MA13, a novel homozygous null mutation in C8orf37, c.555G>A, p.W185*, was identified. Both mutations segregated with the disease phenotype as expected in a recessive manner and were absent in 8,244 unrelated individuals of South Asian origin. Conclusions In this report, we describe C8orf37 mutations that cause retinal dystrophy in two families of Pakistani origin, contributing further data on the phenotype and the spectrum of mutations in this form of retinitis pigmentosa. PMID:25802487

Inherited IL-12Rβ1 Deficiency in a Child With BCG Adenitis and Oral Candidiasis: A Case Report.

PubMed

Hatipoglu, Nevin; Güvenç, B Haluk; Deswarte, Caroline; Koksalan, Kaya; Boisson-Dupuis, Stéphanie; Casanova, Jean-Laurent; Bustamante, Jacinta

2017-11-01

Tuberculosis is a major worldwide problem, and protection from it is achieved mainly by live attenuated bacille Calmette-Guérin vaccine, which is capable of causing disease in immunocompromised host. Oral thrush is abnormal in healthy children, which suggests an underlying immunodeficiency. Mendelian susceptibility to mycobacterial disease is a rare primary immunodeficiency characterized by a selective predisposition to weakly virulent Mycobacteria and Salmonella and also predisposition to chronic mucocutaneous candidiasis. Interleukin 12 receptor β1 (IL-12Rβ1) deficiency is the most common disease of Mendelian susceptibility to mycobacterial disease, and to date only 50 IL-12Rβ1 deficient patients with clinical signs of chronic mucocutaneous candidiasis have been reported. We report a 2.5-year-old daughter of consanguineous parents with both regional bacille Calmette-Guérin lymphadenitis and recurrent oral candidiasis carrying biallelic R175W mutation in the IL12RB1 gene, resulting in complete loss of expression of IL-12Rβ1. To our knowledge, this is the first report of bacille Calmette-Guérin lymphadenitis with concurrent oral candidiasis displaying such a mutation. New mutations and wide clinical diversities are the indisputable fact of populations with a high rate of consanguineous marriages. Copyright © 2017 by the American Academy of Pediatrics.

Cortical atrophy and hypofibrinogenemia due to FGG and TBCD mutations in a single family: a case report.

PubMed

Stephen, Joshi; Nampoothiri, Sheela; Vinayan, K P; Yesodharan, Dhanya; Remesh, Preetha; Gahl, William A; Malicdan, May Christine V

2018-05-16

Blended phenotypes or co-occurrence of independent phenotypically distinct conditions are extremely rare and are due to coincidence of multiple pathogenic mutations, especially due to consanguinity. Hereditary fibrinogen deficiencies result from mutations in the genes FGA, FGB, and FGG, encoding the three different polypeptide chains that comprise fibrinogen. Neurodevelopmental abnormalities have not been associated with fibrinogen deficiencies. In this study, we report an unusual patient with a combination of two independently inherited genetic conditions; fibrinogen deficiency and early onset cortical atrophy. The study describes a male child from consanguineous family presented with hypofibrinogenemia, diffuse cortical atrophy, microcephaly, hypertonia and axonal motor neuropathy. Through a combination of homozygosity mapping and exome sequencing, we identified bi-allelic pathogenic mutations in two genes: a homozygous novel truncating mutation in FGG (c.554del; p.Lys185Argfs*14) and a homozygous missense mutation in TBCD (c.1423G > A;p.Ala475Thr). Loss of function mutations in FGG have been associated with fibrinogen deficiency, while the c.1423G > A mutation in TBCD causes a novel syndrome of neurodegeneration and early onset encephalopathy. Our study highlights the importance of homozygosity mapping and exome sequencing in molecular prenatal diagnosis, especially when multiple gene mutations are responsible for the phenotype.

Isonymy structure of four Venezuelan states.

PubMed

Rodríguez-Larralde, A; Barrai, I; Alfonzo, J C

1993-01-01

The isonymy structure of four Venezuelan States-Falcón, Mérida, Nueva Esparta and Yaracuy-was studied using the surnames of the Venezuelan register of electors updated in 1984. The surname distributions of 155 counties were obtained and, for each county, estimates of consanguinity due to random isonymy and Fisher's alpha were calculated. It was shown that for large sample sizes the inverse of Fisher's alpha is identical to the unbiased estimate of within-population random isonymy. A three-dimensional isometric surface plot was obtained for each State, based on the counties' random isonymy estimates. The highest estimates of random consanguinity were found in the States of Nueva Esparta and Mérida, while the lowest were found in Yaracuy. Other microdifferentiation indicators from the same data gave similar results, and an interpretation was attempted, based on the particular economic and geographic characteristics of each State. Four different genetic distances between all possible pairs of counties were calculated within States; geographic distance shows the highest correlations with random isonymy and Euclidean distance, with the exception of the State of Nueva Esparta, where there is no correlation between geographic distance and random isonymy. It was possible to group counties in clusters, from dendrograms based on Euclidean distance. Isonymy clustering was also consistent with socioeconomic and geographic characteristics of the counties.

Molecular genetic analysis of consanguineous Pakistani families with autosomal recessive hypohidrotic ectodermal dysplasia.

PubMed

Bibi, Nosheen; Ahmad, Saeed; Ahmad, Wasim; Naeem, Muhammad

2011-02-01

Hypohidrotic ectodermal dysplasia is an inherited disorder characterized by defective development of teeth, hairs and sweat glands. X-linked hypohidrotic ectodermal dysplasia is caused by mutations in the EDA gene, and autosomal forms of hypohidrotic ectodermal dysplasia are caused by mutations in either the EDAR or the EDARADD genes. To study the molecular genetic cause of autosomal recessive hypohidrotic ectodermal dysplasia in three consanguineous Pakistani families (A, B and C), genotyping of 13 individuals was carried out by using polymorphic microsatellite markers that are closely linked to the EDAR gene on chromosome 2q11-q13 and the EDARADD gene on chromosome 1q42.2-q43. The results revealed linkage in the three families to the EDAR locus. Sequence analysis of the coding exons and splice junctions of the EDAR gene revealed two mutations: a novel non-sense mutation (p.E124X) in the probands of families A and B and a missense mutation (p.G382S) in the proband of family C. In addition, two synonymous single-nucleotide polymorphisms were also identified. The finding of mutations in Pakistani families extends the body of evidence that supports the importance of EDAR for the development of hypohidrotic ectodermal dysplasia. © 2010 The Authors. Australasian Journal of Dermatology © 2010 The Australasian College of Dermatologists.

Exome analysis identified a novel mutation in the RBP4 gene in a consanguineous pedigree with retinal dystrophy and developmental abnormalities.

PubMed

Cukras, Catherine; Gaasterland, Terry; Lee, Pauline; Gudiseva, Harini V; Chavali, Venkata R M; Pullakhandam, Raghu; Maranhao, Bruno; Edsall, Lee; Soares, Sandra; Reddy, G Bhanuprakash; Sieving, Paul A; Ayyagari, Radha

2012-01-01

Retinitis Pigmentosa (RP) is a common form of retinal degeneration characterized by photoreceptor degeneration and retinal pigment epithelium (RPE) atrophy causing loss of visual field and acuities. Exome sequencing identified a novel homozygous splice site variant (c.111+1G>A) in the gene encoding retinol binding protein 4 (RBP4). This change segregated with early onset, progressive, and severe autosomal recessive retinitis pigmentosa (arRP) in an eight member consanguineous pedigree of European ancestry. Additionally, one patient exhibited developmental abnormalities including patent ductus arteriosus and chorioretinal and iris colobomas. The second patient developed acne from young age and extending into the 5(th) decade. Both patients had undetectable levels of RBP4 in the serum suggesting that this mutation led to either mRNA or protein instability resulting in a null phenotype. In addition, the patients exhibited severe vitamin A deficiency, and diminished serum retinol levels. Circulating transthyretin levels were normal. This study identifies the RBP4 splice site change as the cause of RP in this pedigree. The presence of developmental abnormalities and severe acne in patients with retinal degeneration may indicate the involvement of genes that regulate vitamin A absorption, transport and metabolism.

Exome Analysis Identified a Novel Mutation in the RBP4 Gene in a Consanguineous Pedigree with Retinal Dystrophy and Developmental Abnormalities

PubMed Central

Cukras, Catherine; Gaasterland, Terry; Lee, Pauline; Gudiseva, Harini V.; Chavali, Venkata R. M.; Pullakhandam, Raghu; Maranhao, Bruno; Edsall, Lee; Soares, Sandra; Reddy, G. Bhanuprakash; Sieving, Paul A.; Ayyagari, Radha

2012-01-01

Retinitis Pigmentosa (RP) is a common form of retinal degeneration characterized by photoreceptor degeneration and retinal pigment epithelium (RPE) atrophy causing loss of visual field and acuities. Exome sequencing identified a novel homozygous splice site variant (c.111+1G>A) in the gene encoding retinol binding protein 4 (RBP4). This change segregated with early onset, progressive, and severe autosomal recessive retinitis pigmentosa (arRP) in an eight member consanguineous pedigree of European ancestry. Additionally, one patient exhibited developmental abnormalities including patent ductus arteriosus and chorioretinal and iris colobomas. The second patient developed acne from young age and extending into the 5th decade. Both patients had undetectable levels of RBP4 in the serum suggesting that this mutation led to either mRNA or protein instability resulting in a null phenotype. In addition, the patients exhibited severe vitamin A deficiency, and diminished serum retinol levels. Circulating transthyretin levels were normal. This study identifies the RBP4 splice site change as the cause of RP in this pedigree. The presence of developmental abnormalities and severe acne in patients with retinal degeneration may indicate the involvement of genes that regulate vitamin A absorption, transport and metabolism. PMID:23189188

Inbreeding levels in Northeast Brazil: Strategies for the prospecting of new genetic disorders.

PubMed

Santos, Silvana; Kok, Fernando; Weller, Mathias; de Paiva, Francisco Rennan Lopes; Otto, Paulo A

2010-04-01

A new autosomal recessive genetic condition, the SPOAN syndrome (an acronym for spastic paraplegia, optic atrophy and neuropathy syndrome), was recently discovered in an isolated region of the State of Rio Grande do Norte in Northeast Brazil, in a population that was identified by the IBGE (Brazilian Institute of Geography and Statistics) as belonging to the Brazilian communities with the highest rates of "deficiencies" (Neri, 2003), a term used to describe diseases, malformations, and handicaps in general. This prompted us to conduct a study of consanguinity levels in five of its municipal districts by directly interviewing their inhabitants. Information on 7,639 couples (corresponding to about 40% of the whole population of the studied districts) was obtained. The research disclosed the existence of very high frequencies of consanguineous marriages, which varied from about 9% to 32%, suggesting the presence of a direct association between genetic diseases such as the SPOAN syndrome, genetic drift and inbreeding levels. This fact calls for the introduction of educational programs for the local populations, as well as for further studies aiming to identify and characterize other genetic conditions. Epidemiological strategies developed to collect inbreeding data, with the collaboration of health systems available in the region, might be very successful in the prospecting of genetic disorders.

Early-Onset Central Diabetes Insipidus due to Compound Heterozygosity for AVP Mutations.

PubMed

Bourdet, Karine; Vallette, Sophie; Deladoëy, Johnny; Van Vliet, Guy

2016-01-01

Genetic cases of isolated central diabetes insipidus are rare, are mostly due to dominant AVP mutations and have a delayed onset of symptoms. Only 3 consanguineous pedigrees with a recessive form have been published. A boy with a negative family history presented polyuria and failure to thrive in the first months of life and was diagnosed with central diabetes insipidus. Magnetic resonance imaging showed a normal posterior pituitary signal. A molecular genetic analysis of the AVP gene showed that he had inherited a previously reported mutation from his Lebanese father and a novel A>G transition in the splice acceptor site of intron 1 (IVS1-2A>G) from his French-Canadian mother. Replacement therapy resulted in the immediate disappearance of symptoms and in weight gain. The early polyuria in recessive central diabetes insipidus contrasts with the delayed presentation in patients with monoallelic AVP mutations. This diagnosis needs to be considered in infants with very early onset of polyuria-polydipsia and no brain malformation, even if there is no consanguinity and regardless of whether the posterior pituitary is visible or not on imaging. In addition to informing family counseling, making a molecular diagnosis eliminates the need for repeated imaging studies. © 2015 S. Karger AG, Basel.

Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract

PubMed Central

Vivante, Asaf; Hwang, Daw-Yang; Kohl, Stefan; Chen, Jing; Shril, Shirlee; Schulz, Julian; van der Ven, Amelie; Daouk, Ghaleb; Soliman, Neveen A.; Kumar, Aravind Selvin; Senguttuvan, Prabha; Kehinde, Elijah O.; Tasic, Velibor

2017-01-01

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the leading cause of CKD in children, featuring a broad variety of malformations. A monogenic cause can be detected in around 12% of patients. However, the morphologic clinical phenotype of CAKUT frequently does not indicate specific genes to be examined. To determine the likelihood of detecting causative recessive mutations by whole-exome sequencing (WES), we analyzed individuals with CAKUT from 33 different consanguineous families. Using homozygosity mapping and WES, we identified the causative mutations in nine of the 33 families studied (27%). We detected recessive mutations in nine known disease–causing genes: ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, and PKHD1. Notably, when mutated, these genes cause multiorgan syndromes that may include CAKUT as a feature (syndromic CAKUT) or cause renal diseases that may manifest as phenocopies of CAKUT. None of the above monogenic disease–causing genes were suspected on clinical grounds before this study. Follow-up clinical characterization of those patients allowed us to revise and detect relevant new clinical features in a more appropriate pathogenetic context. Thus, applying WES to the diagnostic approach in CAKUT provides opportunities for an accurate and early etiology–based diagnosis and improved clinical management. PMID:27151922

Primary hyperoxaluria type 1 in 18 children: genotyping and outcome.

PubMed

Al Riyami, Mohamed S; Al Ghaithi, Badria; Al Hashmi, Nadia; Al Kalbani, Naifain

2015-01-01

Background. Primary hyperoxaluria belongs to a group of rare metabolic disorders with autosomal recessive inheritance. It results from genetic mutations of the AGXT gene, which is more common due to higher consanguinity rates in the developing countries. Clinical features at presentation are heterogeneous even in children from the same family; this study was conducted to determine the clinical characteristics, type of AGXT mutation, and outcome in children diagnosed with PH1 at a tertiary referral center in Oman. Method. Retrospective review of children diagnosed with PH1 at a tertiary hospital in Oman from 2000 to 2013. Result. Total of 18 children were identified. Females composed 61% of the children with median presentation age of 7 months. Severe renal failure was initial presentation in 39% and 22% presented with nephrocalcinosis and/or renal calculi. Family screening diagnosed 39% of patients. Fifty percent of the children underwent hemodialysis. 28% of children underwent organ transplantation. The most common mutation found in Omani children was c.33-34insC mutation in the AGXT gene. Conclusion. Due to consanguinity, PH1 is a common cause of ESRD in Omani children. Genetic testing is recommended to help in family counseling and helps in decreasing the incidence and disease burden; it also could be utilized for premarital screening.

Primary Hyperoxaluria Type 1 in 18 Children: Genotyping and Outcome

PubMed Central

Al Riyami, Mohamed S.; Al Ghaithi, Badria; Al Hashmi, Nadia; Al Kalbani, Naifain

2015-01-01

Background. Primary hyperoxaluria belongs to a group of rare metabolic disorders with autosomal recessive inheritance. It results from genetic mutations of the AGXT gene, which is more common due to higher consanguinity rates in the developing countries. Clinical features at presentation are heterogeneous even in children from the same family; this study was conducted to determine the clinical characteristics, type of AGXT mutation, and outcome in children diagnosed with PH1 at a tertiary referral center in Oman. Method. Retrospective review of children diagnosed with PH1 at a tertiary hospital in Oman from 2000 to 2013. Result. Total of 18 children were identified. Females composed 61% of the children with median presentation age of 7 months. Severe renal failure was initial presentation in 39% and 22% presented with nephrocalcinosis and/or renal calculi. Family screening diagnosed 39% of patients. Fifty percent of the children underwent hemodialysis. 28% of children underwent organ transplantation. The most common mutation found in Omani children was c.33-34insC mutation in the AGXT gene. Conclusion. Due to consanguinity, PH1 is a common cause of ESRD in Omani children. Genetic testing is recommended to help in family counseling and helps in decreasing the incidence and disease burden; it also could be utilized for premarital screening. PMID:25918646

Congenital combined deficiency of coagulation factors: a study of seven patients.

PubMed

Naderi, Majid; Tabibian, Shadi; Hosseini, Maryam Sadat; Alizadeh, Shaban; Hosseini, Soudabeh; Shamsizadeh, Morteza; Dorgalaleh, Akbar

2015-01-01

Combined deficiency of coagulation factors is considered as an extremely rare bleeding disorder (RBD) inherited in an autosomal recessive pattern. This disorder is more likely to occur in regions with a high rate of consanguineous marriages or in restricted communities. Sistan and Baluchistan, a province in southeast of Iran with a high rate of consanguinity, is a clear model of such regions with a very high prevalence of recessively inherited disorders. The aim of this study was to report the frequency of combined factor deficiency in this province. This descriptive study was conducted on 358 patients with RBD. Demographic information and medical history of each patient were recorded, and the patients were examined by a physician. Routine screening tests were carried out for all patients, and further coagulation tests including coagulation factor activity and antigen assays were subsequently performed for all suspected patients. Among 358 patients, four were found to be affected with combined factor (F)V and FVIII deficiency (F5F8D). In addition, one patient with combined deficiency of FVII-FXIII, one with combined FVII-FX and one with combined FVIII-FIX deficiency were identified. In Sistan and Baluchistan Province, coinheritance of recessively inherited disorders like combined coagulation factor deficiencies was surprisingly higher than expected.

[Usher syndrome: about a case].

PubMed

Daoudi, Chama; Boutimzine, Noureddine; Haouzi, Samia El; Lezrek, Omar; Tachfouti, Samira; Lezrek, Mounir; Laghmari, Mina; Daoudi, Rajae

2017-01-01

Usher syndrome is a genetic disease resulting in double sensory deprivation (auditory and visual) called deafblindness. We report the case of a 50-year old patient, born to consanguineous parents, presenting with congenital deafness associated with normal vestibular function and pigmentary retinopathy responsible for decreased bilateral visual acuity occurred at the age of 16 years. This association composes Usher syndrome type 2, a rare autosomal recessive disorder. Cataract surgery allowed visual acuity improvement in this patient.

X-linked mental retardation syndrome: Three brothers with the Brooks-Wisniewski-Brown syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Morava, E.; Storcz, J.; Kosztolanyi, G.

1996-07-12

We report on 3 brothers with growth and mental retardation, bifrontal narrowness, short palpebral fissures, deeply set eyes with entropion, wide bulbous nose, small mouth, myopia, and spastic diplegia. The patients were born to normal and non-consanguineous parents. The similarity of our cases with those recently reported by Brooks et al. supports their suggestion that these patients are representative of a distinct entity. 8 refs., 3 figs., 1 tab.

Homozygosity for the AATAAA > AATA- - Polyadenylation Site Mutation on the α2-Globin Gene Causing Transfusion-Dependent Hb H Disease in an Iranian Patient: A Case Report.

PubMed

Farashi, Samaneh; Garous, Negin F; Ashki, Mehri; Vakili, Shadi; Zeinali, Fatemeh; Imanian, Hashem; Azarkeivan, Azita; Giordano, Piero C; Najmabadi, Hossein

2015-01-01

We describe a case of Hb H disease associated with homozygosity for a two nucleotide deletion in the polyadenylation signal of the α2-globin gene (HBA2: c.*93_*94delAA). The patient, a 27-year-old son of a consanguineous couple, needs regular blood transfusions every 6 months.

JPRS Report, East Europe Supplement Poland Recent Legislation II.

DTIC Science & Technology

1990-08-13

of the Supreme Court are appointed and recalled by the Pres- ident. Article 30.1. Persons related by ties of consanguinity up to the second remove...may they take part in the same ruling bench of justices and neither may they stand in a direct official superior- subordinate relationship . 30.2...outlets under the jurisdiction of the Minister of Internal Affairs. Article 12.1. The labor relationship of the employees of the organizational units

Statistical Measurement and Analysis of Claimant and Demographic Variables Affecting Processing and Adjudication Duration in The United States Army Physical Disability Evaluation System.

DTIC Science & Technology

1997-02-06

Adjudication Duration 2 2. INTRODUCTION This retrospective study analyzes relationships of variables to adjudication and processing duration in the Army...Package for Social Scientists (SPSS), Standard Version 6.1, June 1994, to determine relationships among the dependent and independent variables... consanguinity between variables. Content and criterion validity is employed to determine the measure of scientific validity. Reliability is also

Sjögren-Larsson syndrome in dizygous twin sisters.

PubMed

David, T J

1980-01-01

Two dizygous twin sisters with the Sjögren-Larsson syndrome are described. There was parental consanguinity, and the condition is inherited as an autosomal recessive. The main features are mental retardation, spastic diplegia and ichthyosis. Sensory defects of gums and abnormal facial movements were found in the twins, these being recognised features of the syndrome. It is suggested that the condition may be due to an abnormality of the neural crest.

A follow-up on Hanhart's dwarfs of Krk.

PubMed

Zergollern, L

1971-05-01

Krk is the largest of the Yugoslav islands. On it, due to isolation and consanguineous marriages, certain hereditary diseases such as dwarfism, albinism and a progressive spastic quadriplegia associated with cataracts and mental defect, appear more frequently than in the rest of the population. In this short review, the primary concern is with the first of the disorders. Evidence is presented that Hanhart's dwarfs, as they have been called, have recessively inherited panhypopituitarism.

Association of PPARγ2 gene variant Pro12Ala polymorphism with hypertension and obesity in the aboriginal Qatari population known for being consanguineous

PubMed Central

Bener, Abdulbari; Darwish, Sarah; Al-Hamaq, Abdulla OAA; Mohammad, Ramzi M; Yousafzai, Mohammad T

2013-01-01

Aim The aim of this study was to investigate the association of the Pro12Ala polymorphism of the human peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene with hypertension and obesity in a highly consanguineous aboriginal Qatari population. Design A cross-sectional survey conducted from January 2011–December 2012. Setting Primary health care clinics. Subjects A random sample of 1,528 Qatari male and female population older than 20 years of age. Materials and methods Data on age, sex, income, level of education, occupation status, body mass index, and blood pressure and lipid profile were obtained. The Pro12Ala in the PPARγ2 gene was detected on the LightCycler® using two specific probes: (Sensor [G] 5′-CTC CTA TTG ACG CAG AAA GCG-FL and PPAR Anchor 5′ LC Red 640- TCC TTC ACT GAT ACA CTG TCT GCA AAC ATA TC-PH). Univariate and multivariate logistic regression were performed. Result Out of a total 1,528 participants, 220 were diagnosed with essential hypertension, and 420 were obese. Participants with consanguinity were significantly higher among hypertensive than normotensive (41.9% versus 30.8%; P=0.001). Altogether, more than three-fourths (89%) of the participants had a wild genotype (Pro12Pro), 9.8% were heterozygous with Pro12Ala, and only 1.2% was homozygous with the Ala12Ala genotype. The frequency of the Pro allele was 94.5% in normotensive versus 90.5% in hypertensive, while the distribution of the Ala allele was 5.5% in normotensive versus 9.5% in the hypertensive group (P=0.001). The odds of hypertension were 1.7 times higher among the participants with the Ala allele as compared to those with the Pro, while adjusting for other potential confounders (adjusted odds ratio 1.69; 95% confidence interval 1.12–2.55; P=0.012). There was no association between the PPARγ2Ala allele and obesity (P=0.740). Conclusion The current study revealed an association between the PPARγ2Ala allele and hypertension in Qatar’s population. On the other hand, this study found no association between the Ala allele and obesity. PMID:24187509

Usher syndrome associated with a variant of Dandy-Walker malformation.

PubMed

Simsek, Tulay; Ozdamar, Yasemin; Simsek, Enver; Men, Gamze

2010-05-21

Three cases of Usher syndrome associated with a variant of Dandy-Walker malformation in three siblings from consanguineous Turkish parents are described. The siblings had retinitis pigmentosa and hearing loss. Two of the siblings also had mental retardation, which is not a constant finding in Usher syndrome. Dandy-Walker malformation might have contributed to the mental retardation in two of these patients and might be a coincidental finding with Usher syndrome. Copyright 2010, SLACK Incorporated.

Autosomal recessive Oliver-McFarlane syndrome: retinitis pigmentosa, short stature (GH deficiency), trichomegaly, and hair anomalies or CPD syndrome (chorioretinopathy-pituitary dysfunction).

PubMed

Haimi, Motti; Gershoni-Baruch, Ruth

2005-10-15

We describe a brother and sister with retinitis pigmentosa (RP), growth failure, long eyelashes, and sparse hair. They were born to young healthy consanguineous parents and presented at birth with IUGR. Evolving pigmentary retinopathy was diagnosed at the age of 5 years. A similar condition (Oliver-McFarlane) syndrome was reported previously. Our two sibs confirm the existence of this autosomal recessive syndrome.

Probable high prevalence of limb-girdle muscular dystrophy type 2D in Taiwan.

PubMed

Liang, Wen-Chen; Chou, Po-Ching; Hung, Chia-Cheng; Su, Yi-Ning; Kan, Tsu-Min; Chen, Wan-Zi; Hayashi, Yukiko K; Nishino, Ichizo; Jong, Yuh-Jyh

2016-03-15

Limb-girdle muscular dystrophy type 2D (LGMD2D), an autosomal-recessive inherited LGMD, is caused by the mutations in SGCA. SGCA encodes alpha-sarcoglycan (SG) that forms a heterotetramer with other SGs in the sarcolemma, and comprises part of the dystrophin-glycoprotein complex. The frequency of LGMD2D is variable among different ethnic backgrounds, and so far only a few patients have been reported in Asia. We identified five patients with a novel homozygous mutation of c.101G>T (p.Arg34Leu) in SGCA from a big aboriginal family ethnically consisting of two tribes in Taiwan. Patient 3 is the maternal uncle of patients 1 and 2. All their parents, heterozygous for c.101G>T, denied consanguineous marriages although they were from the same tribe. The heterozygous parents of patients 4 and 5 were from two different tribes, originally residing in different geographic regions in Taiwan. Haplotype analysis showed that all five patients shared the same mutation-associated haplotype, indicating the probability of a founder effect and consanguinity. The results suggest that the carrier rate of c.101G>T in SGCA may be high in Taiwan, especially in the aboriginal population regardless of the tribes. It is important to investigate the prevalence of LGMD2D in Taiwan for early diagnosis and treatment. Copyright © 2016. Published by Elsevier B.V.

WDR73 missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in a consanguineous family.

PubMed

Jiang, Chen; Gai, Nan; Zou, Yongyi; Zheng, Yu; Ma, Ruiyu; Wei, Xianda; Liang, Desheng; Wu, Lingqian

2017-01-01

Galloway-Mowat syndrome (GMS) is a very rare autosomal-recessive disorder characterized by nephrotic syndrome associated with microcephaly, and various central nervous system abnormalities, mostly cerebral hypoplasia or cerebellar atrophy, intellectual disability and neural-migration defects. WDR73 is the only gene known to cause GMS, and has never been implicated in other disease. Here we present a Chinese consanguineous family with infantile onset intellectual disability and cerebellar hypoplasia but no microcephaly. Whole exome sequencing identified a WDR73 p.W371G missense mutation. The mutation is confirmed to be segregated in this family by Sanger sequencing according to a recessive inheritance pattern. It is predicted to be deleterious by multiple algorithms and affect highly conserved site. Structural modeling revealed conformational differences between the wild type protein and the p.W371G protein. Real-time PCR and Western blotting revealed altered mRNA and protein levels in mutated samples. Our study indicates the novel WDR73 p.W371G missense mutation causes infantile onset intellectual disability and cerebellar hypoplasia in recessive mode of inheritance. Our findings imply that microcephaly is a variable phenotype in WDR73-related disease, suggest WDR73 to be a candidate gene of severe intellectual disability and cerebellar hypoplasia, and expand the molecular spectrum of WDR73-related disease. Copyright © 2016 Elsevier B.V. All rights reserved.

Novel SIL1 nonstop mutation in a Chinese consanguineous family with Marinesco-Sjögren syndrome and Dandy-Walker syndrome.

PubMed

Gai, Nan; Jiang, Chen; Zou, Yong-Yi; Zheng, Yu; Liang, De-Sheng; Wu, Ling-Qian

2016-07-01

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder, which is characterized by congenital cataracts, cerebellar ataxia, progressive muscle weakness, and delayed psychomotor development. SIL1, which is located at 5q31.2, is the only gene known to cause MSS. Dandy-Walker syndrome (DWS) is defined by hypoplasia, upward rotation of the cerebellar vermis, and cystic dilation of the fourth ventricle; however, its genetic pathogeny remains unclear. Here, we report a Chinese consanguineous family with MSS and DWS. Whole exome sequencing identified a novel nonstop mutation in SIL1. Sanger sequencing revealed that the mutation was segregated in this family according to a recessive mode of inheritance. We found that the mutation changed a stop codon (TGA) to an arginine codon (CGA), and no in-frame termination codon in the 3' untranslated region (UTR) of SIL1 could be found. The mRNA levels of SIL1 were decreased by 56.6% and 37.5% in immortalized lymphoblasts of the patients respectively; the protein levels of SIL1 were substantially decreased. This case study is the first report on Chinese MSS patients, MSS complicated by DWS, and a nonstop mutation in SIL1. Our findings imply the pathogenetic association between DWS and MSS. Copyright © 2016 Elsevier B.V. All rights reserved.

Towards a complete North American Anabaptist Genealogy II: analysis of inbreeding.

PubMed

Agarwala, R; Schäffer, A A; Tomlin, J F

2001-08-01

We describe a large genealogy data base, which can be searched by computer, of 295,095 Amish and Mennonite individuals. The data base was constructed by merging our existing Anabaptist Genealogy Database 2.0 containing approximately 85,000 individuals with a genealogy file containing approximately 242,000 individuals, kindly provided by Mr. James Hostetler. The merging process corrected thousands of inconsistencies and eliminated hundreds of duplicate individuals. Geneticists have long been interested in Anabaptist populations because they are closed and have detailed written genealogies. The creation of an enlarged and unified data base affords the opportunity to examine inbreeding trends and correlates in these populations. We show the following results. The frequency of consanguineous marriages shows steady increase over time and reached approximately 85% for individuals born in 1940-1959. Among consanguineous marriages, the median kinship coefficient stayed stable in the 19th century, but rose from 0.0115 to 0.0151 in the 20th century. There are statistically significant associations (p < 0.0001) between inbreeding and family size and interbirth intervals in the 20th century. There is an association (p < 0.0005) between inbreeding and early death for individuals born in 1920-1959. However, this association reverses dramatically (p < 0.0005 in the opposite direction) for individuals born in 1960-1979. We tested for an association between inbreeding and being the mother of twins, but found none.

Correlation between incidences of self-inflicted burns and means of inbreeding coefficients, an ecologic study.

PubMed

Saadat, Mostafa; Zendeh-Boodi, Zahra

2006-09-01

The aim of the study is to obtain more insight into the possible association between consanguinity and the incidence of deliberate self-burning. Data were obtained by analysis of medical records of patients hospitalized in two referral burn centers: Chormy Burn Center (Bushehr Province, south of Iran) from March 21, 1998, through March 20, 2004, and Shahid Sadoqi Center of Burns and Injuries (Yazd Province, center of Iran) from March 21, 2000, through March 20, 2004. The incidence of suicidal burns was 6.51 and 2.32/100,000 person-years for Bushehr and Yazd Provinces, respectively. The observed sex ratio of patients in both centers indicated there was a female predominance in patients with self-inflicted burns. Using patients' home addresses, patients were sorted into 16 cities. The incidence of suicide by self-burning ranged from 0.80 (for Tabas, located in Yazd Province) to 12.60/100,000 person-years (for Dilam, located in Bushehr Province). The coefficient of inbreeding defines the probability that an individual received both alleles of a pair from an identical ancestral source. There was a significant correlation between incidences of suicidal burns and mean coefficient of inbreeding (r = 0.782, df = 14, p < 0.001). In addition to other factors, consanguineous marriage may be a risk factor that influences the incidence of suicidal burns in a population.

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

PubMed Central

Abou Jamra, R; Wohlfart, Sigrun; Zweier, Markus; Uebe, Steffen; Priebe, Lutz; Ekici, Arif; Giesebrecht, Susanne; Abboud, Ahmad; Al Khateeb, Mohammed Ayman; Fakher, Mahmoud; Hamdan, Saber; Ismael, Amina; Muhammad, Safia; Nöthen, Markus M; Schumacher, Johannes; Reis, André

2011-01-01

Non-specific intellectual disability of autosomal recessive inheritance (NS-ARID) represents an important fraction of severe cognitive dysfunction disorders. To date, only 10 genes have been identified, and further 24 linked-ARID loci have been reported, as well as others with suggestive linkage. To discover novel genes causing NS-ARID, we undertook genome-wide homozygosity mapping in 64 consanguineous multiplex families of Syrian descent. A total of 11 families revealed unique, significantly linked loci at 4q26-4q28 (MRT17), 6q12-q15 (MRT18), 18p11 (MRT19), 16p12-q12 (MRT20), 11p15 (MRT21), 11p13-q14 (MRT23), 6p12 (MRT24), 12q13-q15 (MRT25), 14q11-q12 (MRT26), 15q23-q26 (MRT27), and 6q26-q27 (MRT28), respectively. Loci ranged between 1.2 and 45.6 Mb in length. One family showed linkage to chromosome 8q24.3, and we identified a mutation in TRAPPC9. Our study further highlights the extreme heterogeneity of NS-ARID, and suggests that no major disease gene is to be expected, at least in this study group. Systematic analysis of large numbers of affected families, as presented here, will help discovering the genetic causes of ID. PMID:21629298

Exome Sequencing Discerns Syndromes in Patients from Consanguineous Families with Congenital Anomalies of the Kidneys and Urinary Tract.

PubMed

Vivante, Asaf; Hwang, Daw-Yang; Kohl, Stefan; Chen, Jing; Shril, Shirlee; Schulz, Julian; van der Ven, Amelie; Daouk, Ghaleb; Soliman, Neveen A; Kumar, Aravind Selvin; Senguttuvan, Prabha; Kehinde, Elijah O; Tasic, Velibor; Hildebrandt, Friedhelm

2017-01-01

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the leading cause of CKD in children, featuring a broad variety of malformations. A monogenic cause can be detected in around 12% of patients. However, the morphologic clinical phenotype of CAKUT frequently does not indicate specific genes to be examined. To determine the likelihood of detecting causative recessive mutations by whole-exome sequencing (WES), we analyzed individuals with CAKUT from 33 different consanguineous families. Using homozygosity mapping and WES, we identified the causative mutations in nine of the 33 families studied (27%). We detected recessive mutations in nine known disease-causing genes: ZBTB24, WFS1, HPSE2, ATRX, ASPH, AGXT, AQP2, CTNS, and PKHD1 Notably, when mutated, these genes cause multiorgan syndromes that may include CAKUT as a feature (syndromic CAKUT) or cause renal diseases that may manifest as phenocopies of CAKUT. None of the above monogenic disease-causing genes were suspected on clinical grounds before this study. Follow-up clinical characterization of those patients allowed us to revise and detect relevant new clinical features in a more appropriate pathogenetic context. Thus, applying WES to the diagnostic approach in CAKUT provides opportunities for an accurate and early etiology-based diagnosis and improved clinical management. Copyright © 2016 by the American Society of Nephrology.

Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity.

PubMed

Abiri, Maryam; Talebi, Saeed; Uitto, Jouni; Youssefian, Leila; Vahidnezhad, Hassan; Shirzad, Tina; Salehpour, Shadab; Zeinali, Sirous

2016-10-01

Most inborn errors of metabolism (IEMs) are inherited in an autosomal recessive manner. IEMs are one of the major concerns in Iran due to its extensive consanguineous marriages. Herein, we report two patients with two co-existent IEMs: a girl affected by classic phenylketonuria (PKU) and maple syrup urine disease (MSUD) and a male patient affected with Sandhoff disease and PKU, where Sandhoff disease was suspected due to the presence of a cherry-red spot in the eyes at 6 months which is unrelated to PKU. Sequencing of candidate genes in the first patient revealed one novel and three recurrent compound heterozygous mutations of p.Ser231Pro and p.Ala300Ser in the PAH gene and p.Glu330Lys and p.Arg170Cys mutations in the BCKDHB gene. Genetic testing results in the second patient showed previously reported homozygous mutations of p.Arg261Gln in the PAH and p.Arg533Cys mutation in the HEXB gene. Genetic testing confirmed the clinical diagnosis of both diseases in both patients. To the best of our knowledge; this is the first report of the co-existence of two distinct genetic disorders in two individuals from Iran. Co-existent different IEMs in patients complicated the clinical diagnosis and management of the diseases.

SYNE1 related cerebellar ataxia presents with variable phenotypes in a consanguineous family from Turkey.

PubMed

Yucesan, E; Ugur Iseri, Sibel A; Bilgic, B; Gormez, Z; Bakir Gungor, B; Sarac, A; Ozdemir, O; Sagiroglu, M; Gurvit, H; Hanagasi, H; Ozbek, U

2017-12-01

SYNE1 related autosomal recessive cerebellar ataxia type 1 (ARCA1) is a late-onset cerebellar ataxia with slow progression originally demonstrated in French-Canadian populations of Quebec, Canada. Nevertheless, recent studies on SYNE1 ataxia have conveyed the condition from a geographically limited pure cerebellar recessive ataxia to a complex multisystem phenotype that is relatively common on the global scale. To determine the underlying genetic cause of the ataxia phenotype in a consanguineous family from Turkey presenting with very slow progressive cerebellar symptoms including dysarthria, dysmetria, and gait ataxia, we performed SNP-based linkage analysis in the family along with whole exome sequencing (WES) in two affected siblings. We identified a homozygous variant in SYNE1 (NM_033071.3: c.13086delC; p.His4362GlnfsX2) in all four affected siblings. This variant presented herein has originally been associated with only pure ataxia in a single case. We thus present segregation and phenotypic manifestations of this variant in four affected family members and further extend the pure ataxia phenotype with upper motor neuron involvement and peripheral neuropathy. Our findings in turn established a precise molecular diagnosis in this family, demonstrating the use of WES combined with linkage analysis in families as a powerful tool for establishing a quick and precise genetic diagnosis of complex neurological phenotypes.

dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure.

PubMed

Dos Santos, Reinaldo Sousa; Daures, Mathilde; Philippi, Anne; Romero, Sophie; Marselli, Lorella; Marchetti, Piero; Senée, Valérie; Bacq, Delphine; Besse, Céline; Baz, Baz; Marroquí, Laura; Ivanoff, Sarah; Masliah-Planchon, Julien; Nicolino, Marc; Soulier, Jean; Socié, Gérard; Eizirik, Decio L; Gautier, Jean-François; Julier, Cécile

2017-04-01

We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase ( DUT ) gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this DUT mutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for β-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance. © 2017 by the American Diabetes Association.

The Spectrum of Familial Hypercholesterolemia (FH) in Saudi Arabia: Prime Time for Patient FH Registry

PubMed Central

Alallaf, Faisal; H.Nazar, Fatima Amanullah; Alnefaie, Majed; Almaymuni, Adel; Rashidi, Omran Mohammed; Alhabib, Khalid; Alnouri, Fahad; Alama, Mohamed-Nabil; Athar, Mohammad; Awan, Zuhier

2017-01-01

Background: Familial hypercholesterolemia (FH) is a life-threatening inherited condition. Untreated patients have the risk to develop raised plasma levels of cholesterol, atherosclerosis and cardiovascular disease (CVD). If diagnosed and treated early in life, the pathological consequences due to atherosclerosis could be avoided and patients with FH can have an anticipated normal life. Mounting evidence suggests that FH is underdiagnosed and undertreated in all populations. The underlying molecular basis of FH is the presence of mutations in one or more genes in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin 9 (PCSK9). However, their prevalence is largely unknown in Saudi Arabia but given the high rates of consanguinity, the prevalence appears to be higher. Furthermore, the high prevalence of obesity and diabetes mellitus in Saudi Arabia increases the vascular disease burden in FH cases by adding additional CVD risk factors. Objective: This article explores the spectrum of FH-causing mutations in the highly consanguineous Saudi community, the need for establishing the Saudi FH registry, the challenges in creating gene databases, and cascade screening. Conclusion: The establishment of FH registry and genetic testing should raise awareness not only among healthcare professionals, but the general population as well. It also helps to provide the best treatment regimen in a cost effective manner to this under-recognised population of FH patients. PMID:28868092

Cost-benefit analysis: newborn screening for inborn errors of metabolism in Lebanon.

PubMed

Khneisser, I; Adib, S; Assaad, S; Megarbane, A; Karam, P

2015-12-01

Few countries in the Middle East-North Africa region have adopted national newborn screening for inborn errors of metabolism by tandem mass spectrometry (MS/MS). We aimed to evaluate the cost-benefit of newborn screening for such disorders in Lebanon, as a model for other developing countries in the region. Average costs of expected care for inborn errors of metabolism cases as a group, between ages 0 and 18, early and late diagnosed, were calculated from 2007 to 2013. The monetary value of early detection using MS/MS was compared with that of clinical "late detection", including cost of diagnosis and hospitalizations. During this period, 126000 newborns were screened. Incidence of detected cases was 1/1482, which can be explained by high consanguinity rates in Lebanon. A reduction by half of direct cost of care, reaching on average 31,631 USD per detected case was shown. This difference more than covers the expense of starting a newborn screening programme. Although this model does not take into consideration the indirect benefits of the better quality of life of those screened early, it can be argued that direct and indirect costs saved through early detection of these disorders are important enough to justify universal publicly-funded screening, especially in developing countries with high consanguinity rates, as shown through this data from Lebanon. © The Author(s) 2015.

Canavan disease: an Arab scenario.

PubMed

Zayed, Hatem

2015-04-10

The autosomal recessive Canavan disease (CD) is a neurological disorder that begins in infancy. CD is caused by mutations in the gene encoding the ASPA enzyme. It has been reported with high frequency in patients with Jewish ancestry, and with low frequency in non-Jewish patients. This review will shed light on some updates regarding CD prevalence and causative mutations across the Arab World. CD was reported in several Arab countries such as Saudi Arabia, Egypt, Jordan, Yemen, Kuwait, and Tunisia. The population with the highest risk is in Saudi Arabia due the prevalent consanguineous marriage culture. In several studies, four novel mutations were found among Arabian CD patients, including two missense mutations (p.C152R, p.C152W), a 3346bp deletion leading to the removal of exon 3 of the ASPA gene, and an insertion mutation (698insC). Other previously reported mutations, which led to damage in the ASPA enzyme activities found among CD Arab patients are c.530 T>C (p.I177T), c.79G>A (p.G27R), IVS4+1G>T, and a 92kb deletion, which is 7.16kb upstream from the ASPA start site. This review will help in developing customized molecular diagnostic approaches and promoting CD carrier screening in the Arab world in areas where consanguineous marriage is common particularly within Saudi Arabia. Copyright © 2015 Elsevier B.V. All rights reserved.

Diagnostic survey at Yamanashi School for Blind: importance of heredity.

PubMed

Tsukahara, S; Sasamoto, M; Watanabe, I; Phillips, C I

1985-01-01

The commonest cause of blindness among the 67 patients at the Yamanashi School for the Blind was congenital cataract (16). Next was retinitis pigmentosa or choroido-retinal degeneration (8), then retinopathy of prematurity (7). Congenital glaucoma and brain tumor each contributed five. Four were due to microphthalmia/micro-cornea and five to high myopia. Direct ocular trauma caused three. Two each were attributable to complete albinism, aniridia, congenital nystagmus and bilateral retinoblastoma. Single cases each of anophthalmos, Behçet's disease, Hallerman-Streiff syndrome, hydrocephalus, macular degeneration and optic atrophy were recorded. 41.8% of all cases were "very probably" hereditary and a further 10.4% "probably" so. 12.2% of the hereditary cases had consanguineous parents. An autosomal recessive (AR) cause is the likeliest explanation for the majority of the nonenvironmental causes (42.9% very probably AR and 14.3% probably AR), so that the possibility of prevention by genetic counseling was limited, but should have been given as soon as the first affected child was born. Parental consanguinity supports an autosomal recessive cause. 10.2% are very definitely due to an autosomal dominant gene; in them, counseling may well also have had a limited effect but might have prevented the birth of one or both of the siblings with aniridia inherited from the mother, and at least two, if not all three, of the three siblings with congenital cataract also inherited from the mother.

Congenital color blindness in young Turkish men.

PubMed

Citirik, Mehmet; Acaroglu, Golge; Batman, Cosar; Zilelioglu, Orhan

2005-04-01

We investigated a healthy population of men from different regions of Turkey for the presence of congenital red-green color blindness. Using Ishihara pseudoisochromatic plates, 941 healthy men from the Turkish army were tested for congenital red-green color blindness. The prevalence of red-green color blindness was 7.33 +/- 0.98% (5.10% protans and 2.23% deutans). These ratios were higher than other reported samples from Mediterranean Europe. Higher percentages of color blindness were found in regions with a lower education level and more consanguineous marriages.

Dwarfism with gloomy face: a new syndrome with features of 3-M syndrome.

PubMed Central

Le Merrer, M; Brauner, R; Maroteaux, P

1991-01-01

Nine children with primordial dwarfism are described and a new syndrome is delineated. The significant features of this syndrome include facial dysmorphism with gloomy face and very short stature, but no radiological abnormality or hormone deficiency. Mental development is normal. The mode of inheritance seems to be autosomal recessive because of consanguinity in three of the four sibships. Some overlap with the 3-M syndrome is discussed but the autonomy of the gloomy face syndrome seems to be real. Images PMID:2051454

Study of a large Anglo-Saxon family with beta-thalassaemia trait.

PubMed

Raik, E; Powell, E; Gordon, S

1976-01-01

Study of a large Anglo-Saxon family with beta-thalassaemia trait revealed evidence of consanguinity, moreover both branches of the family shared a Spanish ancestor. The manifestations of the disorder were varied in severity and yet the degree of severity appeared to breed true within any individual part of the family. Our explanation for the inheritance pattern observed in the family was to postulate the existence of two non-allelic genes influencing the rate of beta-chain synthesis.

Association of monoclonal expansion of Epstein-Barr virus-negative CD158a+ NK cells secreting large amounts of gamma interferon with hemophagocytic lymphohistiocytosis.

PubMed

López-Alvarez, María R; Martínez-Sánchez, María V; Salgado-Cecilia, María G; Campillo, José A; Heine-Suñer, Damian; Villar-Permuy, Florentina; Fuster, José L; Bas, Agueda; Gil-Herrera, Juana; Muro, Manuel; García-Alonso, Ana M; Alvarez-López, María R; Minguela, Alfredo

2009-01-01

We report the first case of hemophagocytic lymphohistiocytosis (HLH) induced by the monoclonal expansion of Epstein-Barr virus (EBV)-negative NK cells. Consanguinity of the patient's parents made it necessary to discard familial HLH in the patient and her sister with identical HLA markers and demonstrate that no cause other than the expansion of NK cells, which secrete high levels of gamma interferon, was inducing HLH in this patient.

[Cryptorchidism with didymo-epididymal dissociation and Robinow's syndrome: 2 case reports].

PubMed

Fabbro, M A; D'Agostino, S; Costa, L; Musi, L; Cappellari, F

1997-01-01

Two brothers of normal not consanguineous parents, with bilateral intrabdominal cryptorchidism, were admitted to our Institution. Both children had short stature, limb and hand malformations and craniofacial patterns of Robinow syndrome. During the orchidopexy, bilateral epididymal and vasal abnormalities were found in both of them. This anomaly associated with Robinow syndrome has never been reported before. These two cases provides the Authors with the opportunity of reviewing clinical features, genetics and radiological patterns of this rare syndrome.

Acral peeling skin syndrome: a case of two brothers.

PubMed

Wakade, Oojwala; Adams, Beth; Shwayder, Tor

2009-01-01

We report two brothers of Middle Eastern descent with consanguineous parents who present with numerous fragile, flaccid blisters on the hands and feet. In addition to spontaneous peeling, they can manually peel skin from acral areas without pain. The symptoms worsen with warm temperatures, excessive water exposure, and perspiration. Two biopsies from flaccid blisters on the feet were taken from the older brother, which revealed cleavage at the level of the stratum corneum. A diagnosis of acral peeling skin syndrome was made.

The Effect of Bin Laden’s Death and Arab Spring on Al Qaeda’s Operational Center of Gravity

DTIC Science & Technology

2012-05-04

strongest links with its geographic allies in Pakistan’s FATA, to include the Pakistani Taliban and Haqqani Network; these relationships enable Core AQ to...this relationship with al-Awalaki, AQAP’s English-langauge jihadist. 15 These groups also provide a venue for training camps and facilitate the...point of consanguinity , the affinity between AQ’s ideology and the local insurgents and population, with the goal disconnecting the population from

Breaking the Code for Operational Planners: A Comparative Analysis of National Security Strategies Since the End of the Cold War

DTIC Science & Technology

2007-04-04

their continual complaints to their own British brethren have also been ignored: They too have been deaf to the voice of justice and of consanguinity ...nations would be more likely to support free trade and democracy, that nations with growing economies and good trade relationships would be more likely to...interests such as a stable Europe, integrating Russia into the world market, strong relationships with allies, and access to space. The chapter

RBBP8 syndrome with microcephaly, intellectual disability, short stature and brachydactyly.

PubMed

Mumtaz, Sara; Yıldız, Esra; Jabeen, Saliha; Khan, Amjad; Tolun, Aslıhan; Malik, Sajid

2015-12-01

Primary microcephaly is clinically variable and genetically heterogeneous. Four phenotypically distinct types of autosomal recessive microcephaly syndromes are due to different RBBP8 mutations. We report on a consanguineous Pakistani family with homozygous RBBP8 mutation c.1808_1809delTA (p.Ile603Lysfs*7) manifesting microcephaly and a distinct combination of skeletal, limb and ectodermal defects, mild intellectual disability, minor facial anomalies, anonychia, disproportionate short stature and brachydactyly, and additionally talipes in one patient. © 2015 Wiley Periodicals, Inc.

Perrault's syndrome in two sisters.

PubMed

Bösze, P; Skripeczky, K; Gaál, M; Tóth, A; László, J

1983-10-01

We report on two sisters with Perrault's syndrome, i.e., autosomal recessive ovarian dysgenesis associated with sensorineural deafness. They were deaf-mute and of normal height with a few minor somatic anomalies. Both had streak gonads and an apparently normal female 46,XX chromosome constitution. The parents were apparently not consanguineous. The mother had normal hearing. Other relatives were not available for study. Epilepsy, which occurred in three relatives including one of the index patients, may have been inherited coincidentally from the mother's family.

Studying the determinant factors leading to congenital heart disease in newborns.

PubMed

Arjmandnia, Mohammadhossein; Besharati, Mahsa; Rezvan, Sajad

2018-01-01

Congenital heart disease (CHD) is an important cause of death during the 1 st year of life and includes a special group of cardiac diseases that exist from birth. These conditions arise due to the abnormal development of an embryo's normal structures. A case-control study was conducted to investigate the determinant factors leading to CHD. All newborns who have been diagnosed with CHD upon echocardiography in 2013 were considered as cases. The number of samples required was randomly selected from the newborns who lacked CHD on cardiography. The mothers of both groups were handed the questionnaires. SPSS 23 was employed to analyze the data. A statistically significant association was seen between CHD and a positive family history (FH) ( P < 0.001), consanguinity ( P < 0.001), maternal diabetes ( P = 0.004), the use of antiepileptics during the first 45 days of gestation ( P = 0.002), and the mother's education status ( P > 0.001). No significant association was observed between CHD in the newborn and the age below 20 and above 35 years and ( P = 0.11), maternal body mass index (BMI) ( P = 0.44), smoking during the first 45 days of gestation ( P = 0.017), and maternal rheumatologic diseases ( P = 0.4). Newborns are at a greater risk of having CHD born from mothers with a FH of CHD, from consanguineous marriages, history of diabetes, antiepileptic use, and lack of folic acid use. However, no significant associations were found between newborn CHD and maternal age, BMI, or cigarette smoking.

Ectrodactyly with aplasia of long bones (OMIM; 119100) in a large inbred Arab family with an apparent autosomal dominant inheritance and reduced penetrance: clinical and genetic analysis.

PubMed

Naveed, Mohammed; Al-Ali, Mahmoud T; Murthy, Sabita K; Al-Hajali, Sarah; Al-Khaja, Najib; Deutsch, Samuel; Bottani, Armand; Antonarakis, Stylianos E; Nath, Swapan K; Radhakrishna, Uppala

2006-07-01

Ectrodactyly with aplasia of long bones syndrome is one of the most recognizable defects involving the extremities. We have studied a very large eight-generation consanguineous Arab family from the United Arab Emirates (UAE) with multiple severe limb anomalies resembling this condition (OMIM; 119100), for which the affected gene is unknown. The pedigree consists of 145 individuals including 23 affected (14 males/9 females) with limb anomalies. Of these, 18 had tibial aplasia (TA) usually on the right side. The expression of the phenotype was variable and ranged from bilateral to unilateral TA with ectrodactyly and other defects of the extremities. The mode of inheritance appears to be autosomal dominant with reduced penetrance. There were 10 consanguineous marriages observed in this pedigree. This could suggest possible pseudodominance due to high frequency of the mutant allele. Candidate loci for the described syndrome include GLI3 (OMIM: 165240) on 7p13, sonic hedgehog; (OMIM: 600725) on 7q36, Langer-Giedion syndrome (OMIM: 150230) on 8q24.1 and split-hand/foot malformation 3 (OMIM: 600095) on 10q24. In addition, bilateral tibial hemimelia and unilateral absence of the ulna was previously observed to co-segregate with deletion of 8q24.1. Two-point linkage and haplotype analyses did not show the involvement of the above regions in this family. (c) 2006 Wiley-Liss, Inc.

Gene mapping in an anophthalmic pedigree of a consanguineous Pakistani family opened new horizons for research

PubMed Central

Ajmal, M; Zafar, S; Hameed, A

2016-01-01

ABSTRACT Clinical anophthalmia is a rare inherited disease of the eye and phenotype refers to the absence of ocular tissue in the orbit of eye. Patients may have unilateral or bilateral anophthalmia, and generally have short palpebral fissures and small orbits. Anophthalmia may be isolated or associated with a broader syndrome and may have genetic or environmental causes. However, genetic cause has been defined in only a small proportion of cases, therefore, a consanguineous Pakistani family of the Pashtoon ethnic group, with isolated clinical anophthalmia was investigated using linkage mapping. A family pedigree was created to trace the possible mode of inheritance of the disease. Blood samples were collected from affected as well as normal members of this family, and screened for disease-associated mutations. This family was analyzed for linkage to all the known loci of clinical anophthalmia, using microsatellite short tandem repeat (STR) markers. Direct sequencing was performed to find out disease-associated mutations in the candidate gene. This family with isolated clinical anophthalmia, was mapped to the SOX2 gene that is located at chromosome 3q26.3-q27. However, on exonic and regulatory regions mutation screening of the SOX2 gene, the disease-associated mutation was not identified. It showed that another gene responsible for development of the eye might be present at chromosome 3q26.3-q27 and needs to be identified and screened for the disease-associated mutation in this family. PMID:27785411

A Founder Effect of c.257 + 2T > C Mutation in NCF2 Gene Underlies Severe Chronic Granulomatous Disease in Eleven Patients.

PubMed

Ben-Farhat, Khaoula; Ben-Mustapha, Imen; Ben-Ali, Meriem; Rouault, Karen; Hamami, Saber; Mekki, Najla; Ben-Chehida, Amel; Larguèche, Beya; Fitouri, Zohra; Abdelmoula, Selim; Khemiri, Monia; Guediche, Mohamed-Neji; Boukthir, Samir; Barsaoui, Sihem; Chemli, Jalel; Barbouche, Mohamed-Ridha

2016-08-01

Chronic granulomatous disease (CGD) is the prototypic functional neutrophil disorder caused by genetic defects in one of the five genes encoding the superoxide-generating nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase subunits of phagocytes. Mutations causing the most prevalent form of CGD in western populations are located in the X-linked-CYBB gene. The four remaining autosomal recessive (AR) forms collectively account for one-third of CGD cases. We investigated the clinical and molecular features of eleven patients with CGD from 6 consanguineous families, originating from contiguous regions in the west of Tunisia. The patients' clinical phenotype is characterized by a high incidence of mycobacterial infections. Five out of the eleven patients died despite treatment arguing in favor of a severe clinical form of CGD. These findings correlated with the absence of functional p67phox protein as well as the absence of residual reactive oxygen intermediates (ROI) production. Genetic analysis showed the presence, in all patients, of a unique mutation (c.257 + 2T > C) in NCF2 gene predicted to affect RNA splicing. Segregating analysis using nine polymorphic markers overlapping the NCF2 gene revealed a common haplotype spanning 4.1 Mb. The founder event responsible for this mutation was estimated to have arisen approximately 175 years ago. These findings will facilitate the implementation of preventive approaches through genetic counseling in affected consanguineous families.

RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans

PubMed Central

Shamseldin, Hanan; Alazami, Anas M.; Manning, Melanie; Hashem, Amal; Caluseiu, Oana; Tabarki, Brahim; Esplin, Edward; Schelley, Susan; Innes, A. Micheil; Parboosingh, Jillian S.; Lamont, Ryan; Majewski, Jacek; Bernier, Francois P.; Alkuraya, Fowzan S.

2015-01-01

Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963∗] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. PMID:26608784

Familial steroid-sensitive nephrotic syndrome in Southern Israel: clinical and genetic observations.

PubMed

Landau, Daniel; Oved, Tal; Geiger, Dan; Abizov, Luba; Shalev, Hanna; Parvari, Ruti

2007-05-01

Reports on genetically informative steroid-responsive (sensitive) idiopathic nephrotic syndrome (SSNS) families are lacking. We studied an extended SSNS Bedouin (B) family with a high rate of consanguinity. The clinical presentation and steroid response of its 11 affected individuals were similar to those of sporadic SSNS (spontaneous remission towards puberty and minimal change disease by kidney biopsy). Genome-wide linkage analysis, using a 382 microsatellite-markers mapping set and additional markers adjacent to 80 candidate genes of the index family, did not support linkage to any chromosomal locus. Retrospective analysis of all additional children with SSNS treated by our institution in the past 20 years (n=96, 50% of them of Jewish origin) revealed another five non-related B families with 2-3 first-degree cousins affected with SSNS in each. The overall familial SSNS rate among the B population (excluding the index family) was 28%, compared with 4% among Jews (Js) (OR 1.8-64, P<0.005). There were more Bs with simple SSNS than there were Js (71% and 40%, respectively; OR 3.58, 95% CI 1.41-9.23, P<0.01). In summary, SSNS in this index family was not linked to any of the presently known chromosomal loci nor predicted to be caused by mutation in any one of a list of genes associated with nephrotic syndrome (NS). The presence of other B families affected by SSNS supports the role for susceptibility genes enrichment, exposing highly consanguineous populations to an increased incidence of SSNS.

Obesity susceptibility loci in Qataris, a highly consanguineous Arabian population.

PubMed

Tomei, Sara; Mamtani, Ravinder; Al Ali, Rashid; Elkum, Naser; Abdulmalik, Maryam; Ismail, Awatef; Cheema, Sohaila; Rouh, Hekmat A; Aigha, Idil I; Hani, Fatima; Al-Samraye, Sura; Taher Aseel, Mona; El Emadi, Nada; Al Mujalli, Azza; Abdelkerim, Ahmed; Youssif, Siddik; Worschech, Andrea; El Sebakhy, Emad; Temanni, Ramzi; Khanna, Vineesh; Wang, Ena; Kizhakayil, Dhanya; Al-Thani, Al-Anood; Al-Thani, Mohammed; Lowenfels, Albert; Marincola, Francesco M; Sheikh, Javaid; Chouchane, Lotfi

2015-04-13

In Qataris, a population characterized by a small size and a high rate of consanguinity, between two-thirds to three-quarters of adults are overweight or obese. We investigated the relevance of 23 obesity-related loci in the Qatari population. Eight-hundred-four individuals assessed to be third generation Qataris were included in the study and assigned to 3 groups according to their body mass index (BMI): 190 lean (BMI < 25 kg/m(2)); 131 overweight (25 kg/m(2) ≤ BMI < 30 kg/m(2)) and 483 obese (BMI ≥ 30 kg/m(2)). Genomic DNA was isolated from peripheral blood and genotyped by TaqMan. Two loci significantly associated with obesity in Qataris: the TFAP2B variation (rs987237) (A allele versus G allele: chi-square = 10.3; P = 0.0013) and GNPDA2 variation (rs10938397) (A allele versus G allele: chi-square = 6.15; P = 0.013). The TFAP2B GG genotype negatively associated with obesity (OR = 0.21; P = 0.0031). Conversely, the GNDPA2 GG homozygous genotype associated with higher risk of obesity in subjects of age < 32 years (P = 0.0358). We showed a different genetic profile associated with obesity in the Qatari population compared to Western populations. Studying the genetic background of Qataris is of primary importance as the etiology of a given disease might be population-specific.

Identification of forty cases with alkaptonuria in one village in Jordan.

PubMed

Al-Sbou, Mohammed; Mwafi, Nesrin; Lubad, Mohammad Abu

2012-12-01

Alkaptonuria (AKU) is one of the four initially identified inborn errors of metabolism. The prevalence of AKU is unknown in Jordan. Therefore, a research project was started in April 2009 at the Faculty of Medicine/Mutah University in southern Jordan. The aims of the project were to identify people with AKU, to screen all family members with history of AKU, and to increase the awareness about the disease among health care professionals and the community in southern Jordan. Targeted family screening method was used to identify patients with AKU. In this paper, we present preliminary results of screening 17 families with history of AKU in a single village in southern region of Jordan. Forty cases with AKU were identified in this village (age range, 1-60 years). Early cases with AKU were diagnosed through out this study, two-third of patients (n = 28) were under the age of thirty. Interestingly, nine cases with AKU were identified in one family. Our experience suggests that for the identification of cases with AKU where consanguinity is common, the focus for screening should be extended to all family members. The prevalence of AKU among Jordanian is likely to be greater than the prevalence rates worldwide due to high rates of consanguineous marriages. Further studies and effective screening programs are needed to detect undiagnosed cases of AKU, to provide genetic counseling, and ultimately to prevent the occurrence of new cases of AKU in Jordan.

Analyses of MMP20 Missense Mutations in Two Families with Hypomaturation Amelogenesis Imperfecta.

PubMed

Kim, Youn Jung; Kang, Jenny; Seymen, Figen; Koruyucu, Mine; Gencay, Koray; Shin, Teo Jeon; Hyun, Hong-Keun; Lee, Zang Hee; Hu, Jan C-C; Simmer, James P; Kim, Jung-Wook

2017-01-01

Amelogenesis imperfecta is a group of rare inherited disorders that affect tooth enamel formation, quantitatively and/or qualitatively. The aim of this study was to identify the genetic etiologies of two families presenting with hypomaturation amelogenesis imperfecta. DNA was isolated from peripheral blood samples obtained from participating family members. Whole exome sequencing was performed using DNA samples from the two probands. Sequencing data was aligned to the NCBI human reference genome (NCBI build 37.2, hg19) and sequence variations were annotated with the dbSNP build 138. Mutations in MMP20 were identified in both probands. A homozygous missense mutation (c.678T>A; p.His226Gln) was identified in the consanguineous Family 1. Compound heterozygous MMP20 mutations (c.540T>A, p.Tyr180 * and c.389C>T, p.Thr130Ile) were identified in the non-consanguineous Family 2. Affected persons in Family 1 showed hypomaturation AI with dark brown discoloration, which is similar to the clinical phenotype in a previous report with the same mutation. However, the dentition of the Family 2 proband exhibited slight yellowish discoloration with reduced transparency. Functional analysis showed that the p.Thr130Ile mutant protein had reduced activity of MMP20, while there was no functional MMP20 in the Family 1 proband. These results expand the mutational spectrum of the MMP20 and broaden our understanding of genotype-phenotype correlations in amelogenesis imperfecta.

Homozygosity mapping and targeted genomic sequencing reveal the gene responsible for cerebellar hypoplasia and quadrupedal locomotion in a consanguineous kindred

PubMed Central

Gulsuner, Suleyman; Tekinay, Ayse Begum; Doerschner, Katja; Boyaci, Huseyin; Bilguvar, Kaya; Unal, Hilal; Ors, Aslihan; Onat, O. Emre; Atalar, Ergin; Basak, A. Nazli; Topaloglu, Haluk; Kansu, Tulay; Tan, Meliha; Tan, Uner; Gunel, Murat; Ozcelik, Tayfun

2011-01-01

The biological basis for the development of the cerebro-cerebellar structures required for posture and gait in humans is poorly understood. We investigated a large consanguineous family from Turkey exhibiting an extremely rare phenotype associated with quadrupedal locomotion, mental retardation, and cerebro-cerebellar hypoplasia, linked to a 7.1-Mb region of homozygosity on chromosome 17p13.1–13.3. Diffusion weighted imaging and fiber tractography of the patients' brains revealed morphological abnormalities in the cerebellum and corpus callosum, in particular atrophy of superior, middle, and inferior peduncles of the cerebellum. Structural magnetic resonance imaging showed additional morphometric abnormalities in several cortical areas, including the corpus callosum, precentral gyrus, and Brodmann areas BA6, BA44, and BA45. Targeted sequencing of the entire homozygous region in three affected individuals and two obligate carriers uncovered a private missense mutation, WDR81 p.P856L, which cosegregated with the condition in the extended family. The mutation lies in a highly conserved region of WDR81, flanked by an N-terminal BEACH domain and C-terminal WD40 beta-propeller domains. WDR81 is predicted to be a transmembrane protein. It is highly expressed in the cerebellum and corpus callosum, in particular in the Purkinje cell layer of the cerebellum. WDR81 represents the third gene, after VLDLR and CA8, implicated in quadrupedal locomotion in humans. PMID:21885617

Hidden Genetic Variation in LCA9-Associated Congenital Blindness Explained by 5'UTR Mutations and Copy-Number Variations of NMNAT1.

PubMed

Coppieters, Frauke; Todeschini, Anne Laure; Fujimaki, Takuro; Baert, Annelot; De Bruyne, Marieke; Van Cauwenbergh, Caroline; Verdin, Hannah; Bauwens, Miriam; Ongenaert, Maté; Kondo, Mineo; Meire, Françoise; Murakami, Akira; Veitia, Reiner A; Leroy, Bart P; De Baere, Elfride

2015-12-01

Leber congenital amaurosis (LCA) is a severe autosomal-recessive retinal dystrophy leading to congenital blindness. A recently identified LCA gene is NMNAT1, located in the LCA9 locus. Although most mutations in blindness genes are coding variations, there is accumulating evidence for hidden noncoding defects or structural variations (SVs). The starting point of this study was an LCA9-associated consanguineous family in which no coding mutations were found in the LCA9 region. Exploring the untranslated regions of NMNAT1 revealed a novel homozygous 5'UTR variant, c.-70A>T. Moreover, an adjacent 5'UTR variant, c.-69C>T, was identified in a second consanguineous family displaying a similar phenotype. Both 5'UTR variants resulted in decreased NMNAT1 mRNA abundance in patients' lymphocytes, and caused decreased luciferase activity in human retinal pigment epithelial RPE-1 cells. Second, we unraveled pseudohomozygosity of a coding NMNAT1 mutation in two unrelated LCA patients by the identification of two distinct heterozygous partial NMNAT1 deletions. Molecular characterization of the breakpoint junctions revealed a complex Alu-rich genomic architecture. Our study uncovered hidden genetic variation in NMNAT1-associated LCA and emphasized a shift from coding to noncoding regulatory mutations and repeat-mediated SVs in the molecular pathogenesis of heterogeneous recessive disorders such as hereditary blindness. © 2015 The Authors. **Human Mutation published by Wiley Periodicals, Inc.

Novel mutations in the genes TGM1 and ALOXE3 underlying autosomal recessive congenital ichthyosis

PubMed Central

Ullah, Rahim; Ansar, Muhammad; Durrani, Zaka Ullah; Lee, Kwanghyuk; Santos-Cortez, Regie Lyn P.; Muhammad, Dost; Ali, Mahboob; Zia, Muhammad; Ayub, Muhammad; Khan, Suliman; Smith, Josh D.; Nickerson, Deborah A.; Shendure, Jay; Bamshad, Michael; Leal, Suzanne M.; Ahmad, Wasim

2016-01-01

Background Ichthyoses are clinically characterized by scaling or hyperkeratosis of the skin or both. It can be an isolated condition limited to the skin or appear secondarily with involvement of other cutaneous or systemic abnormalities. Methods The present study investigated clinical and molecular characterization of three consanguineous families (A, B, C) segregating two different forms of autosomal recessive congenital ichthyosis (ARCI). Linkage in three consanguineous families (A, B, C) segregating two different forms of ARCI was searched by typing microsatellite and single nucleotide polymorphism marker analysis. Sequencing of the two genes TGM1 and ALOXE3 was performed by the dideoxy chain termination method. Results Genome-wide linkage analysis established linkage in family A to TGM1 gene on chromosome 14q11 and in families B and C to ALOXE3 gene on chromosome 17p13. Subsequently, sequencing of these genes using samples from affected family members led to the identification of three novel mutations: a missense variant p.Trp455Arg in TGM1 (family A); a nonsense variant p.Arg140* in ALOXE3 (family B); and a complex rearrangement in ALOXE3 (family C). Conclusion The present study further extends the spectrum of mutations in the two genes involved in causing ARCI. Characterizing the clinical spectrum resulting from mutations in the TGM1 and ALOXE3 genes will improve diagnosis and may direct clinical care of the family members. PMID:26578203

Genetic analysis of fructose-1,6-bisphosphatase (FBPase) deficiency in nine consanguineous Pakistani families.

PubMed

Ijaz, Sadaqat; Zahoor, Muhammad Yasir; Imran, Muhammad; Ramzan, Khushnooda; Bhinder, Munir Ahmad; Shakeel, Hussain; Iqbal, Muhammad; Aslam, Asim; Shehzad, Wasim; Cheema, Huma Arshad; Rehman, Habib

2017-10-26

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare inherited metabolic disorder characterized by recurrent episodes of hypoglycemia, ketosis and lactic acidosis. FBPase is encoded by FBP1 gene and catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate in the last step of gluconeogenesis. We report here FBP1 mutations in nine consanguineous Pakistani families affected with FBPase deficiency. Nine families having one or two individuals affected with FBPase deficiency were enrolled over a period of 3 years. All FBP1 exonic regions including splicing sites were PCR-amplified and sequenced bidirectionally. Familial cosegregation of mutations with disease was confirmed by direct sequencing and PCR-RFLP analysis. Three different FBP1 mutations were identified. Each of two previously reported mutations (c.472C>T (p.Arg158Trp) and c.841G>A (p.Glu281Lys)) was carried by four different families. The ninth family carried a novel 4-bp deletion (c.609_612delAAAA), which is predicted to result in frameshift (p.Lys204Argfs*72) and loss of FBPase function. The novel variant was not detected in any of 120 chromosomes from normal ethnically matched individuals. FBPase deficiency is often fatal in the infancy and early childhood. Early diagnosis and prompt treatment is therefore crucial to preventing early mortality. We recommend the use of c.472C>T and c.841G>A mutations as first choice genetic markers for molecular diagnosis of FBPase deficiency in Pakistan.

Novel homozygous variants in ATCAY, MCOLN1, and SACS in complex neurological disorders.

PubMed

Manzoor, Humera; Brüggemann, Norbert; Hussain, Hafiz Muhammad Jafar; Bäumer, Tobias; Hinrichs, Frauke; Wajid, Muhammad; Münchau, Alexander; Naz, Sadaf; Lohmann, Katja

2018-06-01

Neurological disorders comprise a large group of clinically and genetically heterogeneous disorders, many of which have a genetic cause. In addition to a detailed neurological examination, exome sequencing is being increasingly used as a complementary diagnostic tool to identify the underlying genetic cause in patients with unclear, supposedly genetically determined disorders. To identify the genetic cause of a complex movement disorder in five consanguineous Pakistani families. We included five consanguineous Pakistani families with complex recessively inherited movement disorders. Clinical investigation including videotaping was carried out in a total of 59 family members (4-21 per family) and MRI in six patients. Exome sequencing was performed in 4-5 family members per pedigree to explore the underlying genetic cause. Patients presented a wide spectrum of neurological symptoms including ataxia and/or dystonia. We identified three novel homozygous, segregating variants in ATCAY (p.Pro200Profs*20), MCOLN1 (p.Ile184Thr), and SACS (p.Asn3040Lysfs*4) in three of the families. Thus, we were able to identify the likely cause of the disease in a considerable number of families (60%) with the relatively simple and nowadays widely available method of exome sequencing. Of note, close collaboration of neurologists and geneticists was instrumental for proper data interpretation. We expand the phenotypic, genotypic, and ethnical spectrum of mutations in these genes. Our findings alert neurologists that rare genetic causes should be considered in complex phenotypes regardless of ethnicity. Copyright © 2018 Elsevier Ltd. All rights reserved.

Autism in children and correlates in Lebanon: a pilot case-control study.

PubMed

Hamadé, Aline; Salameh, Pascale; Medlej-Hashim, Myrna; Hajj-Moussa, Elie; Saadallah-Zeidan, Nina; Rizk, Francine

2013-09-17

Autism spectrum disorder (ASD) is a neurological disorder typically appearing before the age of three. The exact cause of autism remains uncertain, and several factors may be involved in its onset: genetic factors and possible environmental factors. The aim of this study was to assess the correlates of autism in the Lebanese population. We investigated the association of autism with several factors in 86 autism cases from specialized schools for children with developmental disabilities and 172 control children from regular public schools in the same regions. Several risk factors for autism were investigated after comparison with a cohort control on parental age, sex, maternal unhappy feeling during pregnancy, consanguineous marriage, and province of residence. The Chi-square test was used to compare nominal variables, and Fisher exact test was used in case expected values within cells were inferior to five. For quantitative variables, we used t-test to compare means between two groups, after checking their distribution normality. For multivariate analysis, we used a forward stepwise likelihood ratio logistic regression. We observed male predominance (79.1%) among autistic infants. There was a significant association between autism and older parents age (OR=1.27), male sex (OR=3.38), unhappy maternal feeling during pregnancy (OR=5.77), living close to industry (OR=6.58), previous childhood infection (OR=8.85), but none concerning maternal age, paternal age and consanguinity. In this pilot epidemiological study of autism in Lebanon, we found several prenatal and perinatal risk factors for autism that could be modified.

Depression, Hopelessness and Social Support among Breast Cancer Patients: in Highly Endogamous Population

PubMed Central

Bener, Abdulbari; Alsulaiman, Reem; Doodson, Lisa; Agathangelou, Tony

2017-01-01

Aim: The aim of this study was to assess the relationship between different demographic variables, hopelessness, depression and social support of Breast cancer patients in Qatari’s population. Design: This is an observational cohort hospital based study. Subjects and Methods: The study included 678 breast cancer patients. The questionnaires included a demographic questionnaire, the Beck Hopelessness Scale (BHS), Back Depression Scale (BDS) and Multidimensional Scale of Perceived Social Support (MSPSS). The demographic questionnaire was used to assess patients’ basic information including gender, age, marital status, education, family size, and place of residence. Medical information regarding cancer stage, the time passed since diagnosis, treatment, and duration of disease were recorded. Results: The mean age of the studied women was 47.7±10.2 years. Among the studied patients, 34.7% were Qataris and 65.3% were Arab expatriates. Nearly 39.2% of the patients were in pre-menopausal status and 60.8% in post-menopausal status. 86.1% of women were married. 14.6% were illiterate women, 20.9% were university graduates and 37.2% were housewives. Smoking habit was less common in studied Arab women (9.1%), but, sheesha smoking was more common, 17.7%. Daily physical activity indicated 25.7% were walking 30 minutes per-day and 14% were walking 60 minutes per day. 30.4% of them had consanguineous parents. Breast feeding was practiced among 67.7% of women and over 73% were considered overweight and obese. Furthermore, over 75% of breast cancer women were at the Stage 3 (40.9%) and Stage 4 (35.8%) of cancer. The percentage of patients who underwent mastectomy and lumpectomy were 49.3 % and 50.7%, respectively. It was observed that 27.7% of BDI patients had moderate depression and 19.5% of the BDI patients had severe depression and with mean and standard deviation 25.1±7.7. Also, the mean and SD of BDI for consanguineous has showed statistically significant 28.4±5.7 than non- consanguineous 23.2± 8.0 (p<0.001). All socio-demographic variables showed statistically significant differences with the total BHS score. The highest score belongs to the family sub-dimension. Conclusion: The present study indicates that hopelessness of the patients with breast cancer decreased with the increase in their social support. Therefore, activating patient social support systems is of importance in increasing their levels of hope. The present study revealed the coexistence of the socio-demographic, physical, psychological, and cognitive problems faced by patients with cancer. PMID:28749617

Depression, Hopelessness and Social Support among Breast Cancer Patients: in Highly Endogamous Population

PubMed

Bener, Abdulbari; Alsulaiman, Reem; Doodson, Lisa; Agathangelou, Tony

2017-07-27

Aim: The aim of this study was to assess the relationship between different demographic variables, hopelessness, depression and social support of Breast cancer patients in Qatari’s population. Design: This is an observational cohort hospital based study. Subjects and Methods: The study included 678 breast cancer patients. The questionnaires included a demographic questionnaire, the Beck Hopelessness Scale (BHS), Back Depression Scale (BDS) and Multidimensional Scale of Perceived Social Support (MSPSS). The demographic questionnaire was used to assess patients’ basic information including gender, age, marital status, education, family size, and place of residence. Medical information regarding cancer stage, the time passed since diagnosis, treatment, and duration of disease were recorded. Results: The mean age of the studied women was 47.7±10.2 years. Among the studied patients, 34.7% were Qataris and 65.3% were Arab expatriates. Nearly 39.2% of the patients were in pre-menopausal status and 60.8% in post-menopausal status. 86.1% of women were married. 14.6% were illiterate women, 20.9% were university graduates and 37.2% were housewives. Smoking habit was less common in studied Arab women (9.1%), but, sheesha smoking was more common, 17.7%. Daily physical activity indicated 25.7% were walking 30 minutes per-day and 14% were walking 60 minutes per day. 30.4% of them had consanguineous parents. Breast feeding was practiced among 67.7% of women and over 73% were considered overweight and obese. Furthermore, over 75% of breast cancer women were at the Stage 3 (40.9%) and Stage 4 (35.8%) of cancer. The percentage of patients who underwent mastectomy and lumpectomy were 49.3 % and 50.7%, respectively. It was observed that 27.7% of BDI patients had moderate depression and 19.5% of the BDI patients had severe depression and with mean and standard deviation 25.1±7.7. Also, the mean and SD of BDI for consanguineous has showed statistically significant 28.4±5.7 than non- consanguineous 23.2± 8.0 (p<0.001). All socio-demographic variables showed statistically significant differences with the total BHS score. The highest score belongs to the family sub-dimension. Conclusion: The present study indicates that hopelessness of the patients with breast cancer decreased with the increase in their social support. Therefore, activating patient social support systems is of importance in increasing their levels of hope. The present study revealed the coexistence of the socio-demographic, physical, psychological, and cognitive problems faced by patients with cancer. Creative Commons Attribution License

Kindler syndrome in a Saudi kindred.

PubMed

Al Aboud, K; Al Hawsawi, K; Al Aboud, D; Al Githami, A

2002-11-01

We report a large consanguineous Saudi-Arabian pedigree containing 11 individuals with the autosomal recessive genodermatosis, Kindler syndrome. Three affected cases died in infancy but the remaining eight had signs of photosensitivity, generalized poikiloderma, webbed fingers, loss of dermatoglyphics and nail dystrophy. The majority also had oral involvement with bleeding gums. Additional features seen in some cases included pseudoainhum of the toes, sclerotic bands on the wrists and hand deformities. The aetiology of Kindler syndrome is not yet known, but the underlying defect leads to both cutaneous and oral inflammation, along with photosensitivity and scarring.

Striatal necrosis in type 1 glutaric aciduria: Different stages in two siblings.

PubMed

Sen, Anitha; Pillay, Rajesh Subramonia

2011-07-01

Two siblings born of a consanguineous marriage with history of neurologic deterioration were imaged. Imaging features are classical of glutaric aciduria type 1 (GA-1), acute (striatal necrosis) stage in younger sibling, and chronic stage in older sibling. GA-1 is an autosomal recessive disease with typical imaging features. Greater awareness about this condition among clinicians and radiologists is essential for early diagnosis and prevention of its catastrophic consequences. Striatal necrosis with stroke-like signal intensity on imaging correlates with clinical stage of patients.

Striatal necrosis in type 1 glutaric aciduria: Different stages in two siblings

PubMed Central

Sen, Anitha; Pillay, Rajesh Subramonia

2011-01-01

Two siblings born of a consanguineous marriage with history of neurologic deterioration were imaged. Imaging features are classical of glutaric aciduria type 1 (GA-1), acute (striatal necrosis) stage in younger sibling, and chronic stage in older sibling. GA-1 is an autosomal recessive disease with typical imaging features. Greater awareness about this condition among clinicians and radiologists is essential for early diagnosis and prevention of its catastrophic consequences. Striatal necrosis with stroke-like signal intensity on imaging correlates with clinical stage of patients. PMID:22408669

Thomsen or Becker myotonia? A novel autosomal recessive nonsense mutation in the CLCN1 gene associated with a mild phenotype.

PubMed

Gurgel-Giannetti, Juliana; Senkevics, Adriano S; Zilbersztajn-Gotlieb, Dinorah; Yamamoto, Lydia U; Muniz, Viviane P; Pavanello, Rita C M; Oliveira, Acary B; Zatz, Mayana; Vainzof, Mariz

2012-02-01

We describe a large Brazilian consanguineous kindred with 3 clinically affected patients with a Thomsen myotonia phenotype. They carry a novel homozygous nonsense mutation in the CLCN1 gene (K248X). None of the 6 heterozygote carriers show any sign of myotonia on clinical evaluation or electromyography. These findings confirm the autosomal recessive inheritance of the novel mutation in this family, as well as the occurrence of phenotypic variability in the autosomal recessive forms of myotonia. Copyright © 2011 Wiley Periodicals, Inc.

Alkaptonuria diagnosed in a 4-month-old baby girl: a case report

PubMed Central

Datta, Asok K; Mandal, Syamali; Dasgupta, Anindya; Ghosh, Tarun K

2008-01-01

The mother of a four month old female baby attended in the well baby clinic with the complaint of black staining of the diaper after few minutes of urination. The baby was born of a non consanguineous marriage, healthy and breast fed. Mother noticed that stain first at the age of two and half month. The urine when kept in a test tube for two hours turned black. Laboratory examination of urine revealed increased concentration of homogentisic acid. The patient was diagnosed as alkaptonuria. PMID:19014543

Le conte Africain: L'univers de l'oralite dans le systeme de l'enseignement

NASA Astrophysics Data System (ADS)

Belpassi, Paola

1994-05-01

According to current interpretations, the stories preserved in the African oral tradition constitute a rich source of themes for the purposes of moral education. The stories focusing on the relationship between brother and sister, for example, develop the theme of how each individual must find a balance between consanguineous and marital relationships. The author also explores other keys to the interpretation of these stories and argues that they could profitably be used within the framework of a multicultural educational programme, on account of their linguistic, narrative and thematic richness.

Effect of maternal education on the rate of childhood handicap.

PubMed

Shawky, S; Milaat, W M; Abalkhail, B A; Soliman, N K

2001-01-01

The objectives of this study were to determine the relation between maternal education and various maternal risk factors, identify the impact of maternal education on the risk of childhood handicap and estimate the proportion of childhood handicap that can be prevented by maternal education. Data was collected from all married women attending the two major maternity and child hospitals in Jeddah during April 1999. Women with at least one living child were interviewed for sociodemographic factors and having at least one handicapped child. The risk of having a handicapped child and the population attributable risk percent were calculated. Some potential risk factors are dominant in our society as approximately 30% of women did not attend school and 84% did not work. Consanguineous marriages accounted for about 43%. Pre-marriage counseling was limited as only 10% of women counseled before marriage. The proportion of unemployment and consanguineous marriages decreased significantly by increase in maternal education level. Conversely, the proportion of women reporting pre-marriage counseling increased significantly by increase in maternal education level. Approximately, 7% of women reported having at least one handicapped child. The risk of having a handicapped child showed a significant sharp decline with increase in maternal education level. At least 25% of childhood handicap can be prevented by achieving female primary education and up to half of cases can be prevented if mothers finish their intermediate education. Female education plays a major role in child health. The results of this study suggest investment in female education, which would have substantial positive effects in reducing incidence of childhood handicap in Jeddah.

Prevalence of Red-Green Color Vision Defects among Muslim Males and Females of Manipur, India

PubMed Central

SHAH, Ahsana; HUSSAIN, Ruqaiya; FAREED, Mohd; AFZAL, Mohammad

2013-01-01

Background: Color blindness is a common X-linked genetic disorder. However, most of color blinds remain undetected due to absence of proper screening. Our study was to determine the prevalence of red-green color vision defects among Manipuri Muslim males and females. The study could help in decreasing birth of children with this disorder as Muslims commonly perform consanguineous marriage among themselves. Methods: Unrelated individuals of both sexes (Male-1352, Female-1302) belonging to six different populations were randomly selected and screened for red-green color vision defects using the Ishihara (pseudo-isochromatic plates) test from the area of Imphal East and Imphal west districts of Manipur, which is a small hilly state, situated in the north eastern extreme corner of India sharing an international boundary with Myanmar (Burma). Results: About 8.73% of males and 1.69% of females were found to be color blind. Among six different populations studied the males of Meitei population shows the highest frequency i.e. 14.93% while Naga population shows the least frequency of 3.75%. Among females, Meitei population again shows the highest frequency of 2.5% and least frequency is shown by Mughal and Naga populations 0.00% as not a single female color blind was found. Conclusion: Present study shows higher prevalence rate of color blindness as compared to other reported rates of India. Deuteranomaly cases occur in higher percentage than other types of color blindness. The higher prevalence rate observed in Muslims may be due to the hidden effect of consanguineous marriages. PMID:23515069

Prevalence of Red-Green Color Vision Defects among Muslim Males and Females of Manipur, India.

PubMed

Shah, Ahsana; Hussain, Ruqaiya; Fareed, Mohd; Afzal, Mohammad

2013-01-01

Color blindness is a common X-linked genetic disorder. However, most of color blinds remain undetected due to absence of proper screening. Our study was to determine the prevalence of red-green color vision defects among Manipuri Muslim males and females. The study could help in decreasing birth of children with this disorder as Muslims commonly perform consanguineous marriage among themselves. Unrelated individuals of both sexes (Male-1352, Female-1302) belonging to six different populations were randomly selected and screened for red-green color vision defects using the Ishihara (pseudo-isochromatic plates) test from the area of Imphal East and Imphal west districts of Manipur, which is a small hilly state, situated in the north eastern extreme corner of India sharing an international boundary with Myanmar (Burma). About 8.73% of males and 1.69% of females were found to be color blind. Among six different populations studied the males of Meitei population shows the highest frequency i.e. 14.93% while Naga population shows the least frequency of 3.75%. Among females, Meitei population again shows the highest frequency of 2.5% and least frequency is shown by Mughal and Naga populations 0.00% as not a single female color blind was found. Present study shows higher prevalence rate of color blindness as compared to other reported rates of India. Deuteranomaly cases occur in higher percentage than other types of color blindness. The higher prevalence rate observed in Muslims may be due to the hidden effect of consanguineous marriages.

Demographic features of subjects with congenital glaucoma

PubMed Central

Tamçelik, Nevbahar; Atalay, Eray; Bolukbasi, Selim; Çapar, Olgu; Ozkok, Ahmet

2014-01-01

Context: Congenital glaucoma is a potentially blinding ocular disease of the childhood. Identification of the possible associated risk factors and may be helpful for prevention or early detection of this public health problem. Aims: To demonstrate the demographic features of congenital glaucoma subjects. Setting and Design: The charts of congenital glaucoma patients referred to Tamcelik Glaucoma Center were retrospectively reviewed through the dates of 2000 and 2013. Materials and Methods: Analyzed data included diagnosis, age at first presentation, symptoms at first presentation, laterality of the disease, sex, presence of consanguinity, family history of congenital glaucoma, maturity of the fetus at delivery, and maternal age at conception. Statistical Analysis Used: Statistical Package for Social Sciences (SPSS) version 19.0 by IBM (SPSS Inc, Chicago, Illinois, USA) was used to compare the mean of continuous variables with Student's t-test and analysis of variance (ANOVA) and χ2 test was used to test differences in proportions of categorical variables. Results: The data of 600 eyes of 311 patients were analyzed. The distribution of primary and secondary congenital glaucoma among the patients were 63.3% (n = 197) and 36.7% (n = 114), respectively. Of the 311 patients, 57.2% (n = 178) were male and 42.8% (n = 133) were female. The overall frequency of bilateral disease was 92.3% (n = 287). Overall rate of consanguinity and positive family history was 45.3% (n = 141) and 21.2% (n = 66), respectively. Conclusions: Bilateral disease in this study was more common than previously reported studies. Positive family history was more frequent in primary congenital glaucoma although not statistically significant. PMID:24881602

Evaluation of social and demographic characteristics of incest cases in a university hospital in Turkey.

PubMed

Yildirim, Ali; Ozer, Erdal; Bozkurt, Hasan; Ozsoy, Sait; Enginyurt, Ozgur; Evcuman, Durmus; Yilmaz, Riza; Kuyucu, Yunus Emre

2014-04-26

Incest is defined as any sexual activity between close blood relatives including step relatives and family members who are forbidden by law to marry. It is a problem that can be seen in all the social classes in developed and undeveloped societies. The World Health Organization classifies this problem as a silent health emergency. Father-daughter incest is reported to be the most common incest type followed by the other types like brother-sister, sister-sister and mother-son incest. Subjects for this study were recruited from a sample of incest cases referred to Forensic Medicine Department of Gaziosmanpasa University Medical Faculty Hospital between 2008 and 2012. Data involved social and demographic characteristics and clinical features of victims, perpetrators and the families. The ethical committee of the faculty of medicine approved the study. The study sample consisted of 43 incest cases (36 females and 7 males) with an age rage 4-40 years. Two third of the victims were under 18 years old. All perpetrators were males. Father - daughter incest (34.9%) was found to be most common incest type followed by brother - sister incest (14%). 75% of the perpetrators were family members and relatives with consanguinity while 25% of them were not consanguineous but faithful and intimate relatives to victims. Increasing awareness about incest and its damaging effects is so important and clinicians should keep in mind sexual abuse or incest when examining the risky population. Multidisciplinary approach is necessary for determining short term or long term results and preventing the negative consequences of incest.

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.

PubMed

Hu, Hao; Matter, Michelle L; Issa-Jahns, Lina; Jijiwa, Mayumi; Kraemer, Nadine; Musante, Luciana; de la Vega, Michelle; Ninnemann, Olaf; Schindler, Detlev; Damatova, Natalia; Eirich, Katharina; Sifringer, Marco; Schrötter, Sandra; Eickholt, Britta J; van den Heuvel, Lambert; Casamina, Chanel; Stoltenburg-Didinger, Gisela; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Kaindl, Angela M

2014-12-01

To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.

RTTN Mutations Cause Primary Microcephaly and Primordial Dwarfism in Humans.

PubMed

Shamseldin, Hanan; Alazami, Anas M; Manning, Melanie; Hashem, Amal; Caluseiu, Oana; Tabarki, Brahim; Esplin, Edward; Schelley, Susan; Innes, A Micheil; Parboosingh, Jillian S; Lamont, Ryan; Majewski, Jacek; Bernier, Francois P; Alkuraya, Fowzan S

2015-12-03

Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963(∗)] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genetic Diagnosis in Consanguineous Families With Kidney Disease by Homozygosity Mapping Coupled With Whole-Exome Sequencing

PubMed Central

Al-Romaih, Khaldoun I.; Genovese, Giulio; Al-Mojalli, Hamad; Al-Othman, Saleh; Al-Manea, Hadeel; Al-Suleiman, Mohammed; Al-Jondubi, Mohammed; Atallah, Nourah; Al-Rodhyan, Maha; Weins, Astrid; Pollak, Martin R.; Adra, Chaker N.

2011-01-01

Background Accurate diagnosis of the primary cause of an individual’s kidney disease can be essential for proper management. Some kidney diseases have overlapping histopathological features despite being caused by defects in different genes. In this report we describe two consanguineous Saudi Arabian families in which individuals presented with kidney failure and mixed clinical and histological features initially thought consistent with focal segmental glomerulosclerosis. Study Design Case series. Setting and participants We studied members of two apparently unrelated families from Saudi Arabia with kidney disease. Measurements Whole-genome single-nucleotide polymorphism analysis followed by targeted isolation and sequencing of exons using genomic DNA samples from affected members of these families, followed by additional focused genotyping and sequence analysis. Results The two apparently unrelated families shared a region of homozygosity on chromosome 2q13. Exome sequence from the affected individuals lacked any sequence reads from the NPHP1 gene, which is located within this homozygous region. Additional PCR based genotyping confirmed that affected individuals had NPHP1 deletions, rather than defects in a known FSGS-associated gene. Limitations The methods used here may not result in a clear genetic diagnosis in many cases of apparent familial kidney disease. Conclusions This analysis demonstrates the power of new high-throughput genotyping and sequencing technologies to aid in the rapid genetic diagnosis of individuals with an inherited form of kidney disease. We believe it is likely that such tools may become useful clinical genetic tools and alter the manner in which diagnoses are made in nephrology. PMID:21658830

A missense mutation in ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), causes an autosomal recessive neurocutaneous syndrome.

PubMed

Bicknell, Louise S; Pitt, James; Aftimos, Salim; Ramadas, Ram; Maw, Marion A; Robertson, Stephen P

2008-10-01

There are several rare syndromes combining wrinkled, redundant skin and neurological abnormalities. Although phenotypic overlap between conditions has suggested that some might be allelic to one another, the aetiology for many of them remains unknown. A consanguineous New Zealand Maori family has been characterised that segregates an autosomal recessive connective tissue disorder (joint dislocations, lax skin) associated with neurological abnormalities (severe global developmental delay, choreoathetosis) without metabolic abnormalities in four affected children. A genome-screen performed under a hypothesis of homozygosity by descent for an ancestral mutation, identified a locus at 10q23 (Z = 3.63). One gene within the candidate interval, ALDH18A1, encoding Delta1-pyrroline-5-carboxylate synthase (P5CS), was considered a plausible disease gene since a missense mutation had previously been shown to cause progressive neurodegeneration, cataracts, skin laxity, joint dislocations and metabolic derangement in a consanguineous Algerian family. A missense mutation, 2350C>T, was identified in ALDH18A1, which predicts the substitution H784Y. H784 is invariant across all phyla and lies within a previously unrecognised, conserved C-terminal motif in P5CS. In an in vivo assay of flux through this metabolic pathway using dermal fibroblasts obtained from an affected individual, proline and ornithine biosynthetic activity of P5CS was not affected by the H784Y substitution. These data suggest that P5CS may possess additional uncharacterised functions that affect connective tissue and central nervous system function.

Alkaptonuria in France: past experience and lessons for the future.

PubMed

Aquaron, Robert Raphael

2011-12-01

Alkaptonuria (AKU) is an autosomal recessive disorder due to homogentisate 1,2-dioxygenase (HGD) deficiency in the liver and characterized by a triad of signs, according to chronology of appearance: homogentisic aciduria (HGA) or alkaptonuria, ochronosis then ochronotic arthropathy. This inborn error of metabolism is caused by mutations in the HGD gene. In this work we report observations of 96 AKU French patients from 81 families collected in the literature since 1882 and from our personal contribution since 1986, giving an incidence of the disease of around 1:680,000 (96/64.10(6)). As expected for an autosomal recessive disorder the main findings of this study were: a slight predominance of males (51/93, 54,8%) over females (42/93, 45,2%), a strong predominance of sibships with one affected individual (68/81, 84,0%) over sibships with two (11/81, 13.6%) and three(2/81, 2.4%) affected individuals. AKU families are scaterred among the French territory suggesting that most cases occured in non-consanguineous unions. Consanguinity was only found in five families. Other peculiarities of this study were (a) ten of these families have both parents from a foreign geographical origin: Poland(3), Italy(3), Portugal(2), Ukraine(1) and India(1) and four families with only one foreign parent (Algeria, Armenia, Serbia, UK), (b) HGD mutations were found in 23 families, (c) four of theses 96 patients were seen by us respectively 28, 29, 39 and 45 years after their report in the literature and (d) seven patients present cardiac and/or renal complications.

Permanent neonatal diabetes caused by a homozygous nonsense mutation in the glucokinase gene.

PubMed

Rubio-Cabezas, O; Díaz González, F; Aragonés, A; Argente, J; Campos-Barros, A

2008-06-01

Glucokinase deficiency is an unfrequent cause of permanent neonatal diabetes (PND), as only seven patients have been reported, either homozygous for a missense or frameshift mutation or compound heterozygous for both of them. We report here the first known case caused by a homozygous nonsense mutation (Y61X) in the glucokinase gene (GCK) that introduces a premature stop codon, generating a truncated protein that is predicted to be completely inactive as it lacks both the glucose- and the adenosine triphosphate-binding sites. The proband, born to consanguineous parents, was a full-term, intra-uterine growth-retarded male newborn who presented with a glycaemia of 129 mg/dL (7.16 mmol/L) on his second day of life, increasing thereafter up to 288 mg/dL (15.98 mmol/L) and 530 mg/dL (29.41 mmol/L) over the next 24 h, in the face of low serum insulin (<3 muIU/mL; <20.83 pmol/L). He was put on insulin on the third day of life. Insulin has never been discontinued since then. The patient was tested negative for anti-insulin and islet cell antibodies at age 5 months. His father had non-progressive, impaired fasting glucose for several years. The mother was found to be mildly hyperglycaemic only when her glucose was checked after the child was diagnosed. In conclusion, biallelic GCK loss should be considered as a potential cause of PND in children born to consanguineous parents, even if they are not known to be diabetic at the time of PND presentation.

Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing.

PubMed

Timal, Sharita; Hoischen, Alexander; Lehle, Ludwig; Adamowicz, Maciej; Huijben, Karin; Sykut-Cegielska, Jolanta; Paprocka, Justyna; Jamroz, Ewa; van Spronsen, Francjan J; Körner, Christian; Gilissen, Christian; Rodenburg, Richard J; Eidhof, Ilse; Van den Heuvel, Lambert; Thiel, Christian; Wevers, Ron A; Morava, Eva; Veltman, Joris; Lefeber, Dirk J

2012-10-01

Congenital disorders of glycosylation type I (CDG-I) form a growing group of recessive neurometabolic diseases. Identification of disease genes is compromised by the enormous heterogeneity in clinical symptoms and the large number of potential genes involved. Until now, gene identification included the sequential application of biochemical methods in blood samples and fibroblasts. In genetically unsolved cases, homozygosity mapping has been applied in consanguineous families. Altogether, this time-consuming diagnostic strategy led to the identification of defects in 17 different CDG-I genes. Here, we applied whole-exome sequencing (WES) in combination with the knowledge of the protein N-glycosylation pathway for gene identification in our remaining group of six unsolved CDG-I patients from unrelated non-consanguineous families. Exome variants were prioritized based on a list of 76 potential CDG-I candidate genes, leading to the rapid identification of one known and two novel CDG-I gene defects. These included the first X-linked CDG-I due to a de novo mutation in ALG13, and compound heterozygous mutations in DPAGT1, together the first two steps in dolichol-PP-glycan assembly, and mutations in PGM1 in two cases, involved in nucleotide sugar biosynthesis. The pathogenicity of the mutations was confirmed by showing the deficient activity of the corresponding enzymes in patient fibroblasts. Combined with these results, the gene defect has been identified in 98% of our CDG-I patients. Our results implicate the potential of WES to unravel disease genes in the CDG-I in newly diagnosed singleton families.

Mutations in the mitochondrial seryl-tRNA synthetase cause hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis, HUPRA syndrome.

PubMed

Belostotsky, Ruth; Ben-Shalom, Efrat; Rinat, Choni; Becker-Cohen, Rachel; Feinstein, Sofia; Zeligson, Sharon; Segel, Reeval; Elpeleg, Orly; Nassar, Suheir; Frishberg, Yaacov

2011-02-11

An uncharacterized multisystemic mitochondrial cytopathy was diagnosed in two infants from consanguineous Palestinian kindred living in a single village. The most significant clinical findings were tubulopathy (hyperuricemia, metabolic alkalosis), pulmonary hypertension, and progressive renal failure in infancy (HUPRA syndrome). Analysis of the consanguineous pedigree suggested that the causative mutation is in the nuclear DNA. By using genome-wide SNP homozygosity analysis, we identified a homozygous identity-by-descent region on chromosome 19 and detected the pathogenic mutation c.1169A>G (p.Asp390Gly) in SARS2, encoding the mitochondrial seryl-tRNA synthetase. The same homozygous mutation was later identified in a third infant with HUPRA syndrome. The carrier rate of this mutation among inhabitants of this Palestinian isolate was found to be 1:15. The mature enzyme catalyzes the ligation of serine to two mitochondrial tRNA isoacceptors: tRNA(Ser)(AGY) and tRNA(Ser)(UCN). Analysis of amino acylation of the two target tRNAs, extracted from immortalized peripheral lymphocytes derived from two patients, revealed that the p.Asp390Gly mutation significantly impacts on the acylation of tRNA(Ser)(AGY) but probably not that of tRNA(Ser)(UCN). Marked decrease in the expression of the nonacylated transcript and the complete absence of the acylated tRNA(Ser)(AGY) suggest that this mutation leads to significant loss of function and that the uncharged transcripts undergo degradation. Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability

PubMed Central

Riazuddin, S; Hussain, M; Razzaq, A; Iqbal, Z; Shahzad, M; Polla, D L; Song, Y; van Beusekom, E; Khan, A A; Tomas-Roca, L; Rashid, M; Zahoor, M Y; Wissink-Lindhout, W M; Basra, M A R; Ansar, M; Agha, Z; van Heeswijk, K; Rasheed, F; Van de Vorst, M; Veltman, J A; Gilissen, C; Akram, J; Kleefstra, T; Assir, M Z; Grozeva, D; Carss, K; Raymond, F L; O'Connor, T D; Riazuddin, S A; Khan, S N; Ahmed, Z M; de Brouwer, A P M; van Bokhoven, H; Riazuddin, S

2017-01-01

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1–3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal–parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID. PMID:27457812

Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability.

PubMed

Riazuddin, S; Hussain, M; Razzaq, A; Iqbal, Z; Shahzad, M; Polla, D L; Song, Y; van Beusekom, E; Khan, A A; Tomas-Roca, L; Rashid, M; Zahoor, M Y; Wissink-Lindhout, W M; Basra, M A R; Ansar, M; Agha, Z; van Heeswijk, K; Rasheed, F; Van de Vorst, M; Veltman, J A; Gilissen, C; Akram, J; Kleefstra, T; Assir, M Z; Grozeva, D; Carss, K; Raymond, F L; O'Connor, T D; Riazuddin, S A; Khan, S N; Ahmed, Z M; de Brouwer, A P M; van Bokhoven, H; Riazuddin, S

2017-11-01

Intellectual disability (ID) is a clinically and genetically heterogeneous disorder, affecting 1-3% of the general population. Although research into the genetic causes of ID has recently gained momentum, identification of pathogenic mutations that cause autosomal recessive ID (ARID) has lagged behind, predominantly due to non-availability of sizeable families. Here we present the results of exome sequencing in 121 large consanguineous Pakistani ID families. In 60 families, we identified homozygous or compound heterozygous DNA variants in a single gene, 30 affecting reported ID genes and 30 affecting novel candidate ID genes. Potential pathogenicity of these alleles was supported by co-segregation with the phenotype, low frequency in control populations and the application of stringent bioinformatics analyses. In another eight families segregation of multiple pathogenic variants was observed, affecting 19 genes that were either known or are novel candidates for ID. Transcriptome profiles of normal human brain tissues showed that the novel candidate ID genes formed a network significantly enriched for transcriptional co-expression (P<0.0001) in the frontal cortex during fetal development and in the temporal-parietal and sub-cortex during infancy through adulthood. In addition, proteins encoded by 12 novel ID genes directly interact with previously reported ID proteins in six known pathways essential for cognitive function (P<0.0001). These results suggest that disruptions of temporal parietal and sub-cortical neurogenesis during infancy are critical to the pathophysiology of ID. These findings further expand the existing repertoire of genes involved in ARID, and provide new insights into the molecular mechanisms and the transcriptome map of ID.

Permanent neonatal diabetes: different aetiology in Arabs compared to Europeans.

PubMed

Habeb, Abdelhadi M; Flanagan, Sarah E; Deeb, Asma; Al-Alwan, Ibrahim; Alawneh, Hussain; Balafrej, Angham A L; Mutair, Angam; Hattersley, Andrew T; Hussain, Khalid; Ellard, Sian

2012-08-01

Mutations in the KCNJ11 and ABCC8 genes that encode the pancreatic K(ATP) channel are the commonest cause of permanent neonatal diabetes mellitus (PNDM). The authors aimed to define the genetic causes of PNDM in a large cohort of Arab patients and compare them with a British cohort tested in the same laboratory. Retrospective observational study. International genetics centre. Arab and British subjects with PNDM who were referred for genetic testing over the same period. Comparison of genotypes and phenotypes between the two cohorts. The aetiology and phenotype of PNDM in an Arab compared to a British cohort. 88 Arab and 77 British probands were referred between 2006 and 2011, inclusive. Consanguinity was higher among Arabs (63.6% vs 10.4%) and a higher percentage had a genetic diagnosis compared to the British cohort (63.6% vs 41.6%). Recessive EIF2AK3 gene mutations were the commonest cause of PNDM in the Arab cohort (22.7%) followed by INS (12.5%), and KCNJ11 and GCK (5.7% each), whereas K(ATP) channel mutations were the commonest cause (29.9%) in the British cohort. In 37.5% of Arab patients PNDM was part of a genetic syndrome compared to 7.8% of the British cohort. PNDM in the Arab population has a different genetic spectrum compared to British patients where KATP channel mutations are the commonest cause, similar to other European populations. In Arabs, PNDM is more likely to be part of a recessively inherited syndrome, possibly due to the higher rate of consanguinity.

Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome.

PubMed

Abouzeid, Hana; Boisset, Gaëlle; Favez, Tatiana; Youssef, Mohamed; Marzouk, Iman; Shakankiry, Nihal; Bayoumi, Nader; Descombes, Patrick; Agosti, Céline; Munier, Francis L; Schorderet, Daniel F

2011-01-07

Waardenburg anophthalmia syndrome, also known as microphthalmia with limb anomalies, ophthalmoacromelic syndrome, and anophthalmia-syndactyly, is a rare autosomal-recessive developmental disorder that has been mapped to 10p11.23. Here we show that this disease is heterogeneous by reporting on a consanguineous family, not linked to the 10p11.23 locus, whose two affected children have a homozygous mutation in SMOC1. Knockdown experiments of the zebrafish smoc1 revealed that smoc1 is important in eye development and that it is expressed in many organs, including brain and somites.

Constitutional trisomy 8 mosaicism syndrome: case report and review

PubMed Central

Udayakumar, Achandira M.; Al-Kindy, Adila

2013-01-01

Trisomy 8 mosaicism (Warkany syndrome) is a rare viable condition with variable phenotypes, ranging from mild dysmorphic features to severe malformations. Karyotyping and fluorescence in-situ hybridization potentially help detecting this low mosaic clone to confirm the diagnosis of patients with classical and unusual clinical presentations. This report reviews few previous cases to describe our case - a boy who had trisomy 8 mosaicism with severe dysmorphic features, born to a consanguineous Arabic couple. This study concludes that careful cytogenetic diagnoses of trisomy 8 mosaicism is essential for appropriate management and follow up of this rare disorder. PMID:27625859

Constitutional trisomy 8 mosaicism syndrome: case report and review.

PubMed

Udayakumar, Achandira M; Al-Kindy, Adila

2013-12-01

Trisomy 8 mosaicism (Warkany syndrome) is a rare viable condition with variable phenotypes, ranging from mild dysmorphic features to severe malformations. Karyotyping and fluorescence in-situ hybridization potentially help detecting this low mosaic clone to confirm the diagnosis of patients with classical and unusual clinical presentations. This report reviews few previous cases to describe our case - a boy who had trisomy 8 mosaicism with severe dysmorphic features, born to a consanguineous Arabic couple. This study concludes that careful cytogenetic diagnoses of trisomy 8 mosaicism is essential for appropriate management and follow up of this rare disorder.

Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V).

PubMed

Abdul Wahab, A; Al Thani, G; Dawod, S T; Kambouris, M; Al Hamed, M

2001-04-01

Twenty-nine subjects (17 families) with cystic fibrosis belonging to the same Bedouin tribe were screened for cystic fibrosis transmembrane regulator gene mutations (CFTR). Homozygous I1234V mutation in exon 19 was identified in all families with a relatively high rate of consanguinity (96.6 per cent). The homozygous I1234V mutation tended to present with a variable degree of pulmonary disease, pancreatic insufficiency and electrolyte imbalance. Homozygous I1234V was found to be a common mutation in the studied Bedouin tribe in Qatar.

Intermittent chronic neutropenia in a patient with familial Mediterranean fever.

PubMed

Ganiou Tidjani, K; Ailal, F; Najib, J; Bellanné-Chantelot, C; Donadieu, J; Bousfiha, A A

2008-11-01

A 12-year-old daughter of consanguineous Moroccan parents was diagnosed with cyclic neutropenia, based on a combination of recurrent gingivostomatitis, a fluctuating neutrophil count, and several episodes of severe neutropenia. No ELA2 gene mutations were found. At age 19 years she presented with edema of the limbs, proteinuria and renal failure. Renal amyloidosis AA was diagnosed by biopsy. Gene mutations associated with family Mediterranean fever (FMF) were sought, and a homozygous mutation (M694V) was found in the MFEV gene. This is the novel finding of FMF that masqueraded as cyclic neutropenia. (c) 2008 Wiley-Liss, Inc.

Bernard-Soulier syndrome in two Afrikaner families.

PubMed

Grové, S S; Kromberg, J G

1985-06-29

The hereditary autosomal recessive disorder of platelet function known as the Bernard-Soulier syndrome (B-SS) is described in two Afrikaner families. Consanguinity exists in one of the families, which is descended from Trekboer Afrikaners who migrated from Rustenburg, Transvaal, to Angola in 1876 and then to SWA/Namibia in the 1920s. Since both families have French Huguenot ancestors and since there are 7 confirmed and 5 reported cases of B-SS in these two families, founder effect may be operating and causing this rare disorder to occur more frequently in this population group than would otherwise be expected.

Congenital yellow nail syndrome: a case report and its relationship to nonimmune fetal hydrops.

PubMed

Nanda, Arti; Al-Essa, Fahad H; El-Shafei, Wael M; Alsaleh, Qasem A

2010-01-01

Yellow nail syndrome (YNS) is an uncommon disorder characterized by a triad of nail dystrophy, lymphedema, and pleural effusion. It is rare in children and congenital occurrence of YNS has been very rarely described. We report a 2-year-old Arab boy having congenital yellow nail syndrome with mild facial dysmorphism and bilateral conjunctival pigmentation born to consanguineous parents. One of his older siblings had died of nonimmune fetal hydrops (NIFH). The case supports the genetic basis of yellow nail syndrome with a possible relationship to nonimmune fetal hydrops. © 2010 Wiley Periodicals, Inc.

[Maxillodental anomalies and consanguineous marriages].

PubMed

Garaev, Z I

1999-01-01

Families of 549 probands and families of 123 probands with cleft lip and/or palate were examined in order to evaluate the relationship between marriages between close relatives and the incidence and structure of maxillodental diseases. Clinical and genealogical analysis of families of probands with maxillodental abnormalities and cleft lip and/or palate showed a significantly higher incidence of marriages between close relatives and an inbreeding coefficient in these families. Analysis of the population and familial incidence of maxillodental abnormalities and the inbreeding coefficient will help the physicians consulting such families more accurately evaluate the risk and improve the efficacy of prevention of such conditions.

Whole-Genome Analysis Reveals that Mutations in Inositol Polyphosphate Phosphatase-like 1 Cause Opsismodysplasia

PubMed Central

Below, Jennifer E.; Earl, Dawn L.; Shively, Kathryn M.; McMillin, Margaret J.; Smith, Joshua D.; Turner, Emily H.; Stephan, Mark J.; Al-Gazali, Lihadh I.; Hertecant, Jozef L.; Chitayat, David; Unger, Sheila; Cohn, Daniel H.; Krakow, Deborah; Swanson, James M.; Faustman, Elaine M.; Shendure, Jay; Nickerson, Deborah A.; Bamshad, Michael J.

2013-01-01

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ∼60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases. PMID:23273567

A Male Infant with Abetalipoproteinemia: A Case Report from Iran

PubMed Central

Rashtian, Parisa; Najafi Sani, Mehri; Jalilian, Rozita

2015-01-01

Abetalipoproteinemia (ABL) is a very rare autosomal recessive disorder caused by mutations in the microsomal triglyceride transfer protein gene (MTTP). ABL is characterized by lack of lipids and apolipoprotein B (apoB) in plasma, fat malabsorption and various clinical manifestations. We describe a 12-month-old infant boy, born from consanguineous parents and presented with diarrhea, steatorrhea, growth retardation, hypothyroidism, intraventricular brain cyst and kidney stones. The patient was diagnosed to have ABL and treated with dietary modification and oral fat-soluble vitamin replacement and followed until he reached 5 years of age. PMID:26396722

Prevalence of prelingual deafness in Italy

PubMed Central

Bubbico, L; Rosano, A; Spagnolo, A

2007-01-01

Summary Neonatal hearing loss is the most frequent sensorial congenital defect in newborns. No data are available on worldwide prevalence of congenital deafness. World Health Organization (WHO) data indicate 1-4 cases per 1,000 individuals, with a considerable increase in developing countries. A prevalence exceeding 1 per 1,000 however, indicates a serious public health problem calling for urgent attention. Aim of the study was the evaluate the prevalence of prelingual deafness in the Italian population and determine the socio-demographic characteristics of the condition. Data were provided by the National Institute of Social Insurance (INPS) and the Italian Central Statistics Institute (ISTAT) and were collected in 18 out of the 20 Italian regions (98.2% of total population). All subjects recognized as deaf-mute by a special medical committee were included. According to law No. 509/1988, they had to present a mean bilateral sensorineural-hearing impairment, detected in neonatal age, which caused the damage in speech development and equal to 60 dB or more for 500-, 1,000- and 2,000-Hz frequency tones in the better ear. Prevalence rates were calculated according to region and age bracket using updated population data from census 2001. Statistical analyses were performed using the SPSS statistical software package. A total of 40,887 cases of prelingual profound sensorineural hearing loss ≥ 60 dB were detected in Italy in 2003, for a total prevalence rate of 0.72 per 1,000. The hearing impairment prevalence differs according to sex. The overall prevalence is 0.78 per 1,000 for males and 0.69 per 1,000 for females (p < 0.001). The hearing impairment prevalence differs according to region of residence (p < 0.001). The geographic distribution of prelingual deafness was found to be: North 15,644 cases (0.63 per 1,000), Central Italy 7,111 cases (0.64 per 1,000), South and Islands 18,132 (0.87 per 1,000). The prelingual hearing loss is highly prevalent in South Italy (Basilicata, Calabria and Sicily). For the southern regions of Italy, the rate observed in the 50-64 and > 64 age groups reached 1.27 and 1.15, respectively. This phenomenon may have been due, in part, to the epidemic incidence of maternal rubella which occurred in the 40’s and 50’s (in Italy, the rubella vaccination was only recommended starting from 1972), and, in part, to the habit of contracting consanguineous marriages. Data from the Vatican Archives on 520,492 consanguineous marriages, for which dispensation was requested in the period 1911-1964, indicate that in the years 1935-1939, in small villages in South Italy (Basilicata, Calabria, Sicily) consanguineous marriages accounted for over 40% of marriages. PMID:17601206

Reliability of information on people with disabilities gathered by community health workers in highly consanguineous communities of Northeastern Brazil.

PubMed

Lopes, Fernando Rocha Lucena; Monteiro, Karolinne Souza; Figueiredo, Thalita; Wanderley, Thyago da Costa; Pequeno, Thiago de Almeida; Lima, Shirley; Santos, Silvana

2017-05-02

In Brazil, community health workers have gathered monthly information on people with disabilities to maintain the Primary Care Information System since 1998; however, few studies have used this database for scientific or public health policy purposes. This study aimed to evaluate the reliability of information on people with disabilities gathered by community health workers in primary care services. This was a cross-sectional population-based study conducted in two highly consanguineous communities, involving a population of 18,458 inhabitants in Northeastern Brazil. To study the prevalence of people with disabilities, estimations performed by health workers were compared with those obtained by researchers who interviewed 15.6% of the total population. To study the agreement of the information, data on 106 people with disabilities completed independently by researchers and health workers were compared to evaluate the degree of agreement for 28 variables analysed. Kappa statistics (κ) were used to calculate the inter-rater agreement. The prevalence of disability estimated by community health workers was 3.01 and 2.00% for city A and B, respectively, while the percentages obtained by researchers were 6.72 and 5.65%, respectively, showing an underestimation of prevalence according to community health workers. The Kappa index value obtained for all data analysed (2,589 items excluding losses) was 0.808 (p < 0.01), indicating an almost perfect consistency of information collected by health workers compared to by researchers. Community health workers collected information with a high degree of reliability, although the identification of the prevalence of disabled individuals was potentially impaired due to the work process.

Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: Two proof-of-concept examples.

PubMed

Giorgio, Elisa; Ciolfi, Andrea; Biamino, Elisa; Caputo, Viviana; Di Gregorio, Eleonora; Belligni, Elga Fabia; Calcia, Alessandro; Gaidolfi, Elena; Bruselles, Alessandro; Mancini, Cecilia; Cavalieri, Simona; Molinatto, Cristina; Cirillo Silengo, Margherita; Ferrero, Giovanni Battista; Tartaglia, Marco; Brusco, Alfredo

2016-07-01

Whole exome sequencing (WES) is a powerful tool to identify clinically undefined forms of intellectual disability/developmental delay (ID/DD), especially in consanguineous families. Here we report the genetic definition of two sporadic cases, with syndromic ID/DD for whom array-Comparative Genomic Hybridization (aCGH) identified a de novo copy number variant (CNV) of uncertain significance. The phenotypes included microcephaly with brachycephaly and a distinctive facies in one proband, and hypotonia in the legs and mild ataxia in the other. WES allowed identification of a functionally relevant homozygous variant affecting a known disease gene for rare syndromic ID/DD in each proband, that is, c.1423C>T (p.Arg377*) in the Trafficking Protein Particle Complex 9 (TRAPPC9), and c.154T>C (p.Cys52Arg) in the Very Low Density Lipoprotein Receptor (VLDLR). Four mutations affecting TRAPPC9 have been previously reported, and the present finding further depicts this syndromic form of ID, which includes microcephaly with brachycephaly, corpus callosum hypoplasia, facial dysmorphism, and overweight. VLDLR-associated cerebellar hypoplasia (VLDLR-CH) is characterized by non-progressive congenital ataxia and moderate-to-profound intellectual disability. The c.154T>C (p.Cys52Arg) mutation was associated with a very mild form of ataxia, mild intellectual disability, and cerebellar hypoplasia without cortical gyri simplification. In conclusion, we report two novel cases with rare causes of autosomal recessive ID, which document how interpreting de novo array-CGH variants represents a challenge in consanguineous families; as such, clinical WES should be considered in diagnostic testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Novel mutations of MYO7A and USH1G in Israeli Arab families with Usher syndrome type 1.

PubMed

Rizel, Leah; Safieh, Christine; Shalev, Stavit A; Mezer, Eedy; Jabaly-Habib, Haneen; Ben-Neriah, Ziva; Chervinsky, Elena; Briscoe, Daniel; Ben-Yosef, Tamar

2011-01-01

This study investigated the genetic basis for Usher syndrome type 1 (USH1) in four consanguineous Israeli Arab families. Haplotype analysis for all known USH1 loci was performed in each family. In families for which haplotype analysis was inconclusive, we performed genome-wide homozygosity mapping using a single nucleotide polymorphism (SNP) array. For mutation analysis, specific primers were used to PCR amplify the coding exons of the MYO7A, USH1C, and USH1G genes including intron-exon boundaries. Mutation screening was performed with direct sequencing. A combination of haplotype analysis and genome-wide homozygosity mapping indicated linkage to the USH1B locus in two families, USH1C in one family and USH1G in another family. Sequence analysis of the relevant genes (MYO7A, USH1C, and USH1G) led to the identification of pathogenic mutations in all families. Two of the identified mutations are novel (c.1135-1147dup in MYO7A and c.206-207insC in USH1G). USH1 is a genetically heterogenous condition. Of the five USH1 genes identified to date, USH1C and USH1G are the rarest contributors to USH1 etiology worldwide. It is therefore interesting that two of the four Israeli Arab families reported here have mutations in these two genes. This finding further demonstrates the unique genetic structure of the Israeli population in general, and the Israeli Arab population in particular, which due to high rates of consanguinity segregates many rare autosomal recessive genetic conditions.

Evaluation of social and demographic characteristics of incest cases in a university hospital in Turkey

PubMed Central

Yildirim, Ali; Ozer, Erdal; Bozkurt, Hasan; Ozsoy, Sait; Enginyurt, Ozgur; Evcuman, Durmus; Yilmaz, Riza; Kuyucu, Yunus Emre

2014-01-01

Background Incest is defined as any sexual activity between close blood relatives including step relatives and family members who are forbidden by law to marry. It is a problem that can be seen in all the social classes in developed and undeveloped societies. The World Health Organization classifies this problem as a silent health emergency. Father-daughter incest is reported to be the most common incest type followed by the other types like brother-sister, sister-sister and mother-son incest. Material/Methods Subjects for this study were recruited from a sample of incest cases referred to Forensic Medicine Department of Gaziosmanpasa University Medical Faculty Hospital between 2008 and 2012. Data involved social and demographic characteristics and clinical features of victims, perpetrators and the families. The ethical committee of the faculty of medicine approved the study. Results The study sample consisted of 43 incest cases (36 females and 7 males) with an age rage 4–40 years. Two third of the victims were under 18 years old. All perpetrators were males. Father – daughter incest (34.9%) was found to be most common incest type followed by brother – sister incest (14%). 75% of the perpetrators were family members and relatives with consanguinity while 25% of them were not consanguineous but faithful and intimate relatives to victims. Conclusions Increasing awareness about incest and its damaging effects is so important and clinicians should keep in mind sexual abuse or incest when examining the risky population. Multidisciplinary approach is necessary for determining short term or long term results and preventing the negative consequences of incest. PMID:24770724

Partial unilateral lentiginosis is mosaic neurofibromatosis type 1 or not?

PubMed

Yaşar, Şirin; Ersanli, Ayşegül; Göktay, Fatih; Aytekin, Sema; Cebeci, Dua; Güneş, Pembegül

2017-01-01

Partial unilateral lentiginosis (PUL) is a rare pigmentation disorder characterized by numerous lentigines with sharp margins in the midline in one or more dermatomes. Its segmental pattern suggests that this presentation accompanied by café-au-lait spots, Lisch nodule or neurofibromas has a close relationship with mosaic neurofibromatosis type 1 or segmental neurofibromatosis (NF) in particular. In a group of 16 patients with PUL, who presented at the dermatology outpatient clinic between 1998 and 2015, an examination was made of consanguineous marriage in the family history, the presence of a similar lesion or NF in first-degree relatives, neurofibroma in the physical examination, the involvement pattern, axillary/inguinal freckling and the presence and number of café-au-lait spots. The ophthalmological examination investigated Lisch nodule and optic glioma. The skeletal system was examined for NF involvement. Of 16 patients, 13 (81.2%) were female and three (18.8%) were male with a mean age of 31.19 years (range, 15-48). There was no family history of PUL in any case. Consanguineous marriage was absent in 15 patients (93.8%). While there were accompanying café-au-lait spots in three patients (18.8%). Lisch nodule was an accompanying finding in three patients (18.8%). Axillary freckling was detected in four (25%) patients. Neurofibroma was found in only one patient. Although café-au-lait spots, axillary freckling, neurofibroma and Lisch nodule were present in a small number of the patients, the presence of the findings may be considered to be specific to NF suggests that PUL is a variant of mosaic NF-1. Genetic studies will help to further elucidate this subject. © 2016 Japanese Dermatological Association.

Population and genomic lessons from genetic analysis of two Indian populations.

PubMed

Juyal, Garima; Mondal, Mayukh; Luisi, Pierre; Laayouni, Hafid; Sood, Ajit; Midha, Vandana; Heutink, Peter; Bertranpetit, Jaume; Thelma, B K; Casals, Ferran

2014-10-01

Indian demographic history includes special features such as founder effects, interpopulation segregation, complex social structure with a caste system and elevated frequency of consanguineous marriages. It also presents a higher frequency for some rare mendelian disorders and in the last two decades increased prevalence of some complex disorders. Despite the fact that India represents about one-sixth of the human population, deep genetic studies from this terrain have been scarce. In this study, we analyzed high-density genotyping and whole-exome sequencing data of a North and a South Indian population. Indian populations show higher differentiation levels than those reported between populations of other continents. In this work, we have analyzed its consequences, by specifically assessing the transferability of genetic markers from or to Indian populations. We show that there is limited genetic marker portability from available genetic resources such as HapMap or the 1,000 Genomes Project to Indian populations, which also present an excess of private rare variants. Conversely, tagSNPs show a high level of portability between the two Indian populations, in contrast to the common belief that North and South Indian populations are genetically very different. By estimating kinship from mates and consanguinity in our data from trios, we also describe different patterns of assortative mating and inbreeding in the two populations, in agreement with distinct mating preferences and social structures. In addition, this analysis has allowed us to describe genomic regions under recent adaptive selection, indicating differential adaptive histories for North and South Indian populations. Our findings highlight the importance of considering demography for design and analysis of genetic studies, as well as the need for extending human genetic variation catalogs to new populations and particularly to those with particular demographic histories.

The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families

PubMed Central

Kahrizi, Kimia; Musante, Luciana; Fattahi, Zohreh; Hosseini, Masoumeh; Maqsoud, Fariba; Farajollahi, Reza; Wienker, Thomas F.; Ropers, H. Hilger; Najmabadi, Hossein

2015-01-01

Cognitive impairment or intellectual disability (ID) is a widespread neurodevelopmental disorder characterized by low IQ (below 70). ID is genetically heterogeneous and is estimated to affect 1–3% of the world’s population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID), we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831), encodes the metabotropic glutamate receptor1 (mGluR1). This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011). We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder. PMID:26308914

The Role of a Novel TRMT1 Gene Mutation and Rare GRM1 Gene Defect in Intellectual Disability in Two Azeri Families.

PubMed

Davarniya, Behzad; Hu, Hao; Kahrizi, Kimia; Musante, Luciana; Fattahi, Zohreh; Hosseini, Masoumeh; Maqsoud, Fariba; Farajollahi, Reza; Wienker, Thomas F; Ropers, H Hilger; Najmabadi, Hossein

2015-01-01

Cognitive impairment or intellectual disability (ID) is a widespread neurodevelopmental disorder characterized by low IQ (below 70). ID is genetically heterogeneous and is estimated to affect 1-3% of the world's population. In affected children from consanguineous families, autosomal recessive inheritance is common, and identifying the underlying genetic cause is an important issue in clinical genetics. In the framework of a larger project, aimed at identifying candidate genes for autosomal recessive intellectual disorder (ARID), we recently carried out single nucleotide polymorphism-based genome-wide linkage analysis in several families from Ardabil province in Iran. The identification of homozygosity-by-descent loci in these families, in combination with whole exome sequencing, led us to identify possible causative homozygous changes in two families. In the first family, a missense variant was found in GRM1 gene, while in the second family, a frameshift alteration was identified in TRMT1, both of which were found to co-segregate with the disease. GRM1, a known causal gene for autosomal recessive spinocerebellar ataxia (SCAR13, MIM#614831), encodes the metabotropic glutamate receptor1 (mGluR1). This gene plays an important role in synaptic plasticity and cerebellar development. Conversely, the TRMT1 gene encodes a tRNA methyltransferase that dimethylates a single guanine residue at position 26 of most tRNAs using S-adenosyl methionine as the methyl group donor. We recently presented TRMT1 as a candidate gene for ARID in a consanguineous Iranian family (Najmabadi et al., 2011). We believe that this second Iranian family with a biallelic loss-of-function mutation in TRMT1 gene supports the idea that this gene likely has function in development of the disorder.

Molecular characterisation of congenital glaucoma in a consanguineous Canadian community: a step towards preventing glaucoma related blindness

PubMed Central

Martin, S; Sutherland, J.; Levin, A.; Klose, R.; Priston, M.; Heon, E.

2000-01-01

Glaucoma is a leading cause of irreversible blindness in Canada. Congenital glaucoma usually manifests during the first years of life and is characterised by severe visual loss and autosomal recessive inheritance. Two disease loci, on chromosomes 1p36 and 2p21, have been associated with various forms of congenital glaucoma. A branch of a large six generation family from a consanguineous Amish community in south western Ontario was affected with congenital glaucoma and was studied by linkage and mutational analysis to identify the glaucoma related genetic defects. Linkage analysis using the MLINK component of the LINKAGE package (v 5.1) showed evidence of linkage to the 2p21 region (Zmax=3.34, θ=0, D2S1348 and D2S1346). Mutational analysis of the primary candidate gene, CYP1B1, was done by direct cycle sequencing, dideoxy fingerprinting analysis, and fragment analysis. Two different disease causing mutations in exon 3, 1410del13 and 1505G→A, both segregated with the disease phenotype. The two different combinations of these alleles appeared to result in a variable expressivity of the phenotype. The compound heterozygote appeared to have a milder phenotype when compared to the homozygotes for the 13 bp deletion. The congenital glaucoma phenotype for this large inbred Amish family is the result of mutations in CYP1B1 (2p21). The molecular information derived from this study will be used to help identify carriers of the CYP1B1 mutation in this community and optimise the management of those at risk of developing glaucoma.


Keywords: congenital glaucoma; CYP1B1; gene; genetic counselling PMID:10851252

Prevalence of IgE mediated cow's milk and egg allergy in children under 2 years of age in Sanliurfa, Turkey: the city that isn't almost allergic to cow's milk.

PubMed

Zeyrek, D; Koruk, I; Kara, B; Demir, C; Cakmak, A

2015-12-01

Food allergy is a common problem in children and adults. The aim of this study was to determine the frequency of cow's milk and egg allergy based on skin prick test and oral food challenge results We recruited 614 children aged 1 month-2 years in from different areas of Sanliurfa. An interview was conducted with each parents and family demographic, and prenatal-antenatal-postnatal information was recorded, then skin prick test was applied to the children for egg white, egg yolk and cow's milk. Cases that are required, sIgE levels for cow's milk, egg white and egg yolk were measured and food challenge tests were applied. Cow's milk and egg allergy was determined in 1 case (0.16%) and 8 cases (1.30%) respectively from the results of the tests applied. Six cases (0.97%) were accepted as sensitive to egg white and egg yolk. Within the factors which were questioned, (only the egg allergy evaluation was made without the cow's milk allergy case) of those with parental consanguinity was determined at a statistically significantly high level (OR=5.8, 95% CI: 1.2-27.2, P=0.01). The prevalence of cow's milk allergy in Sanliurfa is the lowest reported prevalence rate to date in children under 2 years of age. When infants develop a food allergy, this takes the form of egg allergy. Within the several factors evaluated to explain this situation, a significant relationship was determined only with parental consanguinity. However, as reported above, to date there is no genetic or epidemiological study to explain this situation.

A novel loss-of-function mutation in GPR54/KISS1R leads to hypogonadotropic hypogonadism in a highly consanguineous family.

PubMed

Nimri, Revital; Lebenthal, Yael; Lazar, Liora; Chevrier, Lucie; Phillip, Moshe; Bar, Meytal; Hernandez-Mora, Eva; de Roux, Nicolas; Gat-Yablonski, Galia

2011-03-01

The G protein-coupled receptor 54 (GPR54), the kisspeptin receptor, is essential for stimulation of GnRH secretion and induction of puberty. Recently loss-of-function mutations of the GPR54 have been implicated as a cause of isolated idiopathic hypogonadotropic hypogonadism (IHH). The objective of the study was to identify the genetic cause of IHH in a consanguineous pedigree and to characterize the phenotypic features from infancy through early adulthood. In six patients with normosmic IHH belonging to two families of Israeli Muslim-Arab origin highly related to one another, DNA was analyzed for mutations in the GnRHR and GPR54 genes, with functional analysis of the mutation found. The five males underwent comprehensive endocrine evaluation and were under longitudinal follow-up; the one female presented in early adulthood. A new homozygous mutation (c.T815C) in GPR54 leading to a phenylalanine substitution by serine (p.F272S) was detected in all patients. Functional analysis showed an almost complete inhibition of kisspeptin-induced GPR54 signaling and a dramatic decrease of the mutated receptor expression at the cell surface. The males exhibited the same clinical features from infancy to adulthood, characterized by cryptorchidism, a relatively short penis, and no spontaneous pubertal development. The female patient presented at 18 yr with impuberism and primary amenorrhea. Repeated stimulation tests demonstrated complete gonadotropin deficiency throughout follow-up. A novel loss-of-function mutation (p.F272S) in the GPR54 gene is associated with familial normosmic IHH. Underdeveloped external genitalia and impuberism point to the major role of GPR54 in the activation of the gonadotropic axis from intrauterine life to adulthood.

Isonymy structure of Sucre and Táchira, two Venezuelan states.

PubMed

Rodríguez-Larralde, A; Barrai, I

1997-10-01

The isonymy structure of two Venezuelan states, Sucre and Táchira, is described using the surnames of the Register of Electors updated in 1991. The frequency distribution of surnames pooled together by sex was obtained for the 57 counties of Sucre and the 52 counties of Táchira, based on total population sizes of 158,705 and 160,690 individuals, respectively. The coefficient of consanguinity resulting from random isonymy (phi ii), Karlin and McGregor's ni (identical to v), and the proportion of the population included in surnames represented only once (estimator A) and in the seven most frequent surnames (estimator B) were calculated for each county. RST, a measure of microdifferentiation, was estimated for each state. The Euclidean distance between pairs of counties within states was calculated together with the corresponding geographic distances. The correlations between their logarithmic transformations were significant in both cases, indicating differentiation of surnames by distance. Dendrograms based on the Euclidean distance matrix were constructed. From them a first approximation of the effect of internal migration within states was obtained. Ninety-six percent of the coefficient of consanguinity resulting from random isonymy is determined by the proportion of the population included in the seven most frequent surnames, whereas between 72% and 88% of Karlin and McGregor's ni for Sucre and Táchira, respectively, is determined by the proportion of population included in surnames represented only once. Surnames with generalized and with focal distribution were identified for both states, to be used as possible indicators of the geographic origin of their carriers. Our results indicate that Táchira's counties, on average, tend to be more isolated than Sucre's counties, as measured by RST, estimator B, and phi ii. Comparisons with the results obtained for other. Venezuelan states and other non-Venezuelan populations are also given.

Genotype and phenotype relationships in 10 Pakistani unrelated patients with inherited factor VII deficiency.

PubMed

Borhany, M; Boijout, H; Pellequer, J-L; Shamsi, T; Moulis, G; Aguilar-Martinez, P; Schved, J-F; Giansily-Blaizot, M

2013-11-01

Inherited factor VII (FVII) deficiency is one of the commonest rare bleeding disorders. It is characterized by a wide molecular and clinical heterogeneity and an autosomal recessive pattern of inheritance. Factor VII-deficient patients are still scarcely explored in Pakistan although rare bleeding disorders became quite common as a result of traditional consanguineous marriages. The aim of the study was to give a first insight of F7 gene mutations in Pakistani population. Ten unrelated FVII-deficient patients living in Pakistan were investigated (median FVII:C = 2%; range = 2-37%). A clinical questionnaire was filled out for each patient and direct sequencing was performed on the coding regions, intron/exon boundaries and 5' and 3' untranslated regions of the F7 gene. Nine different mutations (eight missense mutations and one located within the F7 promoter) were identified on the F7 gene. Five of them were novel (p.Cys82Tyr, p.Cys322Ser, p.Leu357Phe, p.Thr410Ala, c-57C>T, the last being predicted to alter the binding site of transcription factor HNF-4). Half of the patients had single mutations in Cys residues involved in disulfide bridges. The p.Cys82Arg mutation was the most frequent in our series. Six of seven patients with FVII:C levels below 10% were homozygous in connection with the high percentage of consanguinity in our series. In addition, we graded the 10 patients according to three previously published classifications for rare bleeding disorders. The use of the bleeding score proposed by Tosetto and co-workers in 2006 appears to well qualify the bleeding tendency in our series. © 2013 John Wiley & Sons Ltd.

Paternal factors associated with neonatal deaths and births with low weight: evidence from Pakistan Demographic and Health Survey 2006-2007.

PubMed

Zakar, Rubeena; Zakar, Muhammad Zakria; Aqil, Nauman; Nasrullah, Muazzam

2015-07-01

We aimed to discern paternal factors associated with neonatal deaths and births with low weight, independent of maternal and other socio-demographic factors. We analyzed the nationally representative sample of 5,724 ever-married women of reproductive age (15-49 years) who delivered their last child during the past 5 years preceding the Pakistan Demographic and Health Survey 2006-2007. We assessed adverse birth outcomes using two variables i.e. neonatal deaths (<28 days) and small size births (as a proxy for birth weight). Associations between paternal factors and adverse birth outcomes were assessed by calculating unadjusted and adjusted odds ratios using logistic regression models after controlling for maternal and socio-demographic factors. The analysis was performed by using the statistical package for social sciences (SPSS) version 17. About 4.5 % mothers reported neonatal deaths and 34 % had small size births (SSB). We found that fathers involved in manual occupation were more likely to have neonatal deaths than fathers involved in managerial/professional jobs (adjusted odds ratio (aOR): 1.64; 95 % Confidence Interval (CI) 1.01, 3.55). Similarly, fathers who belonged to poorer wealth index had higher risk of SSB (aOR: 1.62; 95 % CI 1.18, 2.22). Additionally, consanguinity was a major risk factor which was associated with neonatal deaths (aOR: 1.73; 95 % CI 1.09, 2.74) and SSB (aOR: 1.25; 95 % CI 1.03, 1.55). Fathers' occupation including unemployment and consanguinity were associated with increased risk of adverse birth outcomes. Further studies are warranted to discern other paternal risk factors related to adverse birth outcomes.

Autosomal Recessive Mental Retardation, Deafness, Ankylosis, and Mild Hypophosphatemia Associated with a Novel ANKH Mutation in a Consanguineous Family

PubMed Central

Morava, Eva; Kühnisch, Jirko; Drijvers, Jefte M.; Robben, Joris H.; Cremers, Cor; van Setten, Petra; Branten, Amanda; Stumpp, Sabine; de Jong, Alphons; Voesenek, Krysta; Vermeer, Sascha; Heister, Angelien; Claahsen-van der Grinten, Hedi L.; O'Neill, Charles W.; Willemsen, Michèl A.; Lefeber, Dirk; Deen, Peter M. T.; Kornak, Uwe; Kremer, Hannie; Wevers, Ron A.

2011-01-01

Context: Mutations in ANKH cause the highly divergent conditions familial chondrocalcinosis and craniometaphyseal dysplasia. The gene product ANK is supposed to regulate tissue mineralization by transporting pyrophosphate to the extracellular space. Objective: We evaluated several family members of a large consanguineous family with mental retardation, deafness, and ankylosis. We compared their skeletal, metabolic, and serological parameters to that of the autosomal recessive progressive ankylosis (ank) mouse mutant, caused by a loss-of-function mutation in the murine ortholog Ank. Participants: The studied patients had painful small joint soft-tissue calcifications, progressive spondylarthropathy, osteopenia, mild hypophosphatemia, mixed hearing loss, and mental retardation. Results: After mapping the disease gene to 5p15, we identified the novel homozygous ANK missense mutation L244S in all patients. Although L244 is a highly conserved amino acid, the mutated ANK protein was detected at normal levels at the plasma membrane in primary patient fibroblasts. The phenotype was highly congruent with the autosomal recessive progressive ankylosis (ank) mouse mutant. This indicates a loss-of-function effect of the L244S mutation despite normal ANK protein expression. Interestingly, our analyses revealed that the primary step of joint degeneration is fibrosis and mineralization of articular soft tissues. Moreover, heterozygous carriers of the L244S mutation showed mild osteoarthritis without metabolic alterations, pathological calcifications, or central nervous system involvement. Conclusion: Beyond the description of the first human progressive ankylosis phenotype, our results indicate that ANK influences articular soft tissues commonly involved in degenerative joint disorders. Furthermore, this human disorder provides the first direct evidence for a role of ANK in the central nervous system. PMID:20943778

Autosomal recessive mental retardation, deafness, ankylosis, and mild hypophosphatemia associated with a novel ANKH mutation in a consanguineous family.

PubMed

Morava, Eva; Kühnisch, Jirko; Drijvers, Jefte M; Robben, Joris H; Cremers, Cor; van Setten, Petra; Branten, Amanda; Stumpp, Sabine; de Jong, Alphons; Voesenek, Krysta; Vermeer, Sascha; Heister, Angelien; Claahsen-van der Grinten, Hedi L; O'Neill, Charles W; Willemsen, Michèl A; Lefeber, Dirk; Deen, Peter M T; Kornak, Uwe; Kremer, Hannie; Wevers, Ron A

2011-01-01

Mutations in ANKH cause the highly divergent conditions familial chondrocalcinosis and craniometaphyseal dysplasia. The gene product ANK is supposed to regulate tissue mineralization by transporting pyrophosphate to the extracellular space. We evaluated several family members of a large consanguineous family with mental retardation, deafness, and ankylosis. We compared their skeletal, metabolic, and serological parameters to that of the autosomal recessive progressive ankylosis (ank) mouse mutant, caused by a loss-of-function mutation in the murine ortholog Ank. The studied patients had painful small joint soft-tissue calcifications, progressive spondylarthropathy, osteopenia, mild hypophosphatemia, mixed hearing loss, and mental retardation. After mapping the disease gene to 5p15, we identified the novel homozygous ANK missense mutation L244S in all patients. Although L244 is a highly conserved amino acid, the mutated ANK protein was detected at normal levels at the plasma membrane in primary patient fibroblasts. The phenotype was highly congruent with the autosomal recessive progressive ankylosis (ank) mouse mutant. This indicates a loss-of-function effect of the L244S mutation despite normal ANK protein expression. Interestingly, our analyses revealed that the primary step of joint degeneration is fibrosis and mineralization of articular soft tissues. Moreover, heterozygous carriers of the L244S mutation showed mild osteoarthritis without metabolic alterations, pathological calcifications, or central nervous system involvement. Beyond the description of the first human progressive ankylosis phenotype, our results indicate that ANK influences articular soft tissues commonly involved in degenerative joint disorders. Furthermore, this human disorder provides the first direct evidence for a role of ANK in the central nervous system.

Genetic contribution for non-syndromic cleft lip with or without cleft palate (NS CL/P) in different regions of Brazil and implications for association studies.

PubMed

Brito, Luciano A; Cruz, Lucas A; Rocha, Kátia M; Barbara, Ligia K; Silva, Camila B F; Bueno, Daniela F; Aguena, Meire; Bertola, Débora R; Franco, Diogo; Costa, André M; Alonso, Nivaldo; Otto, Paulo A; Passos-Bueno, Maria Rita

2011-07-01

Non-syndromic cleft lip with or without cleft palate (NS CL/P) is a complex disease in which heritability estimates vary widely depending on the population studied. To evaluate the importance of genetic contribution to NS CL/P in the Brazilian population, we conducted a study with 1,042 families from five different locations (Santarém, Fortaleza, Barbalha, Maceió, and Rio de Janeiro). We also evaluated the role of consanguinity and ethnic background. The proportion of familial cases varied significantly across locations, with the highest values found in Santarém (44%) and the lowest in Maceió (23%). Heritability estimates showed a higher genetic contribution to NS CL/P in Barbalha (85%), followed by Santarém (71%), Rio de Janeiro (70%), Fortaleza (64%), and Maceió (45%). Ancestry was not correlated with the occurrence of NS CL/P or with the variability in heritability. Only in Rio de Janeiro was the coefficient of inbreeding significantly larger in NS CL/P families than in the local population. Recurrence risk for the total sample was approximately 1.5-1.6%, varying according to the location studied (0.6-0.7% in Maceió to 2.2-2.8% in Barbalha). Our findings show that the degree of genetic contribution to NS CL/P varies according to the geographic region studied, and this difference cannot be attributed to consanguinity or ancestry. These findings suggest that Barbalha is a promising region for genetic studies. The data presented here will be useful in interpreting results from molecular analyses and show that care must be taken when pooling samples from different populations for association studies. Copyright © 2011 Wiley-Liss, Inc.

Genotype and phenotype correlations in Iranian patients with hyperinsulinaemic hypoglycaemia.

PubMed

Senniappan, Senthil; Sadeghizadeh, Atefeh; Flanagan, Sarah E; Ellard, Sian; Hashemipour, Mahin; Hosseinzadeh, Majid; Salehi, Mansour; Hussain, Khalid

2015-08-13

Hyperinsulinaemic hypoglycaemia (HH) is a group of clinically and genetically heterogeneous disorders characterized by unregulated insulin secretion. Abnormalities in nine different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, UCP2 and HNF1A) have been reported in HH, the most common being ABCC8 and KCNJ11. We describe the genetic aetiology and phenotype of Iranian patients with HH. Retrospective clinical, biochemical and genetic information was collected on 23 patients with biochemically confirmed HH. Mutation analysis was carried out for the ATP-sensitive potassium (K(ATP)) channel genes (ABCC8 and KCNJ11), GLUD1, GCK, HADH and HNF4A. 78% of the patients were identified to have a genetic cause for HH. 48% of patients had mutation in HADH, whilst ABCC8/KCNJ11 mutations were identified in 30% of patients. Among the diazoxide-responsive patients (18/23), mutations were identified in 72%. These include two novel homozygous ABCC8 mutations. Of the five patients with diazoxide-unresponsive HH, three had homozygous ABCC8 mutation, one had heterozygous ABCC8 mutation inherited from an unaffected father and one had homozygous KCNJ11 mutation. 52% of children in our cohort were born to consanguineous parents. Patients with ABCC8/KCNJ11 mutations were noted to be significantly heavier than those with HADH mutation (p = 0.002). Our results revealed neurodevelopmental deficits in 30% and epilepsy in 52% of all patients. To the best of our knowledge, this is the first study of its kind in Iran. We found disease-causing mutations in 78% of HH patients. The predominance of HADH mutation might be due to a high incidence of consanguineous marriage in this population. Further research involving a larger cohort of HH patients is required in Iranian population.

The Genetic Causes of Nonsyndromic Congenital Retinal Detachment: A Genetic and Phenotypic Study of Pakistani Families.

PubMed

Keser, Vafa; Khan, Ayesha; Siddiqui, Sorath; Lopez, Irma; Ren, Huanan; Qamar, Raheel; Nadaf, Javad; Majewski, Jacek; Chen, Rui; Koenekoop, Robert K

2017-02-01

To evaluate consanguineous pedigrees from Pakistan with a clinical diagnosis of nonsyndromic congenital retinal nonattachment (NCRNA) and identify genes responsible for the disease as currently only one NCRNA gene is known (atonal basic helix-loop-helix transcription factor 7: ATOH7). We implemented a three-step genotyping platform: single nucleotide polymorphism genotyping to identify loss of heterozygosity regions in patients, Retinal Information Network panel screening for mutations in currently known retinal genes. Negative patients were then subjected to whole exome sequencing. We evaluated 21 consanguineous NCRNA pedigrees and identified the causal mutations in known retinal genes in 13 out of our 21 families. We found mutations in ATOH7 in three families. Surprisingly, we then found mutations in familial exudative vitreoretinopathy (FEVR) genes; low-density lipoprotein receptor-related protein 5 mutations (six families), tetraspanin 12 mutations (two families), and NDP mutations (two families). Thus, 62% of the patients were successfully genotyped in our study with seven novel and six previously reported mutations in known retinal genes. Although the clinical diagnosis of all children was NCRNA with severe congenital fibrotic retinal detachments, the molecular diagnosis determined that the disease process was in fact a very severe form of FEVR in 10 families. Because severe congenital retinal detachment has not been previously associated with all the FEVR genes, we have thus expanded the phenotypic spectrum of FEVR, a highly variable retinal detachment phenotype that has clinical overlap with NCRNA. We identified seven novel mutations. We also established for the first time genetic overlap between the Iranian and Pakistani populations. We identified eight NCRNA families that do not harbor mutations in any known retinal genes, suggesting novel causal genes in these families.

Identification of compound heterozygous patients with primary hyperoxaluria type 1: clinical evaluations and in silico investigations.

PubMed

Kanoun, Houda; Jarraya, Faiçal; Maalej, Bayen; Lahiani, Amina; Mahfoudh, Hichem; Makni, Fatma; Hachicha, Jamil; Fakhfakh, Faiza

2017-10-02

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive inherited disorder of glyoxylate metabolism in which excessive oxalates are formed by the liver and excreted by the kidneys. Calcium oxalate crystallizes in the urine, leading to urolithiasis, nephrocalcinosis, and consequent renal failure if treatment is not initiated promptly. Mutations in the AGXT gene which encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase are responsible of PH1. In the present work, we aimed to analyze AGXT gene and in silico investigations performed in four patients with PH1 among two non consanguineous families. Exhaustive gene sequencing was performed after PCR amplification of coding exons and introns boundaries. Bioinformatic tools were used to predict the impact of AGXT variants on gene expression as well as on the protein structure and function. Direct sequencing of all exons of AGXT gene revealed the emergence of multiple mutations in compound heterozygous state in the two studied families. Two patients were compound heterozygous for the c.731 T > C, c.32C > T, c.1020A > G and c.33_34insC and presented clinically with recurrent urinary tract infection, multiple urolithiasis and nephrocalcinosis under the age of 1 year and a persistent hyperoxaluria at the age of diagnosis. The two other patients presenting a less severe phenotypes were heterozygous for c.731 T > C and homozygous for the c.32C > T and c.1020A > G or compound heterozygous for c.26C > A and c.65A > G variants. In Summary, we provided relevance regarding the compound heterozygous mutations in non consanguineous PH1 families with variable severity.

Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies

PubMed Central

Beck, Bodo B; Baasner, Anne; Buescher, Anja; Habbig, Sandra; Reintjes, Nadine; Kemper, Markus J; Sikora, Przemyslaw; Mache, Christoph; Pohl, Martin; Stahl, Mirjam; Toenshoff, Burkhard; Pape, Lars; Fehrenbach, Henry; Jacob, Dorrit E; Grohe, Bernd; Wolf, Matthias T; Nürnberg, Gudrun; Yigit, Gökhan; Salido, Eduardo C; Hoppe, Bernd

2013-01-01

Identification of mutations in the HOGA1 gene as the cause of autosomal recessive primary hyperoxaluria (PH) type III has revitalized research in the field of PH and related stone disease. In contrast to the well-characterized entities of PH type I and type II, the pathophysiology and prevalence of type III is largely unknown. In this study, we analyzed a large cohort of subjects previously tested negative for type I/II by complete HOGA1 sequencing. Seven distinct mutations, among them four novel, were found in 15 patients. In patients of non-consanguineous European descent the previously reported c.700+5G>T splice-site mutation was predominant and represents a potential founder mutation, while in consanguineous families private homozygous mutations were identified throughout the gene. Furthermore, we identified a family where a homozygous mutation in HOGA1 (p.P190L) segregated in two siblings with an additional AGXT mutation (p.D201E). The two girls exhibiting triallelic inheritance presented a more severe phenotype than their only mildly affected p.P190L homozygous father. In silico analysis of five mutations reveals that HOGA1 deficiency is causing type III, yet reduced HOGA1 expression or aberrant subcellular protein targeting is unlikely to be the responsible pathomechanism. Our results strongly suggest HOGA1 as a major cause of PH, indicate a greater genetic heterogeneity of hyperoxaluria, and point to a favorable outcome of type III in the context of PH despite incomplete or absent biochemical remission. Multiallelic inheritance could have implications for genetic testing strategies and might represent an unrecognized mechanism for phenotype variability in PH. PMID:22781098

Novel findings in patients with primary hyperoxaluria type III and implications for advanced molecular testing strategies.

PubMed

Beck, Bodo B; Baasner, Anne; Buescher, Anja; Habbig, Sandra; Reintjes, Nadine; Kemper, Markus J; Sikora, Przemyslaw; Mache, Christoph; Pohl, Martin; Stahl, Mirjam; Toenshoff, Burkhard; Pape, Lars; Fehrenbach, Henry; Jacob, Dorrit E; Grohe, Bernd; Wolf, Matthias T; Nürnberg, Gudrun; Yigit, Gökhan; Salido, Eduardo C; Hoppe, Bernd

2013-02-01

Identification of mutations in the HOGA1 gene as the cause of autosomal recessive primary hyperoxaluria (PH) type III has revitalized research in the field of PH and related stone disease. In contrast to the well-characterized entities of PH type I and type II, the pathophysiology and prevalence of type III is largely unknown. In this study, we analyzed a large cohort of subjects previously tested negative for type I/II by complete HOGA1 sequencing. Seven distinct mutations, among them four novel, were found in 15 patients. In patients of non-consanguineous European descent the previously reported c.700+5G>T splice-site mutation was predominant and represents a potential founder mutation, while in consanguineous families private homozygous mutations were identified throughout the gene. Furthermore, we identified a family where a homozygous mutation in HOGA1 (p.P190L) segregated in two siblings with an additional AGXT mutation (p.D201E). The two girls exhibiting triallelic inheritance presented a more severe phenotype than their only mildly affected p.P190L homozygous father. In silico analysis of five mutations reveals that HOGA1 deficiency is causing type III, yet reduced HOGA1 expression or aberrant subcellular protein targeting is unlikely to be the responsible pathomechanism. Our results strongly suggest HOGA1 as a major cause of PH, indicate a greater genetic heterogeneity of hyperoxaluria, and point to a favorable outcome of type III in the context of PH despite incomplete or absent biochemical remission. Multiallelic inheritance could have implications for genetic testing strategies and might represent an unrecognized mechanism for phenotype variability in PH.

Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel.

PubMed

Aharoni, Sharon; Barwick, Katy E S; Straussberg, Rachel; Harlalka, Gaurav V; Nevo, Yoram; Chioza, Barry A; McEntagart, Meriel M; Mimouni-Bloch, Aviva; Weedon, Michael; Crosby, Andrew H

2016-11-16

CMT-2 is a clinically and genetically heterogeneous group of peripheral axonal neuropathies characterized by slowly progressive weakness and atrophy of distal limb muscles resulting from length-dependent motor and sensory neurodegeneration. Classical giant axonal neuropathy (GAN) is an autosomal recessively inherited progressive neurodegenerative disorder of the peripheral and central nervous systems, typically diagnosed in early childhood and resulting in death by the end of the third decade. Distinctive phenotypic features are the presence of "kinky" hair and long eyelashes. The genetic basis of the disease has been well established, with over 40 associated mutations identified in the gene GAN, encoding the BTB-KELCH protein gigaxonin, involved in intermediate filament regulation. An Illumina Human CytoSNP-12 array followed by whole exome sequence analysis was used to identify the disease associated gene mutation in a large consanguineous family diagnosed with Charcot-Marie-Tooth disease type 2 (CMT-2) from which all but one affected member had straight hair. Here we report the identification of a novel GAN missense mutation underlying the CMT-2 phenotype observed in this family. Although milder forms of GAN, with and without the presence of kinky hair have been reported previously, a phenotype distinct from that was investigated in this study. All family members lacked common features of GAN, including ataxia, nystagmus, intellectual disability, seizures, and central nervous system involvement. Our findings broaden the spectrum of phenotypes associated with GAN mutations and emphasize a need to proceed with caution when providing families with diagnostic or prognostic information based on either clinical or genetic findings alone.

Peeling skin diseases: 21 cases from Turkey and a review of the literature.

PubMed

Köse, O; Safali, M; Koç, E; Arca, E; Açikgöz, G; Özmen, I; Yeniay, Y

2012-07-01

Peeling skin diseases (PSD) refer to a group of rare autosomal recessive dermatosis which are characterized by spontaneous, continual peeling of the skin. Three different clinical pictures can be distinguished: Inflammatory PSD also referred to as peeling skin syndrome (PSS) type B, non-inflammatory PSD also referred to as PSS type A, and localized forms i.e. acral type PSS. To characterize the clinical and histopathological features of PSD in Turkey. We retrospectively reviewed the medical records and clinical photographs of patients who were given diagnosis of PSD and conducted histopathological evaluation of skin biopsies to identify the site of cleavage. Also we evaluated the cases including age, gender, age onset, clinical and histological findings, family history, associated disorders and PSD type. Twenty-one patients with PSD were seen at Gulhane School of Medicine in Ankara between the years 1994 and 2010 in this retrospective study. All patients were men. Their ages were between 20 and 26 years (22.44±2.30, Mean age±SD). Of the patients, eight cases (40%) were type A, eight cases (40%) were type B, and five cases (20%) were acral type PSS. Eleven cases (52%) had parental consanguinity. Keratoderma, cheilitis, keratosis pilaris, melanonichia, clubbing, hyperhidrosis, onychodystrophy were observed in eight cases as an accompanying disorder. In this case series, PSD occurred rarely and also showed generally mild course of disease in Turkey and most likely related to consanguineous of marriages. Future investigations on PSD will contribute to our progressing alternative targets for pathogenesis-based therapy. © 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness

PubMed Central

Hu, Hao; Matter, Michelle L; Issa-Jahns, Lina; Jijiwa, Mayumi; Kraemer, Nadine; Musante, Luciana; de la Vega, Michelle; Ninnemann, Olaf; Schindler, Detlev; Damatova, Natalia; Eirich, Katharina; Sifringer, Marco; Schrötter, Sandra; Eickholt, Britta J; van den Heuvel, Lambert; Casamina, Chanel; Stoltenburg-Didinger, Gisela; Ropers, Hans-Hilger; Wienker, Thomas F; Hübner, Christoph; Kaindl, Angela M

2014-01-01

Objective To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). Methods We characterized a consanguineous family of Yazidian-Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole-exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild-type and mutant mice and in patient and control fibroblasts. Results In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease-associated peptidyl-tRNA hydrolase 2 (PTRH2) gene. PTRH2 encodes a primarily mitochondrial protein involved in integrin-mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts. Interpretation We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease. PMID:25574476

The Genetic Causes of Nonsyndromic Congenital Retinal Detachment: A Genetic and Phenotypic Study of Pakistani Families

PubMed Central

Keser, Vafa; Khan, Ayesha; Siddiqui, Sorath; Lopez, Irma; Ren, Huanan; Qamar, Raheel; Nadaf, Javad; Majewski, Jacek; Chen, Rui; Koenekoop, Robert K.

2017-01-01

Purpose To evaluate consanguineous pedigrees from Pakistan with a clinical diagnosis of nonsyndromic congenital retinal nonattachment (NCRNA) and identify genes responsible for the disease as currently only one NCRNA gene is known (atonal basic helix-loop-helix transcription factor 7: ATOH7). Methods We implemented a three-step genotyping platform: single nucleotide polymorphism genotyping to identify loss of heterozygosity regions in patients, Retinal Information Network panel screening for mutations in currently known retinal genes. Negative patients were then subjected to whole exome sequencing. Results We evaluated 21 consanguineous NCRNA pedigrees and identified the causal mutations in known retinal genes in 13 out of our 21 families. We found mutations in ATOH7 in three families. Surprisingly, we then found mutations in familial exudative vitreoretinopathy (FEVR) genes; low-density lipoprotein receptor-related protein 5 mutations (six families), tetraspanin 12 mutations (two families), and NDP mutations (two families). Thus, 62% of the patients were successfully genotyped in our study with seven novel and six previously reported mutations in known retinal genes. Conclusions Although the clinical diagnosis of all children was NCRNA with severe congenital fibrotic retinal detachments, the molecular diagnosis determined that the disease process was in fact a very severe form of FEVR in 10 families. Because severe congenital retinal detachment has not been previously associated with all the FEVR genes, we have thus expanded the phenotypic spectrum of FEVR, a highly variable retinal detachment phenotype that has clinical overlap with NCRNA. We identified seven novel mutations. We also established for the first time genetic overlap between the Iranian and Pakistani populations. We identified eight NCRNA families that do not harbor mutations in any known retinal genes, suggesting novel causal genes in these families. PMID:28192794

In silico analysis of SIGMAR1 variant (rs4879809) segregating in a consanguineous Pakistani family showing amyotrophic lateral sclerosis without frontotemporal lobar dementia.

PubMed

Ullah, Muhammad Ikram; Ahmad, Arsalan; Raza, Syed Irfan; Amar, Ali; Ali, Amjad; Bhatti, Attya; John, Peter; Mohyuddin, Aisha; Ahmad, Wasim; Hassan, Muhammad Jawad

2015-10-01

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. It has been found to be associated with frontotemporal lobar degeneration (FTLD). In the present study, we have described homozygosity mapping and gene sequencing in a consanguineous autosomal recessive Pakistani family showing non-juvenile ALS without signs of FTLD. Gene mapping was carried out in all recruited family members using microsatellite markers, and linkage was established with sigma non-opioid intracellular receptor 1 (SIGMAR1) gene at chromosome 9p13.2. Gene sequencing of SIGMAR1 revealed a novel 3'-UTR nucleotide variation c.672*31A>G (rs4879809) segregating with disease in this family. The C9ORF72 repeat region in intron 1, previously implicated in a related phenotype, was excluded through linkage, and further confirmation of exclusion was obtained by amplifying intron 1 of C9ORF72 with multiple primers in affected individuals and controls. In silico analysis was carried out to explore the possible role of 3'-UTR variant of SIGMAR1 in ALS. The Regulatory RNA motif and Element Finder program revealed disturbance in miRNA (hsa-miR-1205) binding site due to this variation. ESEFinder analysis showed new SRSF1 and SRSF1-IgM-BRCA1 binding sites with significant scores due to this variation. Our results indicate that the 3'-UTR SIGMAR1 variant c.672*31A>G may have a role in the pathogenesis of ALS in this family.

Variable Expressivity of a Founder Mutation in the EIF2AK4 Gene in Hereditary Pulmonary Veno-occlusive Disease and Its Impact on Survival.

PubMed

Navas Tejedor, Paula; Palomino Doza, Julián; Tenorio Castaño, Jair Antonio; Enguita Valls, Ana Belén; Rodríguez Reguero, José Julián; Martínez Meñaca, Amaya; Hernández González, Ignacio; Bueno Zamora, Héctor; Lapunzina Badía, Pablo Daniel; Escribano Subías, Pilar

2018-02-01

Hereditary pulmonary veno-occlusive disease (PVOD) has been associated with biallelic mutations in EIF2AK4 with the recent discovery of a founder mutation in Iberian Romani patients with familial PVOD. The aims of this study were phenotypical characterization and survival analysis of Iberian Romani patients with familial PVOD carrying the founder p.Pro1115Leu mutation in EIF2AK4, according to their tolerance to pulmonary vasodilators (PVD). Familial genetic screening was conducted, as well as assessment of sociocultural determinants with a potential influence on disease course. Observational study of Romani patients with familial PVOD included in the Spanish Registry of Pulmonary Arterial Hypertension. Genetic screening of EIF2AK4 was performed in index cases and relatives between November 2011 and July 2016 and histological pulmonary examination was carried out in patients who received a lung transplant or died. The patients were divided into 2 groups depending on their tolerance to PVD, with comparison of baseline characteristics and survival free of death or lung transplant. Eighteen Romani patients were included: 9 index cases and 9 relatives. The biallelic founder mutation in EIF2AK4 was found in all affected cases and 2 unaffected relatives. Family screening showed 34.2% of healthy heterozygotes, high consanguinity, young age at childbirth, and frequent multiparity. Prognosis was bleak, with significant differences depending on tolerance to PVD. We describe 2 phenotypes of hereditary PVOD depending on tolerance to PVD, with prognostic impact and familial distribution. Consanguinity may have a negative impact on the transmission of PVOD, with familial genetic screening showing high effectiveness. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB.

PubMed

Tredano, Mohammed; Griese, Matthias; de Blic, Jacques; Lorant, Tifenn; Houdayer, Claude; Schumacher, Silja; Cartault, François; Capron, Frédérique; Boccon-Gibod, Liliane; Lacaze-Masmonteil, Thierry; Renolleau, Sylvain; Delaisi, Bertrand; Elion, Jacques; Couderc, Rémy; Bahuau, Michel

2003-06-15

We have analyzed surfactant protein B (SP-B) and its encoding gene (SFTPB, MIM 178640) in 40 unrelated pediatric patients with unexplained respiratory distress (URD). There was high consanguinity (eight kindreds) and an underlying autosomal recessive trait could be inferred in most cases, with overall high sex ratio (32/17) suggesting proband's gender to impact on penetrance. The clinical/biological presentations fitted into three major nosologic frameworks. I: SP-B deficiency (nine probands), complete or incomplete, with homozygous/compoundly heterozygous mutations identified (six probands), including one from the population isolate of Réunion Island (496delG). In addition, there was a consanguineous kindred in which incomplete deficiency was unambiguously unlinked to SFTPB. II: pulmonary alveolar proteinosis (PAP, 19 probands), with typical storage of PAS-positive material within the alveoli with foamy macrophages and variable interstitial reaction, which was diagnosed in most patients from Réunion Island. In contrast to previously published findings, mutation and/or segregation analyses excluded SFTPB as a disease locus, although slight metabolic derangement related to SP-B and/or mild SFTPB changes could somehow contribute to disease. III: URD without evidence for SP-B deficiency or PAP (12 probands), equally unlinked to SFTPB, although a single patient had a possibly causal, maternally-derived, heterozygous genetic change (G4521A). The population frequency of five known and four novel SNPs was studied, providing as many potential markers for pulmonary disease related to SFTPB. Overall, URD was found to be heterogeneous, both phenotypically and genetically, even in population isolates where a founder effect might have been expected. When disease loci are identified, patient genotyping will be crucial as a diagnostic aid, for devising proper treatment, and as a basis for genetic counseling. Copyright 2003 Wiley-Liss, Inc.

A novel COL4A3 mutation causes autosomal-recessive Alport syndrome in a large Turkish family.

PubMed

Uzak, Asli Subasioglu; Tokgoz, Bulent; Dundar, Munis; Tekin, Mustafa

2013-03-01

Alport syndrome (AS) is a genetically heterogeneous disorder that is characterized by hematuria, progressive renal failure typically resulting in end-stage renal disease, sensorineural hearing loss, and variable ocular abnormalities. Only 15% of cases with AS are autosomal recessive and are caused by mutations in the COL4A3 or COL4A4 genes, encoding type IV collagen. Clinical data in a large consanguineous family with four affected members were reviewed, and genomic DNA was extracted. For mapping, 15 microsatellite markers flanking COL4A3, COL4A4, and COL4A5 in 16 family members were typed. For mutation screening, all coding exons of COL4A3 were polymerase chain reaction- amplified and Sanger-sequenced from genomic DNA. The disease locus was mapped to chromosome 2q36.3, where COL4A3 and COL4A4 reside. Sanger sequencing revealed a novel mis-sense mutation (c.2T>C; p.M1T) in exon 1 of COL4A3. The identified nucleotide change was not found in 100 healthy ethnicity-matched controls via Sanger sequencing. We present a large consanguineous Turkish family with AS that was found to have a COL4A3 mutation as the cause of the disease. Although the relationship between the various genotypes and phenotypes in AS has not been fully elucidated, detailed clinical and molecular analyses are helpful for providing data to be used in genetic counseling. It is important to identify new mutations to clarify their clinical importance, to assess the prognosis of the disease, and to avoid renal biopsy for final diagnosis.

Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family.

PubMed

Rafiullah, Rafiullah; Aslamkhan, Muhammad; Paramasivam, Nagarajan; Thiel, Christian; Mustafa, Ghulam; Wiemann, Stefan; Schlesner, Matthias; Wade, Rebecca C; Rappold, Gudrun A; Berkel, Simone

2016-02-01

Intellectual disability (ID) is a neurodevelopmental disorder affecting 1%-3% of the population worldwide. It is characterised by high phenotypic and genetic heterogeneity and in most cases the underlying cause of the disorder is unknown. In our study we investigated a large consanguineous family from Baluchistan, Pakistan, comprising seven affected individuals with a severe form of autosomal recessive ID (ARID) and epilepsy, to elucidate a putative genetic cause. Whole exome sequencing (WES) of a trio, including a child with ID and epilepsy and its healthy parents that were part of this large family, revealed a homozygous missense variant p.R53Q in the lectin mannose-binding 2-like (LMAN2L) gene. This homozygous variant was co-segregating in the family with the phenotype of severe ID and infantile epilepsy; unaffected family members were heterozygous variant carriers. The variant was predicted to be pathogenic by five different in silico programmes and further three-dimensional structure modelling of the protein suggests that variant p.R53Q may impair protein-protein interaction. LMAN2L (OMIM: 609552) encodes for the lectin, mannose-binding 2-like protein which is a cargo receptor in the endoplasmic reticulum important for glycoprotein transport. Genome-wide association studies have identified an association of LMAN2L to different neuropsychiatric disorders. This is the first report linking LMAN2L to a phenotype of severe ARID and seizures, indicating that the deleterious homozygous p.R53Q variant very likely causes the disorder. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

Health issues in the Arab American community. Male infertility in Lebanon: a case-controlled study.

PubMed

Kobeissi, Loulou; Inhorn, Marcia C

2007-01-01

The impact of risk factors, such as consanguinity and familial clustering, reproductive infections, traumas, and diseases, lifestyle factors and occupational and war exposures on male infertility, was investigated in a case-controlled study conducted in Lebanon. One-hundred-twenty males and 100 controls of Lebanese, Syrian or Lebanese-Palestinian descents were selected from two in-vitro fertilization (IVF) clinics located in Beirut, Lebanon. All cases suffered from impaired sperm count and function, according to World Health Organization guidelines for semen analysis. Controls were the fertile husbands of infertile women. Data were collected using a semi-structured interview, laboratory blood testing and the results of the most recent semen analysis. Univariate, bivariate and multivariate logistic regression analyses were used for data analysis, along with checks for effect modification and control of confounders. Consanguinity and the familial clustering of male infertility cases, as well as reproductive illnesses and war exposures were independently significant risk factors for male infertility. The odds of having infertility problems in the immediate family were 2.6 times higher in cases than controls. The odds of reproductive illness were 2 times higher in cases than controls. The odds of war exposures were 1.57 times higher in cases than controls. Occupational exposures, such as smoking and caffeine intake, were not shown to be important risk factors. This case-controlled study highlights the importance of investigating the etiology of male infertility in Middle Eastern communities. It suggests the need to expand research on male reproductive health in the Middle East in order to improve the prevention and management of male infertility and other male reproductive health problems.

Germline PMS2 and somatic POLE exonuclease mutations cause hypermutability of the leading DNA strand in biallelic mismatch repair deficiency syndrome brain tumours.

PubMed

Andrianova, Maria A; Chetan, Ghati Kasturirangan; Sibin, Madathan Kandi; Mckee, Thomas; Merkler, Doron; Narasinga, Rao Kvl; Ribaux, Pascale; Blouin, Jean-Louis; Makrythanasis, Periklis; Seplyarskiy, Vladimir B; Antonarakis, Stylianos E; Nikolaev, Sergey I

2017-11-01

Biallelic mismatch repair deficiency (bMMRD) in tumours is frequently associated with somatic mutations in the exonuclease domains of DNA polymerases POLE or POLD1, and results in a characteristic mutational profile. In this article, we describe the genetic basis of ultramutated high-grade brain tumours in the context of bMMRD. We performed exome sequencing of two second-cousin patients from a large consanguineous family of Indian origin with early onset of high-grade glioblastoma and astrocytoma. We identified a germline homozygous nonsense variant, p.R802*, in the PMS2 gene. Additionally, by genome sequencing of these tumours, we found extremely high somatic mutation rates (237/Mb and 123/Mb), as well as somatic mutations in the proofreading domain of POLE polymerase (p.P436H and p.L424V), which replicates the leading DNA strand. Most interestingly, we found, in both cancers, that the vast majority of mutations were consistent with the signature of POLE exo - , i.e. an abundance of C>A and C>T mutations, particularly in special contexts, on the leading strand. We showed that the fraction of mutations under positive selection among mutations in tumour suppressor genes is more than two-fold lower in ultramutated tumours than in other glioblastomas. Genetic analyses enabled the diagnosis of the two consanguineous childhood brain tumours as being due to a combination of PMS2 germline and POLE somatic variants, and confirmed them as bMMRD/POLE exo - disorders. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chronic Diarrhea and Skin Hyperpigmentation: A New Association

PubMed Central

Al Qoaer, Khaled; Al Mehaidib, Ali; Shabib, Sohail; Banemai, Mohammed

2008-01-01

Background/Aims: The objective of this study was to describe patients with chronic diarrhea and abnormal skin hyperpigmentation with distinct distribution. Methods: This is a retrospective review of children who presented with diarrhea and skin hyperpigmentation. The clinical presentation, laboratory investigations as well as endoscopic and histological data were reviewed. Results: Seven patients with chronic diarrhea had abnormal skin hyperpigmentation with distinct distribution and presented in the first two months of life. Six patients had other features such as abnormal hair and facial dysmorphism. Mental retardation was reported in one patient. Consanguinity was positive in six patients, and there was family history of consanguinity in four patients, with two patients being siblings. No significant immunodeficiency was reported. Intestinal biopsies were obtained in six patients and showed active chronic inflammation in three patients, partial villous atrophy in two patients, and eosinophilic infiltrate with mild villous atrophy in one patient. Colonic biopsies showed mild focal colitis in three patients and mild colitis with eosinophilic infiltrate in one patient. Skin biopsies showed a greater number of melanophagies with fibrosis of papillary derma in two patients but skin biopsy was normal in one patient. The hair of two patients was analyzed by electron microscopy, which showed an abnormal pattern with decreased pigmentation and diameter; however, its chemical analysis was normal. Two other patients had trichorrhexis nodosa, but no abnormalities were seen in one patient. Chromosomal number was normal in three patients. One patient died because of sepsis, and only one patient was dependent on total parenteral nutrition. Conclusions: We believe that this association might represent a new syndrome with an autosomal recessive inheritance that warrants further studies. PMID:19568536

Limb Girdle Muscular Dystrophy Type 2E Due to a Novel Large Deletion in SGCB Gene.

PubMed

Ghafouri-Fard, Soudeh; Hashemi-Gorji, Feyzollah; Fardaei, Majid; Miryounesi, Mohammad

2017-01-01

Autosomal recessive limb-girdle muscular dystrophies (LGMD type 2) are a group of clinically and genetically heterogeneous diseases with the main characteristics of weakness and wasting of the pelvic and shoulder girdle muscles. Among them are sarcoglycanopathies caused by mutations in at least four genes named SGCA, SGCB, SGCG and SGCD. Here we report a consanguineous Iranian family with two children affected with LGMD type 2E. Mutation analysis revealed a novel homozygous exon 2 deletion of SGCB gene in the patients with the parents being heterozygous for this deletion. This result presents a novel underlying genetic mechanism for LGMD type 2E.

Clinical, biochemical and molecular investigations of three Taiwanese children with Laron syndrome.

PubMed

Yang, Chen; Chen, Julia Yi-Ru; Lai, Chien-Cherng; Lin, Hsiu-Chen; Yeh, Geng-Chang; Hsu, Hsun-Hui

2004-02-01

Three children of two Taiwanese families were diagnosed with Laron syndrome, two sisters and one boy. Both sets of parents were consanguineous. Clinically, all three presented with the typical craniofacies of Laron syndrome, consisting of prominent forehead and hypoplastic nasal bridge, high-pitched voice, short stature, and central obesity. Biochemically, their levels of serum IGF-I were less than 5 microg/ml before and after an IGF-I generation test, and levels of IGFBP-3 were reduced in all three patients. Sequence analysis of the growth hormone receptor gene revealed that all three carried a homozygous missense D152G mutation in exon 6.

Asperger syndrome in a boy with a balanced de novo translocation: t(17;19)(p13.3;p11)

DOE Office of Scientific and Technical Information (OSTI.GOV)

NONE

The cause of Asperger syndrome is unknown. It is classified as a form of childhood autism. Familial aggregation in infantile autism has been reported. Asperger syndrome has also been considered as being genetically transmitted and certain of its characteristics have tended to occur in other relatives, especially in the fathers. We describe a 10-year-old boy with a clinical diagnosis of Asperger syndrome and a balanced de novo translocation (t(17;19)9p13.3;p11). His parents are not consanguineous and are healthy, as are his three brothers. 5 refs.

The architecture of the porphyry-metal system as a prospecting stratagem in the Southern Rocky Mountains

USGS Publications Warehouse

Neuerburg, George J.

1978-01-01

A model of the porphyry-metal system characteristic of the consanguineous Cretaceous and Tertiary igneous rocks and associated ores of the southern Rocky Mountains is constructed from the bits and pieces exposed in the Colorado mineral belt and the San Juan volcanic field. Hydrothermally altered rocks in a part of the areas of mineralized rock associated with the Platoro caldera are matched against the model, to locate and to characterize latent mineral deposits for optimal prospecting and exploration. The latent deposits are two stockwork molybdenite deposits (porphyry-molybdenum) and one or two copper-gold-silver chimney deposits.

[Regulatory problems regarding bone marrow transplantation from non-consanguinous donors].

PubMed

Moratti, A

1999-01-01

The paper reports the normative rules and the Italian Ministry of Health administrative instructions concerning the bone marrow unrelated donor (MUD) search in the Italian Bone Marrow Donor Registry (IBMDR) and in international registries from the preliminary activation to a MUD bone marrow transplant (BMT), when a volunteer donor, perfectly compatible with a recipient lacking a HLA identical sibling, is found. The article describes all the expenses pertinent to the different stages of search and the documents necessary to obtain the reimbursement of these expenses. A very recent Ministry Decree establishing that all the search costs will be charged to the competent local sanitary authority is added.

Familial chondrocalcinosis in the Chiloe Islands, Chile.

PubMed Central

Reginato, A J; Hollander, J L; Martinez, V; Valenzuela, F; Schiapachasse, V; Covarrubias, E; Jacobelli, S; Arinoviche, R; Silcox, D; Ruiz, F

1975-01-01

Studies about chondrocalcinosis in the Chiloe Islands (Chile) showed the high frequency of the disease there and how most of it is aggregated in a few highly involved families. Pedigrees and the high degree of consanguinity among parents of index cases pointed to a recessive inheritance. The presence of common Caucasian anthropological features of genetic value in the patients and the lack of Indian mixture in three of the involved families, documented back to 1600, suggest a Caucasian origin of the mutation. Biochemical studies of the patients' synovial fluid showed a significant rise in pyrophosphate concentration. Calcium, phosphorus, and alkaline phosphatase concentrations were not different from a control group. PMID:168817

Congenital hepatic fibrosis in a child with Prader-Willi syndrome: a novel association.

PubMed

Al Sarkhy, Ahmed; Hassan, Saeed; Alasmi, Mona; Assiri, Asaad Muhammed; Alkuraya, Fowzan S

2014-01-01

Prader-Willi syndrome (PWS) is a rare genetic disorder caused by deletion or unexpression of the chromosome 15 (q 11-13). Symptomatologies include hypotonia, hyperphagia, cognitive impairment, and characteristic dysmorphic profile. Here, we report a 4-year-old boy with PWS who presented with complications of congenital hepatic fibrosis. The uniparental heterodisomy makes it unlikely that the hepatic fibrosis was caused by unmasking of a recessive mutation on the maternal chromosome 15 although we cannot exclude the possibility of a recessively inherited mutation elsewhere given the parental consanguinity. This is the first report of congenital hepatic fibrosis in PWS.

Microcephaly-capillary malformation syndrome: Brothers with a homozygous STAMBP mutation, uncovered by exome sequencing.

PubMed

Naseer, Muhammad Imran; Sogaty, Sameera; Rasool, Mahmood; Chaudhary, Adeel G; Abutalib, Yousif Ahmed; Walker, Susan; Marshall, Christian R; Merico, Daniele; Carter, Melissa T; Scherer, Stephen W; Al-Qahtani, Mohammad H; Zarrei, Mehdi

2016-11-01

We describe two brothers from a consanguineous family of Egyptian ancestry, presenting with microcephaly, apparent global developmental delay, seizures, spasticity, congenital blindness, and multiple cutaneous capillary malformations. Through exome sequencing, we uncovered a homozygous missense variant in STAMBP (p.K303R) in the two siblings, inherited from heterozygous carrier parents. Mutations in STAMBP are known to cause microcephaly-capillary malformation syndrome (MIC-CAP) and the phenotype in this family is consistent with this diagnosis. We compared the findings in the present brothers with those of earlier reported patients. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

From new genetics to everyday knowledge: Ideas about how genetic diseases are transmitted in two large Brazilian families

NASA Astrophysics Data System (ADS)

Santos, Silvana; Bizzo, Nelio

2005-07-01

This study focuses on everyday or lay understandings of inheritance. In the northeastern Brazil, 100 individuals were interviewed in order to describe how they explain the origin of genetic disorders affecting their relatives for several generations. There were involved 60 individuals from a large consanguineous family with many members affected with a neurodegenerative disorder, SPOAN syndrome (spastic paraplegia, optic atrophy and neuropathy), and 40 individuals of another family living with neurofibromatosis type 1 (NF1). The results indicate that families here studied have built narratives to explain the origin of genetic diseases, saying that an ancestor infected with syphilis gave rise to disorders and birthmarks transmitted to descendents.

Neonatal Death Dwarfism in a Girl with Distinctive Bone Dysplasia Compatible with Grebe Chondrodysplasia: Analysis by CT Scan-based Phenotype.

PubMed

Al Kaissi, Ali; Chehida, Farid Ben; Ganger, Rudolf; Grill, Franz

2014-01-01

We report on a female fetus noted to have severe malformative type of skeletal dysplasia on ultrasonography done at 35 weeks gestation. The girl died shortly after birth. Clinical examination showed a fetus with severe dwarfism, extensive long and short bones, and bone deficiencies associated with multiple dislocations. Computed tomography (CT) scan-based phenotype showed a complex constellation of malformations consistent with the diagnosis of Grebe syndrome. Parents being first cousins (consanguineous marriage) strongly suggests autosomal recessive pattern of inheritance. To our knowledge, this is the first report of neonatal death dwarfism of Grebe syndrome analyzed by CT scan-based phenotype.

Genetics of recessive cognitive disorders.

PubMed

Musante, Luciana; Ropers, H Hilger

2014-01-01

Most severe forms of intellectual disability (ID) have specific genetic causes. Numerous X chromosome gene defects and disease-causing copy-number variants have been linked to ID and related disorders, and recent studies have revealed that sporadic cases are often due to dominant de novo mutations with low recurrence risk. For autosomal recessive ID (ARID) the recurrence risk is high and, in populations with frequent parental consanguinity, ARID is the most common form of ID. Even so, its elucidation has lagged behind. Here we review recent progress in this field, show that ARID is not rare even in outbred Western populations, and discuss the prospects for improving its diagnosis and prevention. Copyright © 2013 Elsevier Ltd. All rights reserved.

Newly recognized recessive syndrome characterized by dysmorphic features, hypogonadotropic hypogonadism, severe microcephaly, and sensorineural hearing loss maps to 3p21.3.

PubMed

Jenkinson, Emma M; Kingston, Helen; Urquhart, Jill; Khan, Naz; Melville, Athalie; Swinton, Martin; Crow, Yanick J; Davis, Julian R E; Trump, Dorothy; Newman, William G

2011-12-01

We present a newly recognized, likely autosomal recessive, pleiotropic disorder seen in four individuals (three siblings and their nephew) from a consanguineous family of Pakistani origin. The condition is characterized by hypogonadotropic hypogonadism, severe microcephaly, sensorineural deafness, moderate learning disability, and distinctive facial dysmorphic features. Autozygosity mapping using SNP array genotyping defined a single, large autozygous region of 13.1 Mb on chromosome 3p21 common to the affected individuals. The critical region contains 227 genes and initial sequence analysis of a functional candidate gene has not identified causative mutations. Copyright © 2011 Wiley Periodicals, Inc.

The phenotype of human STK4 deficiency

PubMed Central

Abdollahpour, Hengameh; Appaswamy, Giridharan; Kotlarz, Daniel; Diestelhorst, Jana; Beier, Rita; Schäffer, Alejandro A.; Gertz, E. Michael; Schambach, Axel; Kreipe, Hans H.; Pfeifer, Dietmar; Engelhardt, Karin R.; Rezaei, Nima; Grimbacher, Bodo; Lohrmann, Sabine; Sherkat, Roya

2012-01-01

We describe a novel clinical phenotype associating T- and B-cell lymphopenia, intermittent neutropenia, and atrial septal defects in 3 members of a consanguineous kindred. Their clinical histories included recurrent bacterial infections, viral infections, mucocutaneous candidiasis, cutaneous warts, and skin abscesses. Homozygosity mapping and candidate gene sequencing revealed a homozygous premature termination mutation in the gene STK4 (serine threonine kinase 4, formerly having the symbol MST1). STK4 is the human ortholog of Drosophila Hippo, the central constituent of a highly conserved pathway controlling cell growth and apoptosis. STK4-deficient lymphocytes and neutrophils exhibit enhanced loss of mitochondrial membrane potential and increased susceptibility to apoptosis. STK4 deficiency is a novel human primary immunodeficiency syndrome. PMID:22294732

Homozygosity Mapping and Candidate Prioritization Identify Mutations, Missed by Whole-Exome Sequencing, in SMOC2, Causing Major Dental Developmental Defects

PubMed Central

Bloch-Zupan, Agnès; Jamet, Xavier; Etard, Christelle; Laugel, Virginie; Muller, Jean; Geoffroy, Véronique; Strauss, Jean-Pierre; Pelletier, Valérie; Marion, Vincent; Poch, Olivier; Strahle, Uwe; Stoetzel, Corinne; Dollfus, Hélène

2011-01-01

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on a severe developmental dental defect that results in a dentin dysplasia phenotype with major microdontia, oligodontia, and shape abnormalities in a highly consanguineous family. Homozygosity mapping revealed a unique zone on 6q27-ter. The two affected children were found to carry a homozygous mutation in SMOC2. Knockdown of smoc2 in zebrafish showed pharyngeal teeth that had abnormalities reminiscent of the human phenotype. Moreover, smoc2 depletion in zebrafish affected the expression of three major odontogenesis genes: dlx2, bmp2, and pitx2. PMID:22152679

[Friedreich's disease in the department of neurology in Dakar].

PubMed

Ndiaye, M; Ndao, A K; Sene-Diouf, F; Diop, A G; Diagne, M; Thiam, A; Ndiaye, M M; Ndiaye, I P

2000-01-01

A retrospective study of Friedreich's ataxia was conducted from january 1960 to december 1997. Eighten cases had been collected. Friedreich's ataxia was the second disorder after Pierre Marie's ataxia among inherited ataxia. Parental consanguinity has been found in 27.77% of cases. The sex-ratio was 2.6 for males. 66,67% of Friedreich's ataxia cases began after 25 years. Clinical signs were: cerebellar ataxia, sensitive disorders in 70%, pyramidal syndrom and cardiomyopathy in 22.22%, bones dysmorphy in 50% of cases. Electromyography indicated severe axonopathy of members with decreased somesthesic potentials in six cases. Glycaemia was normal in all cases. Clinical future presented wide variation between one and fourth years old.

Peeling skin syndrome associated with novel variant in FLG2 gene.

PubMed

Alfares, Ahmed; Al-Khenaizan, Sultan; Al Mutairi, Fuad

2017-12-01

Peeling skin syndrome is a rare genodermatosis characterized by variably pruritic superficial generalized peeling of the skin with several genes involved until now little is known about the association between FLG2 and peeling skin syndrome. We describe multiple family members from a consanguineous Saudi family with peeling skin syndrome. Next Generation Sequencing identifies a cosegregating novel variant in FLG2 c.632C>G (p.Ser211*) as a likely etiology in this family. Here, we reported on the clinical manifestation of homozygous loss of function variant in FLG2 as a disease-causing gene for peeling skin syndrome and expand the dermatology findings. © 2017 Wiley Periodicals, Inc.

Acral peeling skin syndrome resulting from a homozygous nonsense mutation in the CSTA gene encoding cystatin A.

PubMed

Krunic, Aleksandar L; Stone, Kristina L; Simpson, Michael A; McGrath, John A

2013-01-01

Acral peeling skin syndrome (APSS) is a clinically and genetically heterogeneous disorder. We used whole-exome sequencing to identify the molecular basis of APSS in a consanguineous Jordanian-American pedigree. We identified a homozygous nonsense mutation (p.Lys22X) in the CSTA gene, encoding cystatin A, that was confirmed using Sanger sequencing. Cystatin A is a protease inhibitor found in the cornified cell envelope, and loss-of-function mutations have previously been reported in two cases of exfoliative ichthyosis. Our study expands the molecular pathology of APSS and demonstrates the value of next-generation sequencing in the genetic characterization of inherited skin diseases. © 2013 Wiley Periodicals, Inc.

Patients with autosomal nephrogenic diabetes insipidus homozygous for mutations in the aquaporin 2 water-channel gene.

PubMed Central

van Lieburg, A. F.; Verdijk, M. A.; Knoers, V. V.; van Essen, A. J.; Proesmans, W.; Mallmann, R.; Monnens, L. A.; van Oost, B. A.; van Os, C. H.; Deen, P. M.

1994-01-01

Mutations in the X-chromosomal V2 receptor gene are known to cause nephrogenic diabetes insipidus (NDI). Besides the X-linked form, an autosomal mode of inheritance has been described. Recently, mutations in the autosomal gene coding for water-channel aquaporin 2 (AQP2) of the renal collecting duct were reported in an NDI patient. In the present study, missense mutations and a single nucleotide deletion in the aquaporin 2 gene of three NDI patients from consanguineous matings are described. Expression studies in Xenopus oocytes showed that the missense AQP2 proteins are nonfunctional. These results prove that mutations in the AQP2 gene cause autosomal recessive NDI. PMID:7524315

A previously undescribed autosomal recessive multiple congenital anomalies/mental retardation (MCA/MR) syndrome with fronto-nasal dysostosis, cleft lip/palate, limb hypoplasia, and postaxial poly-syndactyly: acro-fronto-facio-nasal dysostosis syndrome.

PubMed

Richieri-Costa, A; Colletto, G M; Gollop, T R; Masiero, D

1985-04-01

We describe two sibs born to a consanguineous couple. Among other clinical findings both have mental retardation, short stature, facial and skeletal abnormalities characterized by hypertelorism, broad notched nasal tip, cleft lip/palate, campto-brachy-poly-syndactyly, fibular hypoplasia, and marked anomalies of foot structures. Facial signs of the reported patients resemble those present in the fronto-nasal "dysplasia" syndrome; however, the whole clinical picture in the present patients suggests a true MCA/MR syndrome, most likely inherited as an autosomal recessive trait. Clinical and genetic aspects of the present family are discussed.

Neurologic syndrome associated with homozygous mutation at MAG sialic acid binding site.

PubMed

Roda, Ricardo H; FitzGibbon, Edmond J; Boucekkine, Houda; Schindler, Alice B; Blackstone, Craig

2016-08-01

The MAG gene encodes myelin-associated glycoprotein (MAG), an abundant protein involved in axon-glial interactions and myelination during nerve regeneration. Several members of a consanguineous family with a clinical syndrome reminiscent of Pelizaeus-Merzbacher disease and demyelinating leukodystrophy on brain MRI were recently found to harbor a homozygous missense p.Ser133Arg MAG mutation. Here, we report two brothers from a nonconsanguineous family afflicted with progressive cognitive impairment, neuropathy, ataxia, nystagmus, and gait disorder. Exome sequencing revealed the homozygous missense mutation p.Arg118His in MAG. This Arg118 residue in immunoglobulin domain 1 is critical for sialic acid binding, providing a compelling mechanistic basis for disease pathogenesis.

Cerebro-oculo-facio-skeletal syndrome.

PubMed

Rafique, Muhammad; Zia, Shumaila

2012-09-01

Cerebro-oculo-facio-skeletal syndrome (COFSS) is a recessively inherited neurodegenerative disorder. We describe an 8 months old Saudi girl, a product of consanguineous parents with unremarkable pre-natal and postnatal history and birth weight 2 kg. She was having microcephaly, micrognathia, micro-ophthalmia, large low set ears, upper lip overhanging the lower lip and congenital contractures. Growth and development were severely retarded. MRI and MRS (magnetic resonance spectrometry) of brain displayed severe brain atrophy and hypo/demyelination of white matter. The relationship between COFSS and differential diagnoses, Cockayne syndrome (CS), Pena-Shokier phenotype (PSP) and Neu-Lexova syndrome (NLS) are discussed. Pre-natal diagnosis followed by appropriate management in time may be helpful to reduce its incidence in the community.

Under-Five Child Mortality and Morbidity Associated with Consanguineous Child Marriage in Pakistan: Retrospective Analysis using Pakistan Demographic and Health Surveys, 1990-91, 2006-07, 2012-13.

PubMed

Mustafa, Mudasir; Zakar, Rubeena; Zakar, Muhammad Zakria; Chaudhry, Ashraf; Nasrullah, Muazzam

2017-05-01

Objective To assess the combined effect of consanguineous and child marriages (CCM) on children health, which has not previously been explored, either globally or locally. Methods We analyzed secondary data from a series of cross-sectional, nationally representative Pakistan Demographic and Health Surveys 1990-91, 2006-07, and 2012-13. A total of 5406 mothers with 10,164 children were included in the analysis. Child health was assessed by variables such as history of diarrhea, acute respiratory infection (ARI), ARI with fever, Under-5 child mortality (U5CM) and small-size birth (SSB). Associations among variables were assessed by calculating unadjusted Odd Ratios (OR) and adjusted OR (AOR). Results A majority (n = 6,247, 61%) of the births were to mothers having CCM as compare to non-CCM (3917, 39%). There was a significant association between CCM and U5CM during 1990-91 (AOR 1.24, 95% CI 1.03-1.49) and 2006-07 (AOR 1.25, 95% CI 1.05-1.51), and infant mortality in 1990-91 (AOR 1.39, 95% CI 1.05-1.85) and 2006-07 (AOR 1.61, 95% CI 1.17-2.21). A significant association was also found between CCM and SSB infants in the period 2006-07 (AOR 1.19, 95% CI 1.01-1.42) and 2012-13 (AOR 1.22, 95% CI 1.02-1.46). We noted no effect of CCM on diarrhea, ARI, and ARI with fever. Conclusion CCM increases the likelihood of U5CM, infant mortality and SSB infants. Further quantitative and qualitative research should be conducted to assess the effects of environmental, congenital and genetic factors on the health of children born to mothers in CCM.

Identification of two new mutations in the GPR98 and the PDE6B genes segregating in a Tunisian family.

PubMed

Hmani-Aifa, Mounira; Benzina, Zeineb; Zulfiqar, Fareeha; Dhouib, Houria; Shahzadi, Amber; Ghorbel, Abdelmonem; Rebaï, Ahmed; Söderkvist, Peter; Riazuddin, Sheikh; Kimberling, William J; Ayadi, Hammadi

2009-04-01

Autosomal recessive retinitis pigmentosa (ARRP) is a genetically heterogeneous disorder. ARRP could be associated with extraocular manifestations that define specific syndromes such as Usher syndrome (USH) characterized by retinal degeneration and congenital hearing loss (HL). The USH type II (USH2) associates RP and mild-to-moderate HL with preserved vestibular function. At least three genes USH2A, the very large G-protein-coupled receptor, GPR98, and DFNB31 are responsible for USH2 syndrome. Here, we report on the segregation of non-syndromic ARRP and USH2 syndrome in a consanguineous Tunisian family, which was previously used to define USH2B locus. With regard to the co-occurrence of these two different pathologies, clinical and genetic reanalysis of the extended family showed (i) phenotypic heterogeneity within USH2 patients and (ii) excluded linkage to USH2B locus. Indeed, linkage analysis disclosed the cosegregation of the USH2 phenotype with the USH2C locus markers, D5S428 and D5S618, whereas the ARRP perfectly segregates with PDE6B flanking markers D4S3360 and D4S2930. Molecular analysis revealed two new missense mutations, p.Y6044C and p.W807R, occurring in GPR98 and PDE6B genes, respectively. In conclusion, our results show that the USH2B locus at chromosome 3p23-24.2 does not exist, and we therefore withdraw this locus designation. The combination of molecular findings for GPR98 and PDE6B genes enable us to explain the phenotypic heterogeneity and particularly the severe ocular affection first observed in one USH2 patient. This report presents an illustration of how consanguinity could increase familial clustering of multiple hereditary diseases within the same family.

Identification of candidate regions for a novel Usher syndrome type II locus.

PubMed

Ben Rebeh, Imen; Benzina, Zeineb; Dhouib, Houria; Hadjamor, Imen; Amyere, Mustapha; Ayadi, Leila; Turki, Khalil; Hammami, Bouthaina; Kmiha, Noureddine; Kammoun, Hassen; Hakim, Bochra; Charfedine, Ilhem; Vikkula, Miikka; Ghorbel, Abdelmonem; Ayadi, Hammadi; Masmoudi, Saber

2008-09-19

Chronic diseases affecting the inner ear and the retina cause severe impairments to our communication systems. In more than half of the cases, Usher syndrome (USH) is the origin of these double defects. Patients with USH type II (USH2) have retinitis pigmentosa (RP) that develops during puberty, moderate to severe hearing impairment with downsloping pure-tone audiogram, and normal vestibular function. Four loci and three genes are known for USH2. In this study, we proposed to localize the gene responsible for USH2 in a consanguineous family of Tunisian origin. Affected members underwent detailed ocular and audiologic characterization. One Tunisian family with USH2 and 45 healthy controls unrelated to the family were recruited. Two affected and six unaffected family members attended our study. DNA samples of eight family members were genotyped with polymorphic markers. Two-point and multipoint LOD scores were calculated using Genehunter software v2.1. Sequencing was used to investigate candidate genes. Haplotype analysis showed no significant linkage to any known USH gene or locus. A genome-wide screen, using microsatellite markers, was performed, allowing the identification of three homozygous regions in chromosomes 2, 4, and 15. We further confirmed and refined these three regions using microsatellite and single-nucleotide polymorphisms. With recessive mode of inheritance, the highest multipoint LOD score of 1.765 was identified for the candidate regions on chromosomes 4 and 15. The chromosome 15 locus is large (55 Mb), underscoring the limited number of meioses in the consanguineous pedigree. Moreover, the linked, homozygous chromosome 15q alleles, unlike those of the chromosome 2 and 4 loci, are infrequent in the local population. Thus, the data strongly suggest that the novel locus for USH2 is likely to reside on 15q. Our data provide a basis for the localization and the identification of a novel gene implicated in USH2, most likely localized on 15q.

Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases

PubMed Central

Ullah, Inayat; Kabir, Firoz; Iqbal, Muhammad; Gottsch, Clare Brooks S.; Naeem, Muhammad Asif; Assir, Muhammad Zaman; Khan, Shaheen N.; Akram, Javed; Riazuddin, Sheikh; Ayyagari, Radha; Hejtmancik, J. Fielding

2016-01-01

Purpose To identify pathogenic mutations responsible for autosomal recessive retinitis pigmentosa (arRP) in consanguineous familial cases. Methods Seven large familial cases with multiple individuals diagnosed with retinitis pigmentosa were included in the study. Affected individuals in these families underwent ophthalmic examinations to document the symptoms and confirm the initial diagnosis. Blood samples were collected from all participating members, and genomic DNA was extracted. An exclusion analysis with microsatellite markers spanning the TULP1 locus on chromosome 6p was performed, and two-point logarithm of odds (LOD) scores were calculated. All coding exons along with the exon–intron boundaries of TULP1 were sequenced bidirectionally. We constructed a single nucleotide polymorphism (SNP) haplotype for the four familial cases harboring the K489R allele and estimated the likelihood of a founder effect. Results The ophthalmic examinations of the affected individuals in these familial cases were suggestive of RP. Exclusion analyses confirmed linkage to chromosome 6p harboring TULP1 with positive two-point LOD scores. Subsequent Sanger sequencing identified the single base pair substitution in exon14, c.1466A>G (p.K489R), in four families. Additionally, we identified a two-base deletion in exon 4, c.286_287delGA (p.E96Gfs77*); a homozygous splice site variant in intron 14, c.1495+4A>C; and a novel missense variation in exon 15, c.1561C>T (p.P521S). All mutations segregated with the disease phenotype in the respective families and were absent in ethnically matched control chromosomes. Haplotype analysis suggested (p<10−6) that affected individuals inherited the causal mutation from a common ancestor. Conclusions Pathogenic mutations in TULP1 are responsible for the RP phenotype in seven familial cases with a common ancestral mutation responsible for the disease phenotype in four of the seven families. PMID:27440997

The Usage of Association Rule Mining to Identify Influencing Factors on Deafness After Birth.

PubMed

Shahraki, Azimeh Danesh; Safdari, Reza; Gahfarokhi, Hamid Habibi; Tahmasebian, Shahram

2015-12-01

Providing complete and high quality health care services has very important role to enable people to understand the factors related to personal and social health and to make decision regarding choice of suitable healthy behaviors in order to achieve healthy life. For this reason, demographic and clinical data of person are collecting, this huge volume of data can be known as a valuable resource for analyzing, exploring and discovering valuable information and communication. This study using forum rules techniques in the data mining has tried to identify the affecting factors on hearing loss after birth in Iran. The survey is kind of data oriented study. The population of the study is contained questionnaires in several provinces of the country. First, all data of questionnaire was implemented in the form of information table in Software SQL Server and followed by Data Entry using written software of C # .Net, then algorithm Association in SQL Server Data Tools software and Clementine software was implemented to determine the rules and hidden patterns in the gathered data. Two factors of number of deaf brothers and the degree of consanguinity of the parents have a significant impact on severity of deafness of individuals. Also, when the severity of hearing loss is greater than or equal to moderately severe hearing loss, people use hearing aids and Men are also less interested in the use of hearing aids. In fact, it can be said that in families with consanguineous marriage of parents that are from first degree (girl/boy cousins) and 2(nd) degree relatives (girl/boy cousins) and especially from first degree, the number of people with severe hearing loss or deafness are more and in the use of hearing aids, gender of the patient is more important than the severity of the hearing loss.

Identification of a novel homozygous mutation Arg459Pro in SYNJ1 gene of an Indian family with autosomal recessive juvenile Parkinsonism.

PubMed

Kirola, Laxmi; Behari, Madhuri; Shishir, Chandan; Thelma, B K

2016-10-01

A novel homozygous missense mutation (c.773G > A, p.Arg258Gln) in Synaptojanin 1 (SYNJ1, 21q22.2) has recently been reported in two Italian and one Iranian consanguineous families with autosomal recessive juvenile Parkinsonism (ARJP). Contribution of this synaptic gene related to Parkinsonism phenotypes in other populations still remains unidentified. An ARJP family with two affected siblings characterized by frequent tremor with bradykinesia and rigidity was recruited in this study. Both siblings showed intense dyskinesia and dystonia on administration of Syndopa. The family was analyzed for both mutations and exon dosage variations in PARKIN, PINK1 and DJ1. Further, whole exome sequencing was performed in two affected and one unaffected sibling in the family. We identified a novel homozygous mutation (c.1376C > G, p.Arg459Pro) in SYNJ1 segregating in this family. This p.Arg459Pro mutation was not observed in 285 additional Parkinson disease (PD) samples (32 familial, 81 early onset and 172 late onset) screened by PCR-Sanger-sequencing. It was also absent in dbSNP, 1000 Genomes, ExAC, NHLBI-ESP database and in >250 ethnically matched exomes available in our laboratory. The arginine residue is highly conserved across species and predicted to be damaging by several in silico tools. As with the previous mutation p.Arg258Gln, p.Arg459Pro is also present in Sac 1 domain of SYNJ1 wherein p.Arg258Gln mutation has already been described to impair the phosphatase activity. We report another novel mutation in SYNJ1 of an Indian consanguineous ARJP family. Finding an additional mutation in this gene further supports the involvement of SYNJ1 in PD pathogenesis across different ethnicities. Copyright © 2016 Elsevier Ltd. All rights reserved.

A mutation in SLC22A4 encoding an organic cation transporter expressed in the cochlea strial endothelium causes human recessive non-syndromic hearing loss DFNB60

PubMed Central

Ben Said, Mariem; Grati, M’hamed; Ishimoto, Takahiro; Zou, Bing; Chakchouk, Imen; Ma, Qi; Yao, Qi; Hammami, Bouthaina; Yan, Denise; Mittal, Rahul; Nakamichi, Noritaka; Ghorbel, Abdelmonem; Neng, Lingling; Tekin, Mustafa; Shi, Xiao Rui; Kato, Yukio; Masmoudi, Saber; Lu, Zhongmin; Hmani, Mounira; Liu, Xuezhong

2016-01-01

The high prevalence/incidence of hearing loss (HL) in humans makes it the most common sensory defect. The majority of the cases are of genetic origin. Non-syndromic hereditary HL is extremely heterogeneous. Genetic approaches have been instrumental in deciphering genes that are crucial for auditory function. In this study, we first used NADf chip to exclude the implication of known North-African mutations in HL in a large consanguineous Tunisian family (FT13) affected by autosomal recessive non-syndromic HL (ARNSHL). We then performed genome-wide linkage analysis and assigned the deafness gene locus to ch:5q23.2-31.1, corresponding to DFNB60 ARNSHL locus. Moreover, we performed whole-exome sequencing on FT13 patient DNA and uncovered aminoacid substitution p.Cys113Tyr in SLC22A4, a transporter of organic cations, cosegregating with HL in FT13 and therefore the cause of ARNSHL DFNB60. We also screened a cohort of small Tunisian HL families and uncovered an additional deaf proband of consanguineous parents that is homozygous for p.Cys113Tyr carried by the same microsatellite marker haplotype as in FT13, indicating that this mutation is ancestral. Using immunofluorescence, we found that Slc22a4 is expressed in stria vascularis (SV) endothelial cells of rodent cochlea and targets their apical plasma membrane. We also found Slc22a4 transcripts in our RNA-seq library from purified primary culture of mouse SV endothelial cells. Interestingly, p.Cys113Tyr mutation affects the trafficking of the transporter and severely alters Ergothioneine uptake. We conclude that SLC22A4 is an organic cation transporter of the SV endothelium that is essential for hearing, and its mutation causes DFNB60 form of HL. PMID:27023905

In silico analysis of novel mutations in maple syrup urine disease patients from Iran.

PubMed

Abiri, Maryam; Karamzadeh, Razieh; Mojbafan, Marziyeh; Alaei, Mohammad Reza; Jodaki, Atefeh; Safi, Masomeh; Kianfar, Soodeh; Bandehi Sarhaddi, Ameneh; Noori-Daloii, Mohammad Reza; Karimipoor, Morteza; Zeinali, Sirous

2017-02-01

Maple Syrup Urine Disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism. The disease is mainly caused by mutations either in the BCKDHA, BCKDHB, DBT or DLD genes encoding components of the E1α, E1β, E2 and E3 subunits of branched-chain α-keto acid dehydrogenase complex (BCKDC), respectively. BCKDC is a mitochondrial enzyme which is responsible for the normal breakdown of BCAA. The rate of consanguineous marriage in Iran is 38.6 %, so the prevalence of autosomal recessive disorders is higher in comparison to other countries. Consanguinity increases the chance of the presence of pathogenic mutations in a homoallelic state. This phenomenon has made homozygosity mapping a powerful tool for finding the probable causative gene in heterogeneous disorders like IEM (Inborn Errors of Metabolism). In this study, two sets of multiplex polymorphic STR (Short Tandem Repeat) markers linked to the above-mentioned genes were selected to identify the probable pathogenic gene in the studied families. The families who showed a homozygous haplotype for the STR markers of the BCKDHB gene were subsequently sequenced. Four novel mutations including c.633 + 1G > A, c.988G > A, c.833_834insCAC, and a homozygous deletion of whole exon 3 c. (274 + 1_275-1) _(343 + 1_344-1), as well as one recently reported (c. 508G > T) mutation have been identified. Interestingly, three families shared a common haplotype structure along with the c. 508G > T mutation. Also, four other families revealed another similar haplotype with c.988G > A mutation. Founder effect can be a suggestive mechanism for the disease. Additionally, structural models of MSUD mutations have been performed to predict the pathogenesis of the newly identified variants.

Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families

PubMed Central

Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N.; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

2015-01-01

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 – 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier. PMID:26147992

Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families.

PubMed

Srilekha, Sundaramurthy; Arokiasamy, Tharigopala; Srikrupa, Natarajan N; Umashankar, Vetrivel; Meenakshi, Swaminathan; Sen, Parveen; Kapur, Suman; Soumittra, Nagasamy

2015-01-01

Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP) south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s) in the homozygous block identified mutations in ten families; AIPL1 - 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60%) mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier.

Epidemiology of human leukocyte antigens among omani population.

PubMed

Al Salmi, Issa; Metry, Abdul Massiah; Al Ismaili, Faisal; Hola, Alan; Shaheen, Faissal; Fakhoury, Hana; Hannawi, Suad

2017-01-01

Oman is located on the Southeastern coast of the Arabian Peninsula, and its population has high levels of consanguinity. Human leukocytic antigen (HLA) typing analysis in human population holds unexploited potential for elucidating the genetic causes of human disease and possibly leads to personalized medicine. This is a retrospective, descriptive study evaluating HLA frequencies of Omani individuals who underwent workup for kidney transplantation at the Royal Hospital (RH) from 2005 to 2016. Data on 870 subjects were collected from the Oman kidney transplant registry at RH as well from electronic medical record system. The mean age (standard deviation) years for the cohort were 33.2 (13.0). Males constituted 56.3% (490) while females constituted 43.7% (380). Seven HLA-A alleles accounted for more than 70% of the total alleles. Of which, HLA-A2 contributed the highest frequency (24%), followed by HLA A11 (9.4%), and A32 (8.1%). Ten alleles accounted for 70% of HLA-B alleles. Of which, HLA-B51 was the most common (18.9%), followed by HLA-B-35 (13.6%), and HLA-B8 (7.9%). Seven HLA-DRB1 alleles accounted for more than 70% of the total HLA DRB1 alleles, of which HLA- DRB1*16 contributed the highest frequency (29.56%). This was followed by HLA-DRB1*03 (14.57%) and HLA-DRB1*11 (9.48%). While three alleles accounted for more than 75% of the total HLA DQB1alleles. Of which, HLA-DQB1*05 contributed the highest frequency (37.56%). This was followed by allele HLA-DQB1*02 (26.48%) and HLA-DQB1*03 (17.18%). This study showed considerable heterogeneity in both HLA Class I and Class II antigens, which reflects admixture of our population with rest of old world countries. Despite the high levels of consanguinity, this population is genetically highly heterogeneous. These findings may be useful for transplantation programs, noncommunicable diseases, epidemiology of HLA linked diseases, pharmacogenomics, and anthropology.

HLA DR phenotypic frequencies and genetic risk of Type 1 diabetes in west region of Algeria, Tlemcen

PubMed Central

Aribi, Mourad; Moulessehoul, Soraya; Benabadji, Ahmed-Bakir; Kendoucitani, Mohammed

2004-01-01

Background The main genomic region controlling the predisposition to type 1 diabetes is the Human Leukocyte Antigens (HLA) class II of the major histocompatibility complex. Association with different HLA types depends also on the studied populations. In our investigation, we tried to measure the phenotypic HLA class II association frequencies of DR3 and/or DR4 antigens, using a serologic method called microlymphocytotoxicity analysis, in diabetic and nondiabetic (ND) subjects originating from the west-Algerian region of Tlemcen. The aim of the present study was to determine which HLA DR antigens represent a high susceptibility to develop the disease in this area. Using a case-control retrospective study design, we randomly recruited ninety-one related subjects, 39 type 1 diabetics and 52 ND as controls, at the Internal Medicine Board of Medical Centre University of Tlemcen. Results DR3 antigen frequencies were comparable between the type 1 diabetics and the ND subjects and showed no association with the disease (p = 1.000, OR = 0.95), whereas DR4 and DR3DR4 antigens were associated with susceptibility to develop type 1 diabetes (DR4; OR = 2.10, DR3DR4; OR = 1.30). Also, no incidence for DR3 (p = 0.2646) or DR3DR4 (p = 0.0699) antigen frequencies was related to the sex ratio. However, significant differences in HLA DR4 frequencies between type 1 diabetics and ND were found to be related to sex (p = 0.0085). Conclusion Taken together, our investigation showed that the strongest association with type 1 diabetes was noticed in the presence of HLA DR4 antigens followed by DR3DR4 antigens. This study highlighted a characteristic of Tlemcen population; a history of consanguineous marriages. Association studies between the disease and genetic polymorphisms should be undertaken in a population where consanguinity is more limited to reduce confounding in result interpretations. PMID:15331022

Assessing Breast Cancer Risk Estimates Based on the Gail Model and Its Predictors in Qatari Women.

PubMed

Bener, Abdulbari; Çatan, Funda; El Ayoubi, Hanadi R; Acar, Ahmet; Ibrahim, Wanis H

2017-07-01

The Gail model is the most widely used breast cancer risk assessment tool. An accurate assessment of individual's breast cancer risk is very important for prevention of the disease and for the health care providers to make decision on taking chemoprevention for high-risk women in clinical practice in Qatar. To assess the breast cancer risk among Arab women population in Qatar using the Gail model and provide a global comparison of risk assessment. In this cross-sectional study of 1488 women (aged 35 years and older), we used the Gail Risk Assessment Tool to assess the risk of developing breast cancer. Sociodemographic features such as age, lifestyle habits, body mass index, breast-feeding duration, consanguinity among parents, and family history of breast cancer were considered as possible risks. The mean age of the study population was 47.8 ± 10.8 years. Qatari women and Arab women constituted 64.7% and 35.3% of the study population, respectively. The mean 5-year and lifetime breast cancer risks were 1.12 ± 0.52 and 10.57 ± 3.1, respectively. Consanguineous marriage among parents was seen in 30.6% of participants. We found a relationship between the 5-year and lifetime risks of breast cancer and variables such as age, age at menarche, gravidity, parity, body mass index, family history of cancer, menopause age, occupation, and level of education. The linear regression analysis identified the predictors for breast cancer in women such as age, age at menarche, age of first birth, family history and age of menopausal were considered the strong predictors and significant contributing risk factors for breast cancer after adjusting for ethnicity, parity and other variables. The current study is the first to evaluate the performance of the Gail model for Arab women population in the Gulf Cooperation Council. Gail model is an appropriate breast cancer risk assessment tool for female population in Qatar.

Survey of familial glaucoma shows a high incidence of cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in non-consanguineous congenital forms in a Spanish population

PubMed Central

Millá, Elena; Mañé, Begoña; Duch, Susana; Hernan, Imma; Borràs, Emma; Planas, Ester; Dias, Miguel de Sousa; Carballo, Miguel

2013-01-01

Purpose To identify myocilin (MYOC) and cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) mutations in a Spanish population with different clinical forms of familial glaucoma or ocular hypertension (OHT). Methods Index patients from 226 families participated in this study. Patients were diagnosed with familial glaucoma or OHT by complete ophthalmologic examination. Screening for MYOC mutations was performed in 207 index patients: 96 with adult-onset primary open-angle glaucoma (POAG), 21 with primary congenital glaucoma (PCG), 18 with juvenile-onset open-angle glaucoma (JOAG), five with Axenfeld-Rieger syndrome (ARS), and 67 with other types of glaucoma. One hundred two of the families (including all those in whom a MYOC mutation was detected) were also screened for CYP1B1 mutations: 45 POAG, 25 PCG, 21 JOAG, four ARS, and seven others. Results We examined 292 individuals (patients and relatives) with a positive family history of glaucoma or OHT. We identified two novel MYOC variants, p.Lys39Arg and p.Glu218Lys, in two families with POAG, and six previously reported MYOC mutations in seven families with POAG (four), JOAG (one), PCG (one), and normotensive glaucoma (one). CYP1B1 mutations were found in 16 index patients with PCG (nine), POAG (three), JOAG (two), and ARS (two). Conclusions The high percentage (9/25=36%) of mutations in CYP1B1 found in non-consanguineous patients with congenital glaucoma mandates genetic testing. However, the percentage of mutations (9/207=4.4%) in MYOC associated with glaucoma is relatively low in our population. The variable phenotype expression of glaucoma, even in families, cannot be explained with a digenic mechanism between MYOC and CYP1B1. PMID:23922489

The potential impact of family history of metabolic syndrome and risk of type 2 diabetes mellitus: In a highly endogamous population.

PubMed

Bener, Abdulbari; Darwish, Sarah; Al-Hamaq, Abdulla O A; Yousafzai, Mohammad T; Nasralla, Eman A

2014-03-01

This study aims to determine the potential impact of positive family history of Metabolic Syndrome (MetS) among two generations, on developing Type 2 Diabetes Mellitus (T2DM) and the potential relation of consanguineous marriage among patients with MetS to the risk of developing T2DM among a sample of Qataris. A cross-sectional study. Primary healthcare (PHC) centers. The survey and measurement were conducted from April 2011 to December 2012 among Qatari nationals above 20 years of age. Of the 2,182 subjects, who were approached to participate in the study, 1,552 (71%) gave their consent. Face-to-face interviews were conducted using a structured questionnaire followed by anthropometric measurements and laboratory tests. Metabolic syndrome was defined using the National Cholesterol Education Program-Third Adult Treatment Panel (ATP III) as well as International Diabetes Federation (IDF). Overall, the prevalence of MetS was 26.2% according to ATP III and 36.9% according to IDF (P < 0.0001). The mean age of MetS patients with T2DM was significantly higher than those without T2DM (Mean 48 ± 9.9 vs. 42.5 ± 9.2; P < 0.001). The proportion of females was higher among MetS patients with T2DM as compared to those without T2DM (61% vs. 51%; P = 0.053). In addition, there were significant differences between MetS patients with and without DM in terms of co-morbidities of hypertension, coronary heart disease, and high cholesterol. The proportion of MetS patients with positive family history for MetS was significantly higher in MetS patients with T2DM as compared to those without T2DM (46.7% vs. 33.8%; P = 0.009). The proportion of positive family history of MetS among fathers (35% vs. 21.9%; P = 0.005), mothers (30.5% vs. 18.8%; P = 0.008), maternal aunt (18.3% vs. 11.2%; P = 0.055), and maternal grand father (19.5% vs. 10%; P = 0.010) were significantly higher in MetS patients with T2DM as compared to the counterpart. The proportion of consanguineous marriages was almost two times higher among MetS patients with T2DM as compared to those without T2DM (80.9% vs. 41.9%; P < 0.001). The proportion of MetS patients with T2DM was lower than MetS patients without DM below 45 years, but after 45 years, the proportion of MetS patients with T2DM remained higher than their counterparts. Family history of MetS among parents, maternal aunt, maternal grandfather, and consanguineous marriages among patients of MetS are significantly associated with the development of T2DM in Qatar. These results support the necessity of earlier screening for T2DM among MetS patients with positive family history of MetS.

Fanconi's Anemia Effect or Sickle Cell Anemia Effect: That is the Question.

PubMed

Unal, Sule; Chui, David H K; Gumruk, Fatma

2015-01-01

A 16-year-old boy who was diagnosed to have sickle cell anemia was referred to our center. The parental consanguinity, growth retardation and dysmorphic features prompted a search for possible Fanconi's Anemia (FA). The diepoxybutane (DEB) test was positive, confirming FA. The interaction of both diseases might account for his relatively mild phenotype in terms of both sickle cell anemia (or Hb S, HBB: c.20A > T) and FA. The high Hb F level that might be related to concomitant FA, may have caused a milder phenotype of sickle cell anemia, whereas nitric oxide (NO) depletion as a consequence of sickle cell anemia, may have caused a delay in the bone marrow failure of FA.

Homozygous mutation of VPS16 gene is responsible for an autosomal recessive adolescent-onset primary dystonia.

PubMed

Cai, Xiaodong; Chen, Xin; Wu, Song; Liu, Wenlan; Zhang, Xiejun; Zhang, Doudou; He, Sijie; Wang, Bo; Zhang, Mali; Zhang, Yuan; Li, Zongyang; Luo, Kun; Cai, Zhiming; Li, Weiping

2016-05-12

Dystonia is a neurological movement disorder that is clinically and genetically heterogeneous. Herein, we report the identification a novel homozygous missense mutation, c.156 C > A in VPS16, co-segregating with disease status in a Chinese consanguineous family with adolescent-onset primary dystonia by whole exome sequencing and homozygosity mapping. To assess the biological role of c.156 C > A homozygous mutation of VPS16, we generated mice with targeted mutation site of Vps16 through CRISPR-Cas9 genome-editing approach. Vps16 c.156 C > A homozygous mutant mice exhibited significantly impaired motor function, suggesting that VPS16 is a new causative gene for adolescent-onset primary dystonia.

Inactivating KISS1 mutation and hypogonadotropic hypogonadism.

PubMed

Topaloglu, A Kemal; Tello, Javier A; Kotan, L Damla; Ozbek, Mehmet N; Yilmaz, M Bertan; Erdogan, Seref; Gurbuz, Fatih; Temiz, Fatih; Millar, Robert P; Yuksel, Bilgin

2012-02-16

Gonadotropin-releasing hormone (GnRH) is the central regulator of gonadotropins, which stimulate gonadal function. Hypothalamic neurons that produce kisspeptin and neurokinin B stimulate GnRH release. Inactivating mutations in the genes encoding the human kisspeptin receptor (KISS1R, formerly called GPR54), neurokinin B (TAC3), and the neurokinin B receptor (TACR3) result in pubertal failure. However, human kisspeptin loss-of-function mutations have not been described, and contradictory findings have been reported in Kiss1-knockout mice. We describe an inactivating mutation in KISS1 in a large consanguineous family that results in failure of pubertal progression, indicating that functional kisspeptin is important for puberty and reproduction in humans. (Funded by the Scientific and Technological Research Council of Turkey [TÜBİTAK] and others.).

A Novel Loss-of-Sclerostin Function Mutation in a First Egyptian Family with Sclerosteosis

PubMed Central

Fayez, Alaaeldin; Aglan, Mona; Esmaiel, Nora; El Zanaty, Taher; Abdel Kader, Mohamed; El Ruby, Mona

2015-01-01

Sclerosteosis is a rare autosomal recessive condition characterized by increased bone density. Mutations in SOST gene coding for sclerostin are linked to sclerosteosis. Two Egyptian brothers with sclerosteosis and their apparently normal consanguineous parents were included in this study. Clinical evaluation and genomic sequencing of the SOST gene were performed followed by in silico analysis of the resulting variation. A novel homozygous frameshift mutation in the SOST gene, characterized as one nucleotide cytosine insertion that led to premature stop codon and loss of functional sclerostin, was identified in the two affected brothers. Their parents were heterozygous for the same mutation. To our knowledge this is the first Egyptian study of sclerosteosis and SOST gene causing mutation. PMID:25984533

LAMM syndrome with middle ear dysplasia associated with compound heterozygosity for FGF3 mutations.

PubMed

Sensi, Alberto; Ceruti, Stefano; Trevisi, Patrizia; Gualandi, Francesca; Busi, Micol; Donati, Ilaria; Neri, Marcella; Ferlini, Alessandra; Martini, Alessandro

2011-05-01

We report on the first cases of FGF3 compound heterozygotes in two European families from non-consanguineous marriages, affected with labyrinthine aplasia, microtia, and microdontia (LAMM) Syndrome. Three not previously described mutations (p.W153VfsX51, p.Y106C, and p.Y49C) and a recurrent one (p.R104X) were found. Analysis of 50 unrelated control subjects (100 chromosomes) of the same European background did not show any of the two newly reported missense variations. We confirm the absence of otodental syndrome in heterozygous carriers, but report unilateral microtia in one of them. We also report on the involvement of the middle ear structures in LAMM Syndrome. Copyright © 2011 Wiley-Liss, Inc.

Dentinogenesis imperfecta associated with short stature, hearing loss and mental retardation: a new syndrome with autosomal recessive inheritance?

PubMed

Cauwels, R G E C; De Coster, P J; Mortier, G R; Marks, L A M; Martens, L C

2005-08-01

The follow-up history and oral findings in two brothers from consanguineous parents suggest that the association of dentinogenesis imperfecta (DI), delayed tooth eruption, mild mental retardation, proportionate short stature, sensorineural hearing loss and dysmorphic facies may represent a new syndrome with autosomal recessive inheritance. Histological examination of the dentin matrix of a permanent molar from one of the siblings reveals morphological similarities with defective dentinogenesis as presenting in patients affected with Osteogenesis Imperfecta (OI), a condition caused by deficiency of type I collagen. A number of radiographic and histological characteristics, however, are inconsistent with classical features of DI. These findings suggest that DI may imply greater genetical heterogeneity than currently assumed.

Le syndrome d’Usher: à propos d’une observation

PubMed Central

Daoudi, Chama; boutimzine, Noureddine; Haouzi, Samia El; Lezrek, Omar; Tachfouti, Samira; Lezrek, Mounir; Laghmari, Mina; Daoudi, Rajae

2017-01-01

Résumé Le syndrome d'Usher est une maladie génétique comportant une double atteinte sensorielle (auditive et visuelle) appelée surdicécité. Nous rapportons l'observation d'un patient de 50 ans, issue d'un mariage consanguin présentant une surdité congénitale avec une fonction vestibulaire normale et une rétinopathie pigmentaire responsable d'une baisse bilatérale de l'acuité visuelle apparue vers l'âge de 16 ans. Cette association compose le type 2 du syndrome d'Usher, affection rare de transmission autosomique récessive. La chirurgie de la cataracte a permis une amélioration de l'acuité visuelle chez ce patient. PMID:28979619

Agammaglobulinaemia despite terminal B-cell differentiation in a patient with a novel LRBA mutation.

PubMed

Al Sukaiti, Nashat; AbdelRahman, Khwater; AlShekaili, Jalila; Al Oraimi, Sumaya; Al Sinani, Aisha; Al Rahbi, Nasser; Cho, Vicky; Field, Matt; Cook, Matthew C

2017-05-01

Mutations in lipopolysaccharide-responsive vesicle trafficking, beach and anchor-containing protein (LRBA) cause immune deficiency and inflammation. Here, we are reporting a novel homozygous mutation in LRBA allele in 7-year-old Omani boy, born to consanguineous parents. He presented with type 1 diabetes, autoimmune haematological cytopenia, recurrent chest infections and lymphocytic interstitial lung disease. The patient was treated with CTLA4-Ig (abatacept) with good outcome every 2 weeks for a period of 3 months. He developed complete IgG deficiency, but remarkably, histological examination revealed germinal centres and plasma cells in lymphoid and inflamed lung tissue. Further charatecterisation showed these cells to express IgM but not IgG. This ex vivo analysis suggests that LRBA mutation confers a defect in class switching despite plasma cell formation.

IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet–Biedl syndrome

PubMed Central

Aldahmesh, Mohammed A.; Li, Yuanyuan; Alhashem, Amal; Anazi, Shams; Alkuraya, Hisham; Hashem, Mais; Awaji, Ali A.; Sogaty, Sameera; Alkharashi, Abdullah; Alzahrani, Saeed; Al Hazzaa, Selwa A.; Xiong, Yong; Kong, Shanshan; Sun, Zhaoxia; Alkuraya, Fowzan S.

2014-01-01

Bardet–Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified genes cannot account for all the BBS cases. The genetic heterogeneity of this disease poses significant challenge to the identification of additional BBS genes. In this study, we coupled human genetics with functional validation in zebrafish and identified IFT27 as a novel BBS gene (BBS19). This is the first time an intraflagellar transport (IFT) gene is implicated in the pathogenesis of BBS, highlighting the genetic complexity of this disease. PMID:24488770

Genomics into Healthcare: the 5th Pan Arab Human Genetics Conference and 2013 Golden Helix Symposium.

PubMed

Fortina, Paolo; Al Khaja, Najib; Al Ali, Mahmoud Taleb; Hamzeh, Abdul Rezzak; Nair, Pratibha; Innocenti, Federico; Patrinos, George P; Kricka, Larry J

2014-05-01

The joint 5th Pan Arab Human Genetics conference and 2013 Golden Helix Symposium, "Genomics into Healthcare" was coorganized by the Center for Arab Genomic Studies (http://www.cags.org.ae) in collaboration with the Golden Helix Foundation (http://www.goldenhelix.org) in Dubai, United Arab Emirates from 17 to 19 November, 2013. The meeting was attended by over 900 participants, doctors and biomedical students from over 50 countries and was organized into a series of nine themed sessions that covered cancer genomics and epigenetics, genomic and epigenetic studies, genomics of blood and metabolic disorders, cytogenetic diagnosis and molecular profiling, next-generation sequencing, consanguinity and hereditary diseases, clinical genomics, clinical applications of pharmacogenomics, and genomics in public health. © 2014 WILEY PERIODICALS, INC.

Genomics into Healthcare: The 5th Pan Arab Human Genetics Conference and 2013 Golden Helix Symposium

PubMed Central

Fortina, Paolo; AlKhaja, Najib; Al Ali, Mahmoud Taleb; Hamzeh, Abdul Rezzak; Nair, Pratibha; Innocenti, Federico; Patrinos, George P.; Kricka, Larry J.

2014-01-01

The joint 5th Pan Arab Human Genetics conference and 2013 Golden Helix Symposium, “Genomics into Healthcare” was coorganized by the Center for Arab Genomic Studies (http://www.cags.org.ae) in collaboration with the Golden Helix Foundation (http://www.goldenhelix.org) in Dubai, United Arab Emirates from 17 to 19 November, 2013. The meeting was attended by over 900 participants, doctors and biomedical students from over 50 countries and was organized into a series of nine themed sessions that covered cancer genomics and epigenetics, genomic and epigenetic studies, genomics of blood and metabolic disorders, cytogenetic diagnosis and molecular profiling, next-generation sequencing, consanguinity and hereditary diseases, clinical genomics, clinical applications of pharmacogenomics, and genomics in public health. PMID:24526565

Causes and anatomical site of blindness and severe visual loss in Isfahan, Islamic Republic of Iran.

PubMed

Dehghan, A; Kianersi, F; Moazam, E; Ghanbari, H

2010-02-01

This study in 2005 evaluated the causes and major anatomical site of blindness and severe visual loss at a school for blind children in Isfahan province, Islamic Republic of Iran. All 211 students were examined according to the modified WHO/PBL eye examination record: 70.4% were blind, 24.3% had severe visual loss and 5.3% were visually impaired. The major causes of abnormality were hereditary factors (42.7%), prenatal/neonatal (18.5%) and unknown etiology (35.5%). The main sites of abnormality were the retina (62.6%), whole globe (17.5%), lens (7.1%) and optic nerve (7.1%). A high proportion of parents were in a consanguineous marriage (49.2%). The pattern of blindness in Isfahan encompasses characteristics of both developed and developing countries.

Pitfalls of mapping a large Turkish consanguineous family with vertical monilethrix inheritance.

PubMed

Celep, F; Uzumcu, A; Sonmez, F M; Uyguner, O; Balci, Y Isik; Bahadir, S; Karaguzel, A

2009-01-01

Monilethrix, a rare autosomal dominant disease characterized by hair fragility and follicular hyperkeratosis, is caused by mutations in three type II hair cortex keratins. The human keratin family comprises 54 members, 28 type I and 26 type II. The phenotype shows variable penetrance and results in hair fragility and patchy dystrophic alopecia. In our study, Monilethrix was diagnosed on the basis of clinical characteristics and microscopic examination in a family with 11 affected members. Haplotype analysis was performed by three Simple Tandem Repeat markers (STR) and KRT86 gene was sequenced for the identification of the disease causing mutation. In the results of this, autosomal dominant mutation (E402K) in exon 7 of KRT86 gene was identified as a cause of Moniltherix in the large family from Turkey.

GM2 gangliosidosis in Saudi Arabia: multiple mutations and considerations for future carrier screening.

PubMed

Kaya, Namik; Al-Owain, Mohammad; Abudheim, Nada; Al-Zahrani, Jawaher; Colak, Dilek; Al-Sayed, Moeen; Milanlioglu, Aysel; Ozand, Pinar T; Alkuraya, Fowzan S

2011-06-01

The GM2 gangliosidose, Tay-Sachs and Sandhoff diseases, are a class of lysosomal storage diseases in which relentless neurodegeneration results in devastating neurological disability and premature death. Primary prevention is the most effective intervention since no effective therapy is currently available. An extremely successful model for the prevention of GM2 gangliosidosis in the Ashkenazi Jewish community is largely attributable to the very limited number of founder mutations in that population. Consistent with our previous observation of allelic heterogeneity in consanguineous populations, we show here that these diseases are largely caused by private mutations which present a major obstacle in replicating the Ashkenazi success story. Alternative solutions are proposed which can also be implemented for other autosomal recessive diseases in our population. Copyright © 2011 Wiley-Liss, Inc.

Whole Exome Sequencing identifies a splicing mutation in NSUN2 as a cause of a Dubowitz-like syndrome

PubMed Central

Martinez, Fernando; Lee, Jeong Ho; Lee, Ji Eun; Blanco, Sandra; Nickerson, Elizabeth; Gabriel, Stacey; Frye, Michaela; Al-Gazali, Lihadh; Gleeson, Joseph G.

2016-01-01

Dubowitz Syndrome is an autosomal recessive disorder characterized by the constellation of mild microcephaly, growth and mental retardation, eczema and peculiar facies, but causes are still unknown. We studied a multiplex consanguineous family with many features of Dubowitz syndrome using whole exome sequencing and identified a splice mutation in NSUN2, encoding a conserved RNA methyltransferase. NSUN2 has been implicated in Myc-induced cell proliferation and mitotic spindle stability, which might help explain the varied clinical presentations that can include chromosomal instability and immunological defects. Patient cells displayed loss of NSUN2-specific methylation at two residues of the aspartate tRNA. Our findings establish NSUN2 as the first causal gene with relationship to the Dubowitz syndrome spectrum phenotype. PMID:22577224

657del5 mutation in the NBS1 gene is associated with Nijmegen breakage syndrome in a Turkish family.

PubMed

Tekin, Mustafa; Doğu, F; Taçyíldiz, N; Akar, E; Ikincioğullari, A; Oğur, G; Yavuz, G; Babacan, E; Akar, N

2002-07-01

We report on a consanguineous Turkish family whose first son died of anal atresia and whose second son presented with severe pre- and post-natal growth retardation as well as striking microcephaly, immunodeficiency, congenital heart disease, chromosomal instability and rhabdomyosarcoma in the anal region. The proband was found to carry the homozygous 657del5 mutation in the NBS1 gene, which is responsible for Nijmegen breakage syndrome (NBS) in most of the Slav populations. Our family, the first diagnosed with NBS in the Turkish population, represents one of the most severely affected examples of the syndrome, with profound pre- and post-natal growth retardation associated with structural abnormalities, and expands the clinical spectrum of this rare disorder.

PROGRESSIVE OSSIFYING FIBRODYSPLASIA: CASE REPORT

PubMed Central

Romani, Fabiana; de Menezes Karam, Simone

2015-01-01

Progressive ossifying fibrodysplasia is a rare genetic disease that affects one individual in every two million births. Its main consequence is heterotopic ossification, i.e. formation of additional bone in abnormal locations. It is an autosomal dominant disease, usually caused by a new mutation in the ACVR1 receptor gene, which is in the signaling pathway for bone morphogenic protein. This abnormality is not related to gender, ethnicity or consanguinity. The present study reports the case of A.C., a 17-year-old girl. Her clinical investigation began at the age of four years, but she was only diagnosed with FOP at the age of 15 years, after being evaluated by several specialists in different centers. The patient has two siblings, but her family history did not reveal any similar cases. PMID:27047836

DOE Office of Scientific and Technical Information (OSTI.GOV)

Landau, D.; Shalev, H.; Carmi, Rivka

The infantile variant of Bartter syndrome (IBS) is usually associated with maternal polyhydramnios, premature birth, postnatal polyuria and hypokalemic hypochloremic metabolic alkalosis and a typical appearance. IBS is thought to be an autosomal recessive trait. Several congenital tubular defects are associated with sensorineural deafness (SND). However, an association between the IBS and SND has not been reported so far. Here we describe 5 children of an extended consanguineous Bedouin family with IBS and SND. In 3 of the cases, the typical electrolyte imbalance and facial appearance were detected neonatally. SND was detected as early as age 1 month, suggesting eithermore » coincidental homozygotization of 2 recessive genes or a pleiotropic effect of one autosomal recessive gene. This association suggests that evaluation of SND is warranted in every case of IBS. 35 refs., 2 figs., 2 tabs.« less

Identification and in silico characterization of p.G380R substitution in FGFR3, associated with achondroplasia in a non-consanguineous Pakistani family.

PubMed

Ajmal, Muhammad; Mir, Asif; Shoaib, Muhammad; Malik, Salman Akbar; Nasir, Muhammad

2017-07-05

The dimerization efficiency of FGFR3 transmembrane domain plays a critical role in the formation of a normal skeleton through the negative regulation of bone development. Recently, gain-of-function mutations in the transmembrane domain of FGFR3 has been described associated with an aberrant negative regulation, leading to the development of achondroplasia-group disorders, including achondroplasia (ACH), hypochondroplasia (HCH) and thanatophoric dysplasia (TD). Here, we describe a non-consanguineous Pakistani family with achondroplasia to explain hereditary basis of the disease. PCR-based linkage analysis using microsatellite markers was employed to localize the disease gene. Gene specific intronic primers were used to amplify the genomic DNA from all affected as well as phenotypically healthy individuals. Amplified PCR products were then subjected to Sanger sequencing and RFLP analysis to identify a potentially pathogenic mutation. The impact of identified mutation on FGFR3 protein's structure and stability was highlighted through different bioinformatics tools. Genetic screening of the family revealed a previously reported heterozygous c.1138 G > A (p.G380R) mutation in the coding exon 8 of FGFR3 gene. Identified genetic variation was confirmed in all affected individuals while healthy individuals and controls were found genotypically normal. The results were further validated by RFLP analysis as c.1138 G > A substitution generates a unique recognition site for SfcI endonuclease. Following SfcI digestion, the electrophoretic pattern of three bands/DNA fragments for each patient is indicative of heterozygous status of the disease allele. In silico studies of the mutant FGFR3 protein predicted to adversely affect the stability of FGFR3 protein. Mutation in the transmembrane domain may adversely affect the dimerization efficiency and overall stability of the FGFR3, leading to a constitutively active protein. As a result, an uncontrolled intracellular signaling or negative bone growth regulation leads to achondroplasia. Our findings support the fact that p.G380R is a common mutation among diverse population of the world and like other countries, can be used as a molecular diagnosis marker for achondroplasia in Pakistan.

Incestuous gene in consanguinophilia and incest: toward a consilience theory of incest taboo.

PubMed

Denic, Srdjan; Nicholls, M Gary

2006-01-01

Westermarck's theory of incest taboo states that inhibition of sexual attraction between biologically close relatives is situational and develops during co-residence in early childhood. By contrast, the biological (genetic) basis of incest taboo is presumed from its universality in all human societies and animals and teleologically, from the need to prevent the detrimental effects of inbreeding. As incest taboo violation is infrequent, the frequency of the presumed gene in the population is believed to be near 100%. We present arguments which suggest that the incestuous gene may exist in all populations and could play an important role in evolution. When malaria emerged 10,000 years ago, human adaptation proceeded by the selection of protective genotypes. Among them, homozygotes for alpha-thalassemia, hemoglobin C, and Duffy antigen negative blood group, have better survival odds in malarious regions than heterozygotes and those with normal genotypes. Since consanguinity increases homozygosity, it increases the number of persons who are resistant to malaria. To pro-create, however, biologically close individuals must not feel sexual aversion that normally develops between those who spend their early childhood together (Westermarck effect). It is reasonable to assume, therefore, that mutation of the gene that discourages inbreeding may have appeared at an early time in evolution, and produced a weak Westermarck effect. This gene (we will call it anti-w) failed to inhibit mating between kins. Inbred offspring of anti-w carriers, would statistically, more likely carry both anti-w and homozygote genotypes which increase fitness in the presence of malaria. Today, alpha-thalassemia is the single most common monogenetic disorders in man with over 500 millions carriers concentrated in malarious regions of the world. The world's consanguineous population is some 500-800 millions and is also concentrated in malarious regions. Population migration has spread the gene outside areas of high malaria endemicity. However, endemicity of malaria provides a worldwide gradient of genotype frequencies which makes the incestuous gene hypothesis testable. We propose that the incestuous anti-w allele was co-selected with some of the genes protective against malaria because anti-w facilitates mating between genetically close individuals whose offspring better survive malaria.

Possible risk factors for Down syndrome and sex chromosomal aneuploidy in Mysore, South India

PubMed Central

Malini, Suttur S.; Ramachandra, Nallur B.

2007-01-01

BACKGROUND: Down syndrome (DS) and sex chromosomal aneuploidy (SA) are common chromosomal anomalies causing congenital malformations and mental retardation in humans. The well-established risk factor, advanced maternal age, was not found in many of the DS and SA cases in India, while the other possible risk factors have not been well studied. In view of this, the present study has been made. MATERIALS AND METHODS: During the last 5 years, 150 clinically suspected DS and 25 SA cases were referred to our laboratory for chromosome investigation from major hospitals of Mysore city. Chromosome preparations were made from these patients after informed consent was obtained. Well-spread G-banded metaphase plates were analyzed by automated LEICA KARYO software. Two hundred and 100 randomly selected families belonging to different religions were used as controls for the DS and SA cases, respectively. Statistical analysis was carried out using logistic regression RESULTS: Out of the 150 cases of DS, 122 had free trisomy 21, two were mosaic trisomy 21, and one had translocation. Logistic regression of case-control study of DS children revealed that the odds ratio of uncle-niece marriages, or second cousin marriages, or parents lived in rural region, or exposure of the parents to chemicals, or parents education status, or habits (tobacco/ alcohol used) of father, or mother not undergone prenatal scanning, or mothers with previous abortions were significant when all the variables of that category were used one at a time. Exposure of the parents to chemicals, parents’ educational status, habits (tobacco/alcohol use) of the father, mother not undergone prenatal scanning, and history of previous abortions were significant when all the variables of that category were used one at a time. Similarly, except for consanguinity, history of previous abortions, and mother not undergone prenatal scanning, all other factors showed significant odds ratios in SA cases. CONCLUSION: Besides the known risk factors, consanguinity, region (rural/urban) of residence of parents, exposure of parents to chemicals, educational status of parents, habits of father, prenatal scanning, and reproductive performance of mother are possible risk factors for chromosomal aneuploidy. PMID:21957357

Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family.

PubMed

Zobor, Ditta; Balousha, Ghassan; Baumann, Britta; Wissinger, Bernd

2014-01-01

Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes. The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister. We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression into severe visual impairment including central vision in the index and overall milder symptoms in the younger brother and sister.

A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts

PubMed Central

Irum, Bushra; Khan, Arif O.; Wang, Qiwei; Li, David; Khan, Asma A.; Husnain, Tayyab; Akram, Javed; Riazuddin, Sheikh

2016-01-01

Purpose This study was performed to investigate the genetic determinants of autosomal recessive congenital cataracts in large consanguineous families. Methods Affected individuals underwent a detailed ophthalmological examination and slit-lamp photographs of the cataractous lenses were obtained. An aliquot of blood was collected from all participating family members and genomic DNA was extracted from white blood cells. Initially, a genome-wide scan was performed with genomic DNAs of family PKCC025 followed by exclusion analysis of our familial cohort of congenital cataracts. Protein-coding exons of CRYBB1, CRYBB2, CRYBB3, and CRYBA4 were sequenced bidirectionally. A haplotype was constructed with SNPs flanking the causal mutation for affected individuals in all four families, while the probability that the four familial cases have a common founder was estimated using EM and CHM-based algorithms. The expression of Crybb3 in the developing murine lens was investigated using TaqMan assays. Results The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis localized the causal phenotype in family PKCC025 to chromosome 22q with statistically significant two-point logarithm of odds (LOD) scores. Subsequently, we localized three additional families, PKCC063, PKCC131, and PKCC168 to chromosome 22q. Bidirectional Sanger sequencing identified a missense variation: c.493G>C (p.Gly165Arg) in CRYBB3 that segregated with the disease phenotype in all four familial cases. This variation was not found in ethnically matched control chromosomes, the NHLBI exome variant server, or the 1000 Genomes or dbSNP databases. Interestingly, all four families harbor a unique disease haplotype that strongly suggests a common founder of the causal mutation (p<1.64E-10). We observed expression of Crybb3 in the mouse lens as early as embryonic day 15 (E15), and expression remained relatively steady throughout development. Conclusion Here, we report a common ancestral mutation in CRYBB3 associated with autosomal recessive congenital cataracts identified in four familial cases of Pakistani origin. PMID:27326458

Homozygosity mapping reveals new nonsense mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in a Palestinian family

PubMed Central

Zobor, Ditta; Balousha, Ghassan; Baumann, Britta

2014-01-01

Purpose: Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 45 genes. Recently, the FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. Methods: We performed a clinical and molecular genetic study of a consanguineous Palestinian family with two three siblings affected with retinitis pigmentosa. DNA samples were collected from the index patient, his father, his affected sister, and two non-affected brothers. DNA sample from the index was subjected to high resolution genome-wide SNP array. Assuming identity-by-descent in this consanguineous family we applied homozygosity mapping to identify disease causing genes. Results: The index patient reported night blindness since the age of 20 years, followed by moderate disease progression with decrease of peripheral vision, the development of photophobia and later on reduced central vision. At the age of 40 his visual acuity was counting fingers (CF) for both eyes, color discrimination was not possible and his visual fields were severely constricted. Funduscopic examination revealed a typical appearance of advanced RP with optic disc pallor, narrowed retinal vessels, bone-spicule like pigmentary changes in the mid-periphery and atrophic changes in the macula. His younger affected brother (37 years) was reported with overall milder symptoms, while the youngest sister (21 years) reported problems only with night vision. Applying high-density SNP arrays we identified several homozygous genomic regions one of which included the recently identified FAM161A gene mutated in RP28-linked autosomal recessive RP. Sequencing analysis revealed the presence of a novel homozygous nonsense mutation, c.1003C>T/p.R335X in the index patient and the affected sister. Conclusion: We identified an RP28-linked RP family in the Palestinian population caused by a novel nonsense mutation in FAM161A. RP in this family shows a typical disease onset with moderate to rapid progression into severe visual impairment including central vision in the index and overall milder symptoms in the younger brother and sister. PMID:24520187

Agammaglobulinaemia despite terminal B-cell differentiation in a patient with a novel LRBA mutation

PubMed Central

Al Sukaiti, Nashat; AbdelRahman, Khwater; AlShekaili, Jalila; Al Oraimi, Sumaya; Al Sinani, Aisha; Al Rahbi, Nasser; Cho, Vicky; Field, Matt; Cook, Matthew C

2017-01-01

Mutations in lipopolysaccharide-responsive vesicle trafficking, beach and anchor-containing protein (LRBA) cause immune deficiency and inflammation. Here, we are reporting a novel homozygous mutation in LRBA allele in 7-year-old Omani boy, born to consanguineous parents. He presented with type 1 diabetes, autoimmune haematological cytopenia, recurrent chest infections and lymphocytic interstitial lung disease. The patient was treated with CTLA4-Ig (abatacept) with good outcome every 2 weeks for a period of 3 months. He developed complete IgG deficiency, but remarkably, histological examination revealed germinal centres and plasma cells in lymphoid and inflamed lung tissue. Further charatecterisation showed these cells to express IgM but not IgG. This ex vivo analysis suggests that LRBA mutation confers a defect in class switching despite plasma cell formation. PMID:28690850

Microcephalic osteodysplastic primordial dwarfism type 1.

PubMed

Ferrell, Steven; Johnson, Aaron; Pearson, Waylon

2016-06-16

Microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1) is an uncommon cause of microcephaly and intrauterine growth retardation in a newborn. Early identifying features include but are not limited to sloping forehead, micrognathia, sparse hair, including of eyebrows and short limbs. Immediate radiological findings may include partial or complete agenesis of the corpus callosum, interhemispheric cyst and shallow acetabula leading to dislocation. Genetic testing displaying a mutation in RNU4ATAC gene is necessary for definitive diagnosis. Early identification is important as MOPD1 is an autosomal recessive condition and could present in subsequent pregnancies. The purpose of this case is to both identify and describe some common physical findings related to MOPD1. We present a case of MOPD1 in a girl born to non-consanguineous parents that was distinct for subglottic stenosis and laryngeal cleft. 2016 BMJ Publishing Group Ltd.

Severe coagulation factor VII deficiency caused by a novel homozygous mutation (p. Trp284Gly) in loop 140s.

PubMed

Hao, Xiuping; Cheng, XiaoLi; Ye, Jiajia; Wang, Yingyu; Yang, LiHong; Wang, Mingshan; Jin, Yanhui

2016-06-01

Congenital coagulation factor VII (FVII) deficiency is a rare disorder caused by mutation in F7 gene. Herein, we reported a patient who had unexplained hematuria and vertigo with consanguineous parents. He has been diagnosed as having FVII deficiency based on the results of reduced FVII activity (2.0%) and antigen (12.8%). The thrombin generation tests verified that the proband has obstacles in producing thrombin. Direct sequencing analysis revealed a novel homozygous missense mutation p.Trp284Gly. Also noteworthy is the fact that the mutational residue belongs to structurally conserved loop 140s, which majorly undergo rearrangement after FVII activation. Model analysis indicated that the substitution disrupts these native hydrophobic interactions, which are of great importance to the conformation in the activation domain of FVIIa.

A novel homozygous missense variant in NECTIN4 (PVRL4) causing ectodermal dysplasia cutaneous syndactyly syndrome.

PubMed

Ahmad, Farooq; Nasir, Abdul; Thiele, Holger; Umair, Muhammad; Borck, Guntram; Ahmad, Wasim

2018-02-12

Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare form of ectodermal dysplasia including anomalies of hair, nails, and teeth along with bilateral cutaneous syndactyly of hands and feet. In the present report, we performed a clinical and genetic characterization of a consanguineous Pakistani family with four individuals affected by EDSS1. We performed exome sequencing using DNA of one affected individual. Exome data analysis identified a novel homozygous missense variant (c.242T>C; p.(Leu81Pro)) in NECTIN4 (PVRL4). Sanger sequencing validated this variant and confirmed its cosegregation with the disease phenotype in the family members. Thus, our report adds a novel variant to the NECTIN4 mutation spectrum and contributes to the NECTIN4-related clinical characterization. © 2018 John Wiley & Sons Ltd/University College London.

Per-oral endoscopic myotomy for esophageal achalasia in a case of Allgrove syndrome.

PubMed

Nakamura, Jun; Hikichi, Takuto; Inoue, Haruhiro; Watanabe, Ko; Kikuchi, Hitomi; Takagi, Tadayuki; Suzuki, Rei; Sugimoto, Mitsuru; Konno, Naoki; Waragai, Yuichi; Asama, Hiroyuki; Takasumi, Mika; Sato, Yuki; Irie, Hiroki; Obara, Katsutoshi; Ohira, Hiromasa

2018-01-30

Allgrove syndrome, also known as Triple A syndrome, is a rare autosomal recessive genetic disease characterized by three signs: esophageal achalasia, adrenocorticotropic hormone refractoriness, and alacrima. A 31-year-old male presented to our hospital for treatment of difficulty swallowing caused by esophageal achalasia. Because he had complicating alacrima, a neurologic disease, and a family history of consanguineous marriage, a genetic neurologic disease was suspected. Then, a mutation in the achalasia-addisonianism-alacrima syndrome gene was identified. With the diagnosis of Allgrove syndrome, a per-oral endoscopic myotomy (POEM) was performed for esophageal achalasia. After the POEM, the symptoms and the esophageal pressure findings ameliorated quickly, with no recurrence noted throughout a follow-up of more than 1 year. Here, we report the first case of POEM performed for esophageal achalasia in Allgrove syndrome.

Exonal deletion of SLC24A4 causes hypomaturation amelogenesis imperfecta.

PubMed

Seymen, F; Lee, K-E; Tran Le, C G; Yildirim, M; Gencay, K; Lee, Z H; Kim, J-W

2014-04-01

Amelogenesis imperfecta is a heterogeneous group of genetic conditions affecting enamel formation. Recently, mutations in solute carrier family 24 member 4 (SLC24A4) have been identified to cause autosomal recessive hypomaturation amelogenesis imperfecta. We recruited a consanguineous family with hypomaturation amelogenesis imperfecta with generalized brown discoloration. Sequencing of the candidate genes identified a 10-kb deletion, including exons 15, 16, and most of the last exon of the SLC24A4 gene. Interestingly, this deletion was caused by homologous recombination between two 354-bp-long homologous sequences located in intron 14 and the 3' UTR. This is the first report of exonal deletion in SLC24A4 providing confirmatory evidence that the function of SLC24A4 in calcium transport has a crucial role in the maturation stage of amelogenesis.

Poikiloderma with neutropenia, Clericuzio type, in a family from Morocco.

PubMed

Mostefai, Rahima; Morice-Picard, Fanny; Boralevi, Franck; Sautarel, Michel; Lacombe, Didier; Stasia, Marie José; McGrath, John; Taïeb, Alain

2008-11-01

Three siblings from Morocco consanguineous family presented with cutaneous poikiloderma following postnatal ichthyosiform lesions, associated with papillomatous lesions, palmoplantar keratoderma, pachyonychia of toenails, fragile carious teeth, and lachrymal duct obstruction. Photosensitivity and blistering improved with age. Atrophic scars were prominent on the limbs. Neutropenia developed in the first year secondary to dysmyelopoiesis affecting the granulocyte lineage, associated with a polyclonal hypergammaglobulinemia. Several broncho-pulmonary infectious episodes complicated the evolution, and cystic fibrosis was first considered on the basis of repeated abnormal sweat chloride tests but not confirmed by molecular analyses. This autosomal recessive disorder matches that described originally as poikiloderma with neutropenia-Clericuzio type in Navajo Indians (OMIM 604173). It is discussed within the group of the major hereditary poikiloderma disorders, that is, Rothmund-Thomson syndrome, dyskeratosis congenita, and Kindler syndrome. Copyright 2008 Wiley-Liss, Inc.

Rare intracranial cholesterol deposition and a homozygous mutation of LDLR in a familial hypercholesterolemia patient.

PubMed

Li, Haoxian; Zhang, Yanghui; Wei, Xianda; Peng, Ying; Yang, Pu; Tan, Hu; Chen, Chen; Pan, Qian; Liang, Desheng; Wu, Lingqian

2015-09-15

Familial hypercholesterolemia (FH MIM# 143890) is one of the most common autosomal inherited diseases. FH is characterized by elevated plasma levels of total cholesterol and low-density lipoprotein-cholesterol. Mutation in the LDLR gene, which encodes the LDL receptor protein, is responsible for most of the morbidity of FH. The incidence of heterozygous FH is about 1/500, whereas the incidence of homozygous FH is only 1/1,000,000 in Caucasian population. In this study, we report a homozygous LDLR mutation (c.298G>A) in a familial hypercholesterolemia patient, who exhibited intracranial cholesterol deposition, which is a rare addition to the common FH phenotypes. The proband's consanguineous parents have the same heterozygous mutation with elevated concentrations of LDL-C but no xanthoma. Copyright © 2015 Elsevier B.V. All rights reserved.

Studies of malformation syndromes in man XXXX: multiple congenital anomalies/mental retardation syndrome or variant familial developmental pattern; differential diagnosis and description of the McDonough syndrome (with XXY son from XY/XXY father).

PubMed

Neuhäuser, G; Opitz, J M

1975-11-13

The McDonough syndrome is a "new" MCA/MR syndrome which was found in 3 children (1 girl, 2 boys) of non-consanguineous parents. The affected children were mentally retarded (IQ 47--67) and had congenital heart defect, sternal deformity, kyphosis and craniofacila anomalies (anteverted auricles, upward slanted palpebral fissures, squint); cryptorchidism was present in the 2 boys. In addition a possible VFDP is postulated as the explanation for similar features in affected and unaffected siblings and parents. However, the McDonough syndrome may be an autosomal recessive trait with minor manifestations in heterozygotes. The klinefelter syndrome in one affected boy and a 46,XY/47,XXY chromosome constitution in the father was a coincidental finding.

XPC gene mutations in families with xeroderma pigmentosum from Pakistan; prevalent founder effect.

PubMed

Ijaz, Ambreen; Basit, Sulman; Gul, Ajab; Batool, Lilas; Hussain, Abrar; Afzal, Sibtain; Ramzan, Khushnooda; Ahmad, Jamil; Wali, Abdul

2018-03-23

Xeroderma pigmentosum (XP) is a rare autosomal recessive skin disorder characterized by hyperpigmentation, premature skin aging, ocular and cutaneous photosensitivity, and increased risk of skin carcinoma. We investigated seven consanguineous XP families with nine patients from Pakistan. All the Patients exhibited typical clinical symptoms of XP since first year of life. Whole genome SNP genotyping identified a 14 Mb autozygous region segregating with the disease phenotype on chromosome 3p25.1. DNA sequencing of XPC gene revealed a founder homozygous splice site mutation (c.2251-1G>C) in patients from six families (A-F) and a homozygous nonsense mutation (c.1399C>T; p.Gln467*) in patients of family G. This is the first report of XPC mutations, underlying XP phenotype, in Pakistani population. © 2018 Japanese Teratology Society.

[Serological Characteristics and Family Survey of 3 Cases of H-deficient Blood Group].

PubMed

Geng, Wei; Gao, Huan-Huan; Zhang, Lin-Wei

2016-06-01

To investigate the serological characteristics and the genetic status of the family of H-deficient blood group in Jining area of Shandong province in China. ABO, H, and Lewis blood groups in 3 probands were screened out by the serological method, and saliva testing was performed on all the individuals. The presence of weak A or B on the RBC was confirmed by using the adsorption-elution procedure. Three cases of H-deficient blood group were identified to be para-Bombay blood group (secretor), out of 3 cases, 2 cases were Bh, 1 case was Ah, and anti-H or anti-HI antibody was detected in their serum. Three cases of H-deficerent blood group are para-Bombay phenotype, among them one proband's parents have been confirmed to be consanguineous relationship.

Unique autosomal recessive variant of palmoplantar keratoderma associated with hearing loss not caused by known mutations*

PubMed Central

Hegazi, Moustafa Abdelaal; Manou, Sommen; Sakr, Hazem; Camp, Guy Van

2017-01-01

Inherited Palmoplantar Keratodermas are rare disorders of genodermatosis that are conventionally regarded as autosomal dominant in inheritance with extensive clinical and genetic heterogeneity. This is the first report of a unique autosomal recessive Inherited Palmoplantar keratoderma - sensorineural hearing loss syndrome which has not been reported before in 3 siblings of a large consanguineous family. The patients presented unique clinical features that were different from other known Inherited Palmoplantar Keratodermas - hearing loss syndromes. Mutations in GJB2 or GJB6 and the mitochondrial A7445G mutation, known to be the major causes of diverse Inherited Palmoplantar Keratodermas -hearing loss syndromes were not detected by Sanger sequencing. Moreover, the pathogenic mutation could not be identified using whole exome sequencing. Other known Inherited Palmoplantar keratoderma syndromes were excluded based on both clinical criteria and genetic analysis. PMID:29267478

Total anomalous pulmonary venous connection and a constellation of craniofacial, skeletal, and urogenital anomalies in a newborn and similar features in his 36-year-old father.

PubMed

Pierson, D M; Taboada, E M; Lofland, G K; Begleiter, M L; Smith, G S; Hall, F; Butler, M G

2001-04-01

We report on a newborn male born to non-consanguineous parents with total anomalous pulmonary venous connection (TAPVC) and additional findings of malformed ears, hypertelorism, brachyphalangy in the hands, pterygium of the elbows, knees, and wrists, complex lower limb pre-axial polydactyly, tibial shortening, clubfeet, horseshoe kidney and a micropenis. He had a 46,XY karyotype. His 36-year-old father had similar craniofacial and limb anomalies suggesting an autosomal dominant syndrome with variable expression. Our patients may represent the 3rd and 4th examples of a newly-described syndrome by Baraitser et al. [(1997) Clin Dysmorphol 6:111-121] which is distinguished by malformed ears, complex pre-axial polydactyly and tibial aplasia in the lower limbs, severe brachyphalangy in the hands, and a micropenis.

The case for re-thinking incest laws.

PubMed

Farrelly, C

2008-09-01

The recent case of German siblings Patrick Stübing (age 30 years) and his sister Susan Karolewski (age 22 years) has reignited debate over the criminalisation of sexual intercourse among consanguine descendants. The primary justification for criminalising incest is the purported increased risk of genetic disabilities among offspring, but is criminalising sexual intercourse an empirically sound and proportionate response to this increased risk? To answer this question we must consider the specifics of the harm in question (eg, is it a harm to the child or a societal harm) and the magnitude of the harms of the intervention. The example of incest law has important implications for liberal societies. If we can justify imprisoning consenting adults for choosing partners who will increase the risk of having children with disabilities, then we set a troubling precedent for all couples who may pass on genetic disorders to their children.

Genetic analysis of the pedigrees and molecular defects of the GH-receptor gene in the Israeli cohort of patients with Laron syndrome.

PubMed

Shevah, Orit; Laron, Zvi

2006-08-01

Out of the 63 patients with Laron Syndrome ( LS) followed in our clinic we were able to perform a genetic analysis on 43 patients belonging to 28 families. Twenty-seven patients were Jews, eight were Arabs, one was Druze, and six were Caucasians from countries other then Israel. Consanguinity was found in 11 families. Molecular analysis of the growth hormone receptor gene was performed in 32 patients and 32 family members. From the study of the pedigrees, as well as the GH receptor gene analysis, we confirmed an earlier report from our group that LS is a recessively inherited disease. One patient with a classical phenotype of LS had a non-classical pattern of inheritance: R43X heterozygosity together with a heterozygous polymorphism G168G; a condition which needs further exploration.

Comparative skeletal features between Homo floresiensis and patients with primary growth hormone insensitivity (Laron Syndrome).

PubMed

Hershkovitz, Israel; Kornreich, Liora; Laron, Zvi

2007-10-01

Comparison between the skeletal remains of Homo floresiensis and the auxological and roentgenological findings in a large Israeli cohort of patients with Laron Syndrome (LS, primary or classical GH insensitivity or resistance) revealed striking morphological similarities, including extremely small stature and reduced cranial volume. LS is an autosomal recessive disease caused by a molecular defect of the Growth Hormone (GH) receptor or in the post-receptor cascades. Epidemiological studies have shown that LS occurs more often in consanguineous families and isolates, and it has been described in several countries in South East Asia. It is our conclusion that the findings from the island of Flores, which were attributed to a new species of the genus Homo, may in fact represent a local, highly inbred, Homo sapiens population in whom a mutation for the GH receptor had occurred. (c) 2007 Wiley-Liss, Inc.

Birth defects: Risk factors and consequences

PubMed Central

Oliveira, Camila Ive Ferreira; Fett-Conte, Agnes Cristina

2013-01-01

Birth defects (BDs) or congenital anomalies include all structural and functional alterations in embryonic or fetal development resulting from genetic, environmental or unknown causes, which result in physical and/or mental impairment. BDs occur in about 3% of newborn babies and in most cases of pregnancy loss. BDs are a very complex and heterogeneous group of single or multiple changes that, in most cases, are of unknown etiology. Among the risk factors are advanced maternal and paternal ages, parental consanguinity, teratogenic agents such as infectious agents and drugs, and poor nutrition, in particular folic acid deficiency. One of the consequences of these defects is the high death rate within the first year of life. Information on BDs is becoming increasingly more important throughout the world so that preventive measures can be taken. Knowledge of BDs enables the development of therapeutic and preventive strategies besides adequate genetic counseling. PMID:27625844

Genetic and functional characterization of PCSK1.

PubMed

Choquet, Hélène; Stijnen, Pieter; Creemers, John W M

2011-01-01

PC1/3 is a neuroendocrine-specific member of the mammalian subtilisin-like proprotein convertase family. This seven-member family is involved in the endoproteolytic cleavage of a large number of precursor proteins including prohormones, proneuropeptides, zymogens, and proreceptors. PC1/3 is synthesized as a zymogen, proPC1/3, and its propeptide is rapidly and autocatalytically cleaved in the endoplasmic reticulum. The mature protein is sorted and stored in dense-core secretory vesicles, together with its substrates. Compound-inactivating mutations in the PCSK1 gene, which encodes PC1/3, cause monogenic obesity. Furthermore, the contribution of two common nonsynonymous variants in PCSK1 to polygenic obesity risk has recently been established. Additional rare variants have been identified in non-consanguineous extremely obese Europeans but functional characterization has not yet been described. Sequencing efforts of larger cohorts of obese patients might reveal more variants conferring risk of obesity.

[Kindler syndrome: clinical and ultra-structural particularities, a propos of three cases].

PubMed

El Fekih, Nadia; Mahfoudh, Anis; Zekri, Samy; Kharfi, Monia; Fazaa, Bécima; Jaafoura, Mohamed Habib; Kamoun, Mohamed Ridha

2011-08-01

Kindler's syndrome is a rare type of genetic skin condition belonging to the class of bullous poikilodermia. We report three new sibling cases of this rare syndrome. The condition was seen in three sisters aged 12, 16 and 20 years, born of a first-degree consanguineous marriage with no family history of Kindler's syndrome. The three patients presented spontaneously regressive bullous eruptions, poikilodermia of gradual onset, major cutaneous atrophy on the back of the hands and the feet, photosensitivity and gingival hypertrophy. Electron microscopy examination of poikilodermic skin showed normal anchoring filaments and intraepidermal cleavage. Diagnosis of Kindler's syndrome is based upon clinical evidence. Kidler's syndrome is a well defined clinical entity. Ultra-structural studies show intraepidermal, junctional, and dermal cleavage. This syndrome must be differentiated from congenital epidermolysis bullosa, Weary's syndrome, and other bullous hereditary poikilodermas. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Mexican American intergenerational caregiving model.

PubMed

Escandón, Socorro

2006-08-01

This study employed grounded theory to formulate a conceptual model of intergenerational caregiving among Mexican American families. The sample consisted of 10 Mexican American caregivers of various generations older than 21 who provided at least one intermittent service (without pay at least once a month) to an elder, related through consanguinal or acquired kinship ties. The inductively generated theory of role acceptance is composed of four phases: (a) introduction--early caregiving experiences, (b) role reconciliation, (c) role imprint, and (d) providing or projecting care. This model can be used to study varied generations of Mexican American caregivers. It also provides a framework for comparison with other groups of caregivers. The results can help in designing nursing interventions to support caregivers based on understanding the issues, to create and design systems that address the varying and ever-changing needs of informal caregivers, and to assist in the formulation of policy that supports Mexican American caregivers.

Hereditary sensory ataxic neuropathy associated with proximal muscle weakness in the lower extremities.

PubMed

Murakami, Tatsufumi; Fukai, Yuta; Rikimaru, Mitsue; Henmi, Shoji; Ohsawa, Yutaka; Sunada, Yoshihide

2010-04-15

We describe three patients from the same family with hereditary sensory ataxic neuropathy followed by proximal muscle weakness in the lower extremities. Sensory ataxic gait began as an initial symptom when patients were in their 50s. Mild proximal weakness in the lower extremities appeared several years later. Serum creatine kinase was mildly elevated. Nerve conduction studies revealed sensory dominant axonal neuropathy, and short sensory evoked potentials showed involvement of the sensory nerve axon, dorsal root ganglia and posterior funiculus of the spinal cord. Needle electromyography showed fibrillation, positive sharp waves, and multiple giant motor unit potentials, suggesting the involvement of anterior horn motor neurons or the anterior root. Autosomal recessive inheritance was considered, because of consanguinity. The disorder described here may be a new clinical entity with unique clinical manifestations. Copyright 2009 Elsevier B.V. All rights reserved.

Confirmation that RIPK4 mutations cause not only Bartsocas-Papas syndrome but also CHAND syndrome.

PubMed

Busa, Tiffany; Jeraiby, Mohammed; Clémenson, Alix; Manouvrier, Sylvie; Granados, Viviana; Philip, Nicole; Touraine, Renaud

2017-11-01

CHAND syndrome is an autosomal recessive disorder characterized by curly hair, ankyloblepharon, and nail dysplasia. Only few patients were reported to date. A homozygous RIPK4 mutation was recently identified by homozygosity mapping and whole exome sequencing in three patients from an expanded consanguineous kindred with a clinical diagnosis of CHAND syndrome. RIPK4 was previously known to be implicated in Bartsocas-Papas syndrome, the autosomal recessive form of popliteal pterygium syndrome. We report here two cases of RIPK4 homozygous mutations in a fetus with severe Bartsocas-Papas syndrome and a patient with CHAND syndrome. The patient with CHAND syndrome harbored the same mutation as the one identified in the family previously reported. We thus confirm the implication of RIPK4 gene in CHAND syndrome in addition to Bartsocas-Papas syndrome and discuss genotype/phenotype correlations. © 2017 Wiley Periodicals, Inc.

Recurrent short rib polydactyly syndrome.

PubMed

Eleftheriades, M; Iavazzo, C; Manolakos, E; Hassiakos, D; Botsis, D; Petersen, M; Konstantinidou, A

2013-01-01

We present three consecutive cases of skeletal dysplasias of a non-consanguineous couple with five pregnancies. The diagnosis of short-rib polydactyly syndrome (SRPS) was feasible by ultrasound during the 1st trimester of pregnancy. SRPS represents a heterogeneous group of lethal skeletal dysplasias. It is characterised by short limb dwarfism complicated by thoracic hypoplasia, polydactyly and different anomalies of major organs such as congenital heart defects and renal dysplasia. Four major types of the SRPS have been described: type I (Saldino-Noonan); type II (Majewski); type III (Verma-Naumoff) and type IV (Beemar-Langer). However, there is phenotypic overlapping between four types and with those of non-lethal skeletal dysplasias (i.e. Ellis-van Creveld syndrome and Jeune syndrome). Our cases show the importance of the nuchal translucency (NT) scan that offers the opportunity to examine fetal anatomy in the 1st trimester and diagnose rare skeletal abnormalities early in pregnancy.

Microsatellite and HLA class II oligonucleotide typing in a population of Yanomami Indians.

PubMed

Roewer, L; Nagy, M; Schmidt, P; Epplen, J T; Herzog-Schröder, G

1993-01-01

We have used three different microsatellites (on chromosome 12 and Y) together with HLA class II oligonucleotide typing (DQA and DQB) to analyze families of Yanomami indians settling in villages in Southern Venezuela. There exist complex networks of biological relationship between villages as a result of wife exchange, village fissioning and changing patterns of alliances associated with inter-village warfare. Social status in this society is largely determined by the kinship system. Polygyny is common, especially among headmen, with additional wives, frequently being chosen among the sisters of the first wife. Our preliminary results mainly obtained from inhabitants of the village HAP show the expected allele distribution in populations with a high degree of consanguinity: (i) deficiency of observed heterozygotes at the autosomal loci and (ii) almost all men carry the same Y chromosomal allele. Nevertheless in the Yanomami village two thirds of the described autosomal microsatellite alleles were identified. Several paternities were clarified.

Own-Choice Marriage and Fertility in Turkey

PubMed Central

Weinreb, Alexander A.

2016-01-01

Goode’s foundational work on the fertility transition identified own-choice marriage as a factor driving fertility decline, part of a widening repertoire of choice pertaining to marriage and childbearing. Yet research supporting this connection in today’s transitional societies is scarce and somewhat contradictory, and it is unclear how other marital traditions, such as consanguineous marriage, shape this relationship. This study evaluates Goode’s theorized connection using pooled Demographic and Health Survey data from Turkey, comparing children ever born, use of contraception, and parity progression across four types of marriage: own-choice and arranged marriage; and marriage to a cousin versus an unrelated spouse. Results are largely consistent with the idea that a move towards own-choice marriage reflects a widening repertoire of choice that also leads to fertility decline. However, they also show that hybrid models like own-choice marriage to a cousin tempers these effects. PMID:28316343

Oral-facial-digital syndrome type IX in a patient with Dandy-Walker malformation.

PubMed Central

Nagai, K; Nagao, M; Nagao, M; Yanai, S; Minagawa, K; Takahashi, Y; Takekoshi, Y; Ishizaka, A; Matsuzono, Y; Kobayashi, O; Itagaki, T

1998-01-01

We report a girl with oral, facial, and digital anomalies including multiple alveolar frenula, lobulated tongue with nodules, a posterior cleft palate, hypertelorism, a prominent forehead with a large anterior fontanelle, and postaxial polydactyly in both hands and the right foot, features compatible with the oral-facial-digital syndrome (OFDS). In addition, she had bilateral microphthalmia, optic disc coloboma, and retinal degeneration with partial detachment, thus establishing a diagnosis of OFDS type IX. Dandy-Walker malformation and retrobulbar cysts were observed on MRI. These additional malformations have not been reported in OFDS type IX. The frequent apnoeic spells which occurred immediately after birth were relieved after cystoperitoneal shunt implantation for hydrocephalus. Considering our case and previous reports of OFDS type IX, including two male sibs, a boy born to consanguineous parents, and three females, inheritance is probably autosomal recessive. Images PMID:9598735

Private multiple congenital anomaly syndromes may result from unbalanced subtle translocations: t(2q;4p) explains the Lambotte syndrome.

PubMed

Herens, C; Jamar, M; Alvarez-Gonzalez, M L; Lesenfants, S; Lombet, J; Bonnivert, J; Koulischer, L; Verloes, A

1997-12-12

In 1990, Lambotte syndrome was reported as an apparently autosomal recessive multiple congenital anomaly/mental retardation (MCA/MR) syndrome observed in 4 of 12 sibs from a probably consanguineous mating [Verloes et al., Am J Med Genet 1990; 37:119-123]. Major manifestations included intrauterine growth retardation (IUGR), microcephaly, large soft pinnae, hypertelorism, beaked nose, and extremely severe neurologic impairment, with holoprosencephaly in one instance. After the observation of a further affected child born of one unaffected sister, in situ hybridization analysis and chromosome painting techniques demonstrated a subtle t(2;4)(q37.1; p16.2) translocation in the mother, suggesting a combination of 2q/4p trisomy/monosomy in all of the affected children of the family. Many private sporadic or recurrent MCA/MR syndromes maybe due to similar symmetric translocations, undetectable by conventional banding techniques.

NDUFS4 mutations cause Leigh syndrome with predominant brainstem involvement.

PubMed

Leshinsky-Silver, E; Lebre, Anne-Sophie; Minai, Limor; Saada, Ann; Steffann, Julie; Cohen, Sarit; Rötig, Agnes; Munnich, Arnold; Lev, Dorit; Lerman-Sagie, Tally

2009-07-01

Complex I deficiency is a frequent cause of Leigh syndrome. We describe a non-consanguineous Ashkenazi-Sephardic Jewish patient with Leigh syndrome due to complex I deficiency. The clinical and neuroradiological presentation showed predominant brainstem involvement. Blue native polyacrylamide gel electrophoresis analysis revealed an impaired assembly of complex I. The patient was found to be compound heterozygous of two mutations in the NDUFS4 gene: p.Asp119His (a novel mutation) and p.Lys154fs (recently described in an Ashkenazi Jewish family). These findings support the suggestion that the p.Lys154fs mutation in NDUFS4 should be evaluated in Ashkenazi Jewish patients presenting with early onset Leigh syndrome even before enzymatic studies. Our results further demonstrated that NDUFS4 presents a hotspot of mutations in the genetic apparatus of oxidative phosphorylation and the correct assembly of the subunit it encodes is essential for completion of the assembly of complex I.

A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family.

PubMed

Anderson, S L; Chung, W K; Frezzo, J; Papp, J C; Ekstein, J; DiMauro, S; Rubin, B Y

2008-12-01

Leigh syndrome is a neurodegenerative disorder of infancy or childhood generally due to mutations in nuclear or mitochondrial genes involved in mitochondrial energy metabolism. We performed linkage analysis in an Ashkenazi Jewish (AJ) family without consanguinity with three affected children. Linkage to microsatellite markers D5S1969 and D5S407 led to evaluation of the complex I gene NDUFS4, in which we identified a novel homozygous c.462delA mutation that disrupts the reading frame. The resulting protein lacks a cAMP-dependent protein kinase phosphorylation site required for activation of mitochondrial respiratory chain complex I. In a random sample of 5000 healthy AJ individuals, the carrier frequency of the NDUFS4 mutation c.462delA was 1 in 1000, suggesting that it should be considered in all AJ patients with Leigh syndrome.

Genetic markers cannot determine Jewish descent

PubMed Central

Falk, Raphael

2015-01-01

Humans differentiate, classify, and discriminate: social interaction is a basic property of human Darwinian evolution. Presumably inherent differential physical as well as behavioral properties have always been criteria for identifying friend or foe. Yet, biological determinism is a relatively modern term, and scientific racism is, oddly enough, largely a consequence or a product of the Age of Enlightenment and the establishment of the notion of human equality. In recent decades ever-increasing efforts and ingenuity were invested in identifying Biblical Israelite genotypic common denominators by analysing an assortment of phenotypes, like facial patterns, blood types, diseases, DNA-sequences, and more. It becomes overwhelmingly clear that although Jews maintained detectable vertical genetic continuity along generations of socio-religious-cultural relationship, also intensive horizontal genetic relations were maintained both between Jewish communities and with the gentile surrounding. Thus, in spite of considerable consanguinity, there is no Jewish genotype to identify. PMID:25653666