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Sample records for large consanguineous family

  1. Homozygous WNT3 mutation causes tetra-amelia in a large consanguineous family.

    PubMed

    Niemann, Stephan; Zhao, Chengfeng; Pascu, Filon; Stahl, Ulrich; Aulepp, Ute; Niswander, Lee; Weber, James L; Müller, Ulrich

    2004-03-01

    Tetra-amelia is a rare human genetic disorder characterized by complete absence of all four limbs and other anomalies. We studied a consanguineous family with four affected fetuses displaying autosomal recessive tetra-amelia and craniofacial and urogenital defects. By homozygosity mapping, the disease locus was assigned to chromosome 17q21, with a maximum multipoint LOD score of 2.9 at markers D17S931, D17S1785, D17SS1827, and D17S1868. Further fine mapping defined a critical interval of approximately 8.9 Mb between D17S1299 and D17S797. We identified a homozygous nonsense mutation (Q83X) in the WNT3 gene in affected fetuses of the family. WNT3, a human homologue of the Drosophila wingless gene, encodes a member of the WNT family known to play key roles in embryonic development. The Q83X mutation truncates WNT3 at its amino terminus, suggesting that loss of function is the most likely cause of the disorder. Our findings contrast with the observation of early lethality in mice homozygous for null alleles of Wnt3. To our knowledge, this is the first report of a mutation in a WNT gene associated with a Mendelian disorder. The identification of a WNT3 mutation in tetra-amelia indicates that WNT3 is required at the earliest stages of human limb formation and for craniofacial and urogenital development. PMID:14872406

  2. Novel homozygous large deletion including the 5′ part of the SPATA7 gene in a consanguineous Israeli Muslim Arab family

    PubMed Central

    Mayer, Anja-Kathrin; Mahajnah, Muhammad; Zobor, Ditta; Bonin, Michael; Sharkia, Rajech

    2015-01-01

    Purpose To identify the genetic defect in a consanguineous Israeli Muslim Arab family with juvenile retinitis pigmentosa (RP). Methods DNA samples were collected from the index patient, her parents, her affected sister, and two non-affected siblings. Genome-wide linkage analysis with 250 K single nucleotide polymorphism (SNP) arrays was performed using DNA from the two affected patients. Owing to consanguinity in the family, we applied homozygosity mapping to identify the disease-causing gene. The candidate gene SPATA7 was screened for mutations with PCR amplifications and direct Sanger sequencing. Results Following high-density SNP arrays, we identified several homozygous genomic regions one of which included the SPATA7 gene. Several mutations in SPATA7 have been reported for various forms of retinal dystrophy, including Leber congenital amaurosis (LCA) and juvenile RP. PCR-based sequence content mapping, long-distance PCR amplifications, and subsequent sequencing analysis revealed a homozygous 63.4 kb large deletion that encompasses the 5′ part of the SPATA7 gene including exons 1–5. The mutation showed concordant segregation with the phenotype in the family as expected for autosomal recessive mode of inheritance and is consistent with a diagnosis of juvenile RP. Conclusions We report a novel homozygous large deletion in SPATA7 associated with juvenile RP in a consanguineous Israeli Muslim Arab family. This is the first larger deletion mutation reported for SPATA7. PMID:25814828

  3. Pendred syndrome in a large consanguineous Brazilian family caused by a homozygous mutation in the SLC26A4 gene.

    PubMed

    Lofrano-Porto, Adriana; Barra, Gustavo B; Nascimento, Paula P; Costa, Patrícia G G; Garcia, Erica C; Vaz, Rodrigo F; Batista, Ana R T; Freitas, Ana C R de; Cherulli, Bruno L B; Bahmad, Fayez; Figueiredo, Larissa G; Neves, Francisco A R; Casulari, Luiz Augusto

    2008-11-01

    Pendred Syndrome (PS) is an autossomal recessive disorder characterized by sensorineural deafness, goiter and iodide organification defect. The hearing loss is associated with inner ear abnormalities, ranging from an isolated enlarged vestibular aqueduct (EVA) to a typical coclear dysplasia. Mutations in the gene that encodes pendrin (SLC26A4), a chloride/iodide transporter, have been shown to be associated with PS. We describe the clinical and molecular characteristics of a large consanguineous family harboring a mutation in the SLC26A4 gene. The proband was a 26-year-old deaf Brazilian woman who presented a bulky multinodular goiter and hypothyroidism since puberty. Five other siblings were deaf: one brother had a similar phenotype, three siblings also had goiters but normal thyroid function tests, and one brother had only a subtle thyroid enlargement. Other 4 siblings had no thyroid or hearing disorder. Parents were first degree cousins and had normal hearing. The mother was healthy, except for subclinical hypothyroidism; the father was deceased. A perchlorate test in the proband showed a discharge of 21% of the incorporated iodide 2h after the administration of 1g of KClO4. Audiological examinations showed profound hearing loss in all deaf subjects; CT and MRI of the temporal bones showed EVA in all of them. Genomic DNA was isolated from whole blood, from the 6 affected and 4 unaffected siblings, the mother and control. The coding region of the PDS gene (exons 2-21), including exon/intron boundaries, were amplified by PCR and sequenced. A single base-pair (T) deletion at position 1197 of exon 10 was detected in homozygous state in the 6 deaf siblings. The mother and 2 unaffected siblings were heterozygous for this mutation, which has been described by Everett et al. The 1197delT mutation is predicted to result in a frameshift and a truncated protein. The existence of PS phenocopies and intrafamilial phenotypic variability are well documented. The definite diagnosis requires molecular analysis. Our study illustrates the value and challenges of mutational analysis in selected patients with PS. PMID:19169484

  4. Mutations in patients with osteogenesis imperfecta from consanguineous Indian families.

    PubMed

    Stephen, Joshi; Girisha, Katta Mohan; Dalal, Ashwin; Shukla, Anju; Shah, Hitesh; Srivastava, Priyanka; Kornak, Uwe; Phadke, Shubha R

    2015-01-01

    Osteogenesis imperfecta (OI) is a spectrum of genetic disorders with decreased bone density and bone fragility. Most of the cases of OI are inherited in autosomal dominant fashion with mutations in COL1A1 or COL1A2 genes. Over last few years, twelve genes for autosomal recessive OI have been identified. In this study we have evaluated seven patients with OI from consanguineous Indian families. Homozygosity mapping using SNP microarray was done and selected candidate genes were sequenced. Candidate genes were identified in four out of seven patients studied. Four mutations, namely; a homozygous non-sense (p.Q178*) and a deletion (p.F277del) mutations in SERPINF1 gene, a missense mutation (p.M101K) in PPIB gene and a nonsense mutation (p.E45*) in CRTAP gene were identified. In three patients for whom the regions of homozygosity did not reveal any known autosomal recessive OI genes, exome sequencing was performed and we identified a known missense mutation (p.G1012S) in COL1A2 gene in one of the patients. As WNT1 gene was not properly covered in exome sequencing in one patient, the gene was sequenced and a homozygous in-frame deletion of four amino acids (p.Phe176_Leu179del) was identified. In one of the three cases the exome sequencing did not reveal a mutation in any known OI genes, suggesting the possibility of mutations in an unidentified gene. The phenotypes of all the cases are described. This work proves the power of homozygosity mapping followed by candidate gene sequencing approach for clinical application in consanguineous families. PMID:25450603

  5. Moroccan consanguineous family with Becker myotonia and review.

    PubMed

    Ratbi, Ilham; Elalaoui, Siham Chafai; Escudero, Adela; Kriouile, Yamina; Molano, Jesus; Sefiani, Abdelaziz

    2011-10-01

    Myotonia congenita is a genetic muscle disorder characterized by clinical and electrical myotonia, muscle hypertrophy, and stiffness. It is inherited as either autosomal-dominant or -recessive, known as Thomsen and Becker diseases, respectively. These diseases are distinguished by the severity of their symptoms and their patterns of inheritance. Becker disease usually appears later in childhood than Thomsen disease and causes more severe muscle stiffness and pain. Mutations in the muscular voltage-dependent chloride channel gene (CLCN1), located at 7q35, have been found in both types. We report here the case of a Moroccan consanguineous family with a myotonic autosomal-recessive condition in two children. The molecular studies showed that the patients reported here are homozygous for mutation p.Gly482Arg in the CLCN1 gene. The parents were heterozygote carriers for mutation p.Gly482Arg. This diagnosis allowed us to provide an appropriate management to the patients and to make a genetic counselling to their family. PMID:22346025

  6. Consanguinity profile in the Gaza Strip of Palestine: large-scale community-based study.

    PubMed

    Sirdah, Mahmoud M

    2014-02-01

    Consanguineous marriages which have been practiced throughout history continue to be practiced within different ethnic, religious and social groups to varying degrees with highest prevalences in North Africa, Middle East and central and south Asia. In the Gaza Strip of Palestine, little is known about the consanguinity profile, so the present large-scale study aims to explore the consanguinity profile of two generations using data from the ?-thalassemia premarital screening program. Sociodemographic data analysis included 156,635 (141,200 males and 15,435 females) persons and their parents, representing 141,200 couples who were referred to the Thalassemia and Hemophilia Center for premarital testing. In addition, the consanguinity characteristics of parents of 217 transfusion-dependent ?-thalassemic non-sibling patients were analyzed. Results revealed a significant decrease in the overall prevalence of consanguineous (first- and second-cousin) marriages between the previous (fathers') generation (45.2%) and the current (groom/bride) generation (39.9%). Among the five governorates of the Gaza Strip, records of Gaza Governorate revealed the lowest occurrence (36.9% current generation and 42.1% previous generation) of consanguineous marriages, as compared to all others. Consanguineous marriages are significantly higher in semi-urban areas (41.6%) than in urban areas (39.1%) in the current generation (previous generation, 46.4% vs 44.7%, respectively). Compound consanguinity (two generation) and a single level of consanguinity were seen in 20.7% and 43.7%, respectively, of the cases. The average age of those with first-cousin marriages is significantly lower (22.4±4.4 years) than those with second-cousin marriages (24.3±6.1 years) and the non-consanguineous (26.5±8.2 years). The rate of consanguineous marriages among never married people (42.2%) is significantly much higher than the rate of people with multiple marriages (18.1%). About 74.7% of the non-sibling thalassemic patients of the Gaza Strip are associated with consanguineous parents, of them 54.4% first-cousins and 20.3% second-cousins. In conclusion, although there is a decline in the consanguinity profile in the present compared to previous generation, consanguineous marriages are still a common practice in the Gaza Strip, which rationalizes the necessity for more awareness and counseling efforts about the potential health-related risks of consanguinity on individual lives and the population overall. PMID:24468669

  7. Autosomal recessive congenital cataract in consanguineous Pakistani families is associated with mutations in GALK1

    PubMed Central

    Yasmeen, Afshan; Kaul, Haiba; Mohsin, Sadia; Khan, Mohsin; Qazi, Zaheeruddin A.; Nasir, Idrees A.; Zafar, Ahmad U.; Khan, Shaheen N.; Husnain, Tayyab; Akram, Javed; Hejtmancik, J. Fielding

    2010-01-01

    Purpose To identify the pathogenic mutations responsible for autosomal recessive congenital cataracts in consanguineous Pakistani families. Methods All affected individuals underwent detailed ophthalmologic and medical examination. Blood samples were collected and genomic DNA was extracted. A genome-wide scan was performed with polymorphic microsatellite markers on genomic DNA from affected and unaffected family members and logarithm of odds (LOD) scores were calculated. All coding exons of galactokinase (GALK1) were sequenced to identify pathogenic lesions. Results Clinical records and ophthalmological examinations suggested that affected individuals have nuclear cataracts. Linkage analysis localized the critical interval to chromosome 17q with a maximum LOD score of 5.54 at ?=0, with D17S785 in family PKCC030. Sequencing of GALK1, a gene present in the critical interval, identified a single base pair deletion: c.410delG, which results in a frame shift leading to a premature termination of GALK1: p.G137fsX27. Additionally, we identified a missense mutation: c.416T>C, in family PKCC055 that results in substitution of a leucine residue at position 139 with a proline residue: p.L139P, and is predicted to be deleterious to the native GALK1 structure. Conclusions Here, we report pathogenic mutations in GALK1 that are responsible for autosomal recessive congenital cataracts in consanguineous Pakistani families. PMID:20405025

  8. Identification of a novel IVD mutation in a consanguineous family with isovaleric acidemia.

    PubMed

    Kaya, Namik; Colak, Dilek; Al-Bakheet, Albandary; Al-Younes, Banan; Tulbah, Sahar; Daghestani, Maha; Al-Mutairi, Fuad; Al-Amoudi, Mohammed; Al-Odaib, Ali; Al-Aqeel, Aida I

    2013-01-25

    Isovaleric acidemia (IVA) is a rare autosomal recessive disorder caused by a deficiency of isovaleryl-CoA dehydrogenase encoded by IVD gene. In this case study we report the first Saudi IVA patients from a consanguineous family with a novel transversion (p.G362V) and briefly discuss likely phenotype-genotype correlation of the disease in the Saudi population. We explored the functional consequences of the mutation by using various bioinformatics prediction algorithms and discussed the likely mechanism of the disease caused by the mutation. PMID:23063737

  9. 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

  10. 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

  11. Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness

    PubMed Central

    Naeem, Muhammad Asif; Gottsch, Alexander D. H.; Ullah, Inayat; 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 undertaken to investigate the causal mutations responsible for autosomal recessive congenital stationary night blindness (CSNB) in consanguineous Pakistani families. Methods Two consanguineous families with multiple individuals manifesting symptoms of stationary night blindness were recruited. Affected individuals underwent a detailed ophthalmological examination, including fundus examination and electroretinography. Blood samples were collected and genomic DNA was extracted. Exclusion analyses were completed by genotyping closely spaced microsatellite markers, and two-point logarithm of odds (LOD) scores were calculated. All coding exons, along with the exon–intron boundaries of GRM6, were sequenced bidirectionally. Results According to the medical history available to us, affected individuals in both families had experienced night blindness from the early years of their lives. Fundus photographs of affected individuals in both the families appeared normal, with no signs of attenuated arteries or bone spicule pigmentation. The scotopic electroretinogram (ERG) response were absent in all of the affected individuals, while the photopic measurements show reduced b-waves. During exclusion analyses, both families localized to a region on chromosome 5q that harbors GRM6, a gene previously associated with autosomal recessive CSNB. Bidirectional sequencing of GRM6 identified homozygous single base pair changes, specifically c.1336C>T (p.R446X) and c.2267G>A (p.G756D) in families PKRP170 and PKRP172, respectively. Conclusions We identified a novel nonsense and a previously reported missense mutation in GRM6 that were responsible for autosomal recessive CSNB in patients of Pakistani decent. PMID:26628857

  12. 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

  13. Sclerosteosis caused by a novel nonsense mutation of SOST in a consanguineous family.

    PubMed

    He, Wen-Tao; Chen, Chen; Pan, Chu; Zhang, Mu-Xun; Yu, Xue-Feng; Wang, Dao-Wen; Hu, Shu-Hong

    2016-02-01

    Sclerosteosis, characterized by the hyperostosis of cranial and tubular bones, is a rare autosomal recessive hereditary disorder caused by mutation of SOST gene. Four nonsense mutations of SOST have been identified worldwide. Here, we report two affected siblings who carried a novel nonsense mutation of SOST in a consanguineous family from China. The proband manifested typical symptoms of sclerosteosis, whereas the symptoms were absent in another affected sibling. Two nucleotide substitutions in exon 2 of SOST were identified, c.444_445TC>AA, resulting in a premature stop codon, p.Cys148?Stop. This truncated mutation loses 66 amino acid residues which contain 3 cysteine residues of the cysteine-knot motif, leading to loss of function of SOST. The symptoms of sclerosteosis may be clinically heterogeneous in some patients, even with the same mutation. Our results support the notion that founder effects from the ancestors contribute to the disease onset. PMID:26283468

  14. 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

  15. Homozygous sequence variants in the FKBP10 gene underlie osteogenesis imperfecta in consanguineous families.

    PubMed

    Umair, Muhammad; Hassan, Annum; Jan, Abid; Ahmad, Farooq; Imran, Muhammad; Samman, Muhammad I; Basit, Sulman; Ahmad, Wasim

    2016-03-01

    Osteogenesis imperfecta (OI, MIM 610968) is a genetically and clinically heterogeneous disorder characterized by bone fragility. It is one of the rare forms of skeletal deformity caused by sequence variants in at least 14 different genes, including FKBP10 (MIM 607063) encoding protein FKBP65. Here we present three consanguineous families of Pakistani origin segregating OI in an autosomal-recessive pattern. Genotyping using either single-nucleotide polymorphism markers by Affymetrix GeneChip Human Mapping 250K Nsp array or polymorphic microsatellite markers revealed a homozygous region, containing a candidate gene FKBP10, among affected members on chromosome 17q21.2. Sequencing the FKBP10 gene revealed a homozygous novel nonsense variant (c.1490G>A, p.Trp497*) in the family A and two previously reported variants, including a missense (c.344G>A, p.Arg115Gln), in the family B and duplication of a nucleotide C (c.831dupC, p.Gly278ArgfsX295) in the family C. Our findings further extend the body of evidence that supports the importance of FKBP10 gene in the development of skeletal system. PMID:26538303

  16. Mutations in the ?-subunit of rod phosphodiesterase identified in consanguineous Pakistani families with autosomal recessive retinitis pigmentosa

    PubMed Central

    Ali, Shahbaz; Riazuddin, S. Amer; Shahzadi, Amber; Nasir, Idrees A.; Khan, Shaheen N.; Husnain, Tayyab; Akram, Javed; Sieving, Paul A.; Hejtmancik, J. Fielding

    2011-01-01

    Purpose This study was designed to identify pathogenic mutations causing autosomal recessive retinitis pigmentosa (RP) in consanguineous Pakistani families. Methods Two consanguineous families affected with autosomal recessive RP were identified from the Punjab Province of Pakistan. All affected individuals underwent a thorough ophthalmologic examination. Blood samples were collected, and genomic DNAs were extracted. Exclusion analysis was completed, and two-point LOD scores were calculated. Bidirectional sequencing of the ? subunit of phosphodiesterase 6 (PDE6?) was completed. Results During exclusion analyses both families localized to chromosome 4p, harboring PDE6?, a gene previously associated with autosomal recessive RP. Sequencing of PDE6? identified missense mutations: c.1655G>A (p.R552Q) and c.1160C>T (p.P387L) in families PKRP161 and PKRP183, respectively. Bioinformatic analyses suggested that both mutations are deleterious for the native three-dimensional structure of the PDE6? protein. Conclusions These results strongly suggest that mutations in PDE6? are responsible for the disease phenotype in the consanguineous Pakistani families. PMID:21655355

  17. Diagnostic exome sequencing for patients with a family history of consanguinity: over 38% of positive results are not autosomal recessive pattern.

    PubMed

    Powis, Zöe; Farwell, Kelly D; Alamillo, Christina L; Tang, Sha

    2016-02-01

    Diagnostic exome sequencing (DES) is an effective tool for diagnosis in intractable cases where the underlying cause is thought be genetic. It is commonly assumed that patients with a family history of consanguinity will have increased detection rates for rare autosomal recessive Mendelian disorders through DES. Herein, we analyzed the diagnostic yield and relevant inheritance patterns within the DES cases with a reported consanguineous family history. Of the first 500 unselected cases referred for DES, 40 (8.0%) had a known consanguineous family history. Among the 40 cases, 13 (32.5%) received a definitive molecular diagnosis through DES and such positive rate is similar to that of families with no reported consanguinity (139/460, 30.2%, P=0.63). Although homozygous alterations likely related to consanguinity have been identified in eight positive cases, the other five (38.4%) causative mutations were unrelated to autosomal recessive inheritance. Our retrospective analysis demonstrated that individuals with known consanguinity were not more likely to have a positive DES result and a significant portion of the positive findings were not within an autosomal recessive gene. These results highlight that all applicable inheritance patterns should be considered for patients with a known family history of consanguinity. PMID:26490185

  18. Autosomal recessive congenital cataract linked to EPHA2 in a consanguineous Pakistani family

    PubMed Central

    Kaul, Haiba; Riazuddin, S. Amer; Shahid, Mariam; Kousar, Samra; Butt, Nadeem H.; Zafar, Ahmad U.; Khan, Shaheen N.; Husnain, Tayyab; Akram, Javed; Hejtmancik, J. Fielding

    2010-01-01

    Purpose To investigate the genetic basis of autosomal recessive congenital cataracts in a consanguineous Pakistani family. Methods All affected individuals underwent a detailed ophthalmological and clinical examination. Blood samples were collected and genomic DNAs were extracted. A genome-wide scan was performed with polymorphic microsatellite markers. Logarithm of odds (LOD) scores were calculated, and Eph-receptor type-A2 (EPHA2), residing in the critical interval, was sequenced bidirectionally. Results The clinical and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Genome-wide linkage analyses localized the critical interval to a 20.78 cM (15.08 Mb) interval on chromosome 1p, with a maximum two-point LOD score of 5.21 at ?=0. Sequencing of EPHA2 residing in the critical interval identified a missense mutation: c.2353G>A, which results in an alanine to threonine substitution (p.A785T). Conclusions Here, we report for the first time a missense mutation in EPHA2 associated with autosomal recessive congenital cataracts. PMID:20361013

  19. A novel homozygous ISPD gene mutation causing phenotype variability in a consanguineous family.

    PubMed

    Baranello, Giovanni; Saredi, Simona; Sansanelli, Serena; Savadori, Paolo; Canioni, Eleonora; Chiapparini, Luisa; Balestri, Paolo; Malandrini, Alessandro; Arnoldi, Maria Teresa; Pantaleoni, Chiara; Morandi, Lucia; Mora, Marina

    2015-01-01

    Within the group of muscular dystrophies, dystroglycanopathies represent an important subgroup of recessively inherited disorders. Their severity varies from the relatively mild forms of adult-onset limb-girdle muscular dystrophy (LGMD), to the severe congenital muscular dystrophies (CMD) with cerebral and ocular involvement. We describe 2 consanguineous children of Pakistani origin, carrying a new homozygous missense mutation c.367G>A (p.Gly123Arg) in the ISPD gene. Mutations in this gene have been recently reported as a common cause of congenital and limb-girdle muscular dystrophy. Patient 1 is an 8-year-old female with an intermediate phenotype between CMD and early LGMD; patient 2 is a 20-month-old male and second cousin of patient 1, showing a CMD phenotype. Cognitive development, brain MRI, eye examination, electrocardiogram and echocardiogram were normal in both patients. To our knowledge, this is the first report on the co-occurrence of both a CMD/early LGMD intermediate phenotype and a CMD within the same family carrying a homozygous ISPD mutation. PMID:25444434

  20. A novel missense NMNAT1 mutation identified in a consanguineous family with Leber congenital amaurosis by targeted next generation sequencing.

    PubMed

    Deng, Ying; Huang, Hui; Wang, Yanping; Liu, Zhen; Li, Nana; Chen, Yanhua; Li, Xin; Li, Mingrong; Zhou, Xiaobo; Mu, Dezhi; Zhong, Jing; Wu, Jing; Su, Yan; Yi, Xin; Zhu, Jun

    2015-09-10

    Leber congenital amaurosis is the earliest onset and most severe inherited retinal dystrophy. Mutations in 21 genes have been identified to be responsible for LCA. To detect the causative variants, we performed targeted next generation sequencing in two affected siblings of a consanguineous Chinese family with suspected LCA. A novel homozygous missense mutation (c.721C>T, p. Pro241Ser) of NMNAT1 has been identified. The mutation was inherited from their consanguineous parents who were heterozygous and was absent in 300 unrelated healthy individuals. NMNAT1, which encodes the nicotinamide mononucleotide adenylyltransferase 1, has been recently identified to be one of the LCA-causing genes. Our results expanded the spectrum of mutations in NMNAT1. In this study, targeted next generation sequencing provides an accurate and efficient method for identifying mutations in hereditary diseases with highly genetic and clinical heterogeneity. PMID:25988908

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

    PubMed Central

    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

    Purpose To identify the genetic defect of a consanguineous Portuguese family with rod-cone dystrophy and varying degrees of decreased audition. Methods 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. Results 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. Conclusions 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. PMID:21738389

  2. 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. PMID:24777706

  3. Specific aspects of consanguinity: some examples from the Tunisian population.

    PubMed

    Romdhane, Lilia; Ben Halim, Nizar; Rejeb, Insaf; Kefi, Rym; Bouyacoub, Yosra; Ben Rekaya, Mariem; Messai, Habib; Messaoud, Olfa; Riahi, Zied; Bonnet, Crystel; Ben Rhouma, Faten; Nagara, Majdi; Petit, Christine; McElreavey, Ken; Romeo, Giovanni; Abdelhak, Sonia

    2014-01-01

    Located at the cross-road between Europe and Africa, Tunisia is a North African country of 11 million inhabitants. Throughout its history, it has been invaded by different ethnic groups. These historical events, and consanguinity, have impacted on the spectrum and frequency of genetic diseases in Tunisia. Investigations of Tunisian families have significantly contributed to elucidation of the genetic bases of rare disorders, providing an invaluable resource of cases due to particular familial structures (large family size, consanguinity and share of common ancestors). In the present study, we report on and review different aspects of consanguinity in the Tunisian population as a case study, representing several features common to neighboring or historically related countries in North Africa and the Middle East. Despite the educational, demographic and behavioral changes that have taken place during the last four decades, familial and geographical endogamy still exist at high frequencies, especially in rural areas. The health implications of consanguinity in Tunisian families include an increased risk of the expression of autosomal recessive diseases and particular phenotypic expressions. With new sequencing technologies, the investigation of consanguineous populations provides a unique opportunity to better evaluate the impact of consanguinity on the genome dynamic and on health, in addition to a better understanding of the genetic bases of diseases. PMID:25060280

  4. Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy

    PubMed Central

    Nikopoulos, Konstantinos; Avila-Fernandez, Almudena; Corton, Marta; Lopez-Molina, Maria Isabel; Perez-Carro, Raquel; Bontadelli, Lara; Di Gioia, Silvio Alessandro; Zurita, Olga; Garcia-Sandoval, Blanca; Rivolta, Carlo; Ayuso, Carmen

    2015-01-01

    Inherited retinal dystrophies present extensive phenotypic and genetic heterogeneity, posing a challenge for patients’ molecular and clinical diagnoses. In this study, we wanted to clinically characterize and investigate the molecular etiology of an atypical form of autosomal recessive retinal dystrophy in two consanguineous Spanish families. Affected members of the respective families exhibited an array of clinical features including reduced visual acuity, photophobia, defective color vision, reduced or absent ERG responses, macular atrophy and pigmentary deposits in the peripheral retina. Genetic investigation included autozygosity mapping coupled with exome sequencing in the first family, whereas autozygome-guided candidate gene screening was performed by means of Sanger DNA sequencing in the second family. Our approach revealed nucleotide changes in CDHR1; a homozygous missense variant (c.1720C > G, p.P574A) and a homozygous single base transition (c.1485 + 2T > C) affecting the canonical 5’ splice site of intron 13, respectively. Both changes co-segregated with the disease and were absent among cohorts of unrelated control individuals. To date, only five mutations in CDHR1 have been identified, all resulting in premature stop codons leading to mRNA nonsense mediated decay. Our work reports two previously unidentified homozygous mutations in CDHR1 further expanding the mutational spectrum of this gene. PMID:26350383

  5. Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy.

    PubMed

    Nikopoulos, Konstantinos; Avila-Fernandez, Almudena; Corton, Marta; Lopez-Molina, Maria Isabel; Perez-Carro, Raquel; Bontadelli, Lara; Di Gioia, Silvio Alessandro; Zurita, Olga; Garcia-Sandoval, Blanca; Rivolta, Carlo; Ayuso, Carmen

    2015-01-01

    Inherited retinal dystrophies present extensive phenotypic and genetic heterogeneity, posing a challenge for patients' molecular and clinical diagnoses. In this study, we wanted to clinically characterize and investigate the molecular etiology of an atypical form of autosomal recessive retinal dystrophy in two consanguineous Spanish families. Affected members of the respective families exhibited an array of clinical features including reduced visual acuity, photophobia, defective color vision, reduced or absent ERG responses, macular atrophy and pigmentary deposits in the peripheral retina. Genetic investigation included autozygosity mapping coupled with exome sequencing in the first family, whereas autozygome-guided candidate gene screening was performed by means of Sanger DNA sequencing in the second family. Our approach revealed nucleotide changes in CDHR1; a homozygous missense variant (c.1720C>G, p.P574A) and a homozygous single base transition (c.1485+2T>C) affecting the canonical 5' splice site of intron 13, respectively. Both changes co-segregated with the disease and were absent among cohorts of unrelated control individuals. To date, only five mutations in CDHR1 have been identified, all resulting in premature stop codons leading to mRNA nonsense mediated decay. Our work reports two previously unidentified homozygous mutations in CDHR1 further expanding the mutational spectrum of this gene. PMID:26350383

  6. Effect of consanguinity among North India Muslims.

    PubMed

    Basu, S K

    1975-01-01

    Endogamous Muslim groups in Delhi and Lucknow, India, were studied to discover the effects of consanguineous marriage on fertility, mortality, and net-fertility rates. Sayyad Shias have a much higher frequency of parental consanguinity. Consanguineous marriages occurred among the following groups in descending order of frequency: Sheikh, Pathan, and Moghul Sumnis. Different forms of inbreeding occurred among the various groups. Most Muslims oppose family planning on religous grounds. In both Sayyad Shias and Sheikh Sumni consanguineous marriages there was a higher fertility rate than among non-consanguineous marriages. The net-fertility rate was not higher, because mortality before 21 was highest among first cousins. PMID:12307582

  7. 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. PMID:25060273

  8. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.

    PubMed

    Alazami, Anas M; Patel, Nisha; Shamseldin, Hanan E; Anazi, Shamsa; Al-Dosari, Mohammed S; Alzahrani, Fatema; Hijazi, Hadia; Alshammari, Muneera; Aldahmesh, Mohammed A; Salih, Mustafa A; Faqeih, Eissa; Alhashem, Amal; Bashiri, Fahad A; Al-Owain, Mohammed; Kentab, Amal Y; Sogaty, Sameera; Al Tala, Saeed; Temsah, Mohamad-Hani; Tulbah, Maha; Aljelaify, Rasha F; Alshahwan, Saad A; Seidahmed, Mohammed Zain; Alhadid, Adnan A; Aldhalaan, Hesham; AlQallaf, Fatema; Kurdi, Wesam; Alfadhel, Majid; Babay, Zainab; Alsogheer, Mohammad; Kaya, Namik; Al-Hassnan, Zuhair N; Abdel-Salam, Ghada M H; Al-Sannaa, Nouriya; Al Mutairi, Fuad; El Khashab, Heba Y; Bohlega, Saeed; Jia, Xiaofei; Nguyen, Henry C; Hammami, Rakad; Adly, Nouran; Mohamed, Jawahir Y; Abdulwahab, Firdous; Ibrahim, Niema; Naim, Ewa A; Al-Younes, Banan; Meyer, Brian F; Hashem, Mais; Shaheen, Ranad; Xiong, Yong; Abouelhoda, Mohamed; Aldeeri, Abdulrahman A; Monies, Dorota M; Alkuraya, Fowzan S

    2015-01-13

    Our knowledge of disease genes in neurological disorders is incomplete. With the aim of closing this gap, we performed whole-exome sequencing on 143 multiplex consanguineous families in whom known disease genes had been excluded by autozygosity mapping and candidate gene analysis. This prescreening step led to the identification of 69 recessive genes not previously associated with disease, of which 33 are here described (SPDL1, TUBA3E, INO80, NID1, TSEN15, DMBX1, CLHC1, C12orf4, WDR93, ST7, MATN4, SEC24D, PCDHB4, PTPN23, TAF6, TBCK, FAM177A1, KIAA1109, MTSS1L, XIRP1, KCTD3, CHAF1B, ARV1, ISCA2, PTRH2, GEMIN4, MYOCD, PDPR, DPH1, NUP107, TMEM92, EPB41L4A, and FAM120AOS). We also encountered instances in which the phenotype departed significantly from the established clinical presentation of a known disease gene. Overall, a likely causal mutation was identified in >73% of our cases. This study contributes to the global effort toward a full compendium of disease genes affecting brain function. PMID:25558065

  9. Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families.

    PubMed

    Hebrard, Maxime; Manes, Gaël; Bocquet, Béatrice; Meunier, Isabelle; Coustes-Chazalette, Delphine; Hérald, Emilie; Sénéchal, Audrey; Bolland-Augé, Anne; Zelenika, Diana; Hamel, Christian P

    2011-12-01

    Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization. PMID:21792230

  10. Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families

    PubMed Central

    Hebrard, Maxime; Manes, Gaël; Bocquet, Béatrice; Meunier, Isabelle; Coustes-Chazalette, Delphine; Hérald, Emilie; Sénéchal, Audrey; Bolland-Augé, Anne; Zelenika, Diana; Hamel, Christian P

    2011-01-01

    Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ?60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization. PMID:21792230

  11. 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

  12. 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. PMID:25060276

  13. Non-progressive cerebellar ataxia, aplasia of pupillary zone of iris, and mental subnormality (Gillespie's syndrome) affecting 3 members of a non-consanguineous family in 2 generations.

    PubMed Central

    Crawfurd, M D; Harcourt, R B; Shaw, P A

    1979-01-01

    A family is reported in which a brother and sister both showed non-progressive cerebellar ataxia, aplasia of the pupillary zone of the iris, and mild mental subnormality. These clinical findings were similar to those in two previous case reports. Despite the birth of an affected son to the affected sister, this family is considered to confirm autosomal recessive inheritance of this syndrome. The paternity of the mother's husband is supported by blood groups and biochemical markers and it is presumed that the husband is a heterozygote, even though no consanguinity could be detected. Images PMID:513084

  14. Mutations in LAMA2 and CAPN3 genes associated with genetic and phenotypic heterogeneities within a single consanguineous family involving both congenital and progressive muscular dystrophies.

    PubMed

    Hadj Salem, Ikhlass; Kamoun, Fatma; Louhichi, Nacim; Rouis, Souad; Mziou, Mariam; Fendri-Kriaa, Nourhene; Makni-Ayadi, Fatma; Triki, Chahnez; Fakhfakh, Faiza

    2011-04-01

    LGMD (limb-girdle muscular dystrophy) and CMD (congenital muscular dystrophy) are two common forms of neuromuscular disorders which are distinguishable by their age of onset but with probably a similar underlying pathway. In the present study, we report immunohistochemical, Western-blot and genetic analyses in a large consanguineous Tunisian family with two branches, including seven patients sharing similar LGMD2 phenotype in one branch and one CMD patient in the other branch. Linkage analyses were compatible with the LGMD2A locus in one branch and the MDC1A (muscular dystrophy congenital type 1A) locus in the other branch. This result was supported by deficiency in merosin and calpain3 in the CMD patient and LGMD patients respectively. Mutation analysis revealed two distinct mutations: a c.8005delT frameshift deletion in exon 56 of the LAMA2 (laminin-?2) gene (MDC1A) was found in the CMD patient and a new homozygous mutation c.1536+1G>T in the donor splice site of intron 12 of the CAPN3 (calpain3) gene (LGMD2A) was found in the LGMD patients. RT-PCR (reverse transcription-PCR) performed on total RNA from a LGMD2A patient's muscle biopsy showed complete retention of intron 12 in CAPN3 cDNA, generating a PTC (premature termination codon) that potentially elicits degradation of the nonsense mRNA by NMD (nonsense-mediated mRNA decay). Our results indicate that mRNA analysis is necessary to clarify the primary effect of genomic mutations on splicing efficiency that alters mRNA processing and expression level. PMID:20477750

  15. Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome.

    PubMed

    Aziz, Abdul; Raza, Syed I; Ali, Salman; Ahmad, Wasim

    2016-01-01

    Ellis-van Creveld syndrome (EVC) is a rare developmental disorder characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, teeth, oral and cardiac abnormalities. It is caused by biallelic mutations in the EVC or EVC2 gene, separated by 2.6 kb of genomic sequence on chromosome 4p16. In the present study, we have investigated two consanguineous families of Pakistani origin, segregating EVC in autosomal recessive manner. Linkage in the families was established to chromosome 4p16. Subsequently, sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families. This further expands the mutations in the EVC or EVC2 genes resulting in the EVC syndrome. PMID:26580685

  16. The Use of High-Density SNP Array to Map Homozygosity in Consanguineous Families to Efficiently Identify Candidate Genes: Application to Woodhouse-Sakati Syndrome.

    PubMed

    Sheridan, Molly B; Wohler, Elizabeth; Batista, Denise A S; Applegate, Carolyn; Hoover-Fong, Julie

    2015-01-01

    Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1?Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified. PMID:26664771

  17. The Use of High-Density SNP Array to Map Homozygosity in Consanguineous Families to Efficiently Identify Candidate Genes: Application to Woodhouse-Sakati Syndrome

    PubMed Central

    Sheridan, Molly B.; Wohler, Elizabeth; Batista, Denise A. S.; Applegate, Carolyn; Hoover-Fong, Julie

    2015-01-01

    Two consanguineous Qatari siblings presented for evaluation: a 17-4/12-year-old male with hypogonadotropic hypogonadism, alopecia, intellectual disability, and microcephaly and his 19-year-old sister with primary amenorrhea, alopecia, and normal cognition. Both required hormone treatment to produce secondary sex characteristics and pubertal development beyond Tanner 1. SNP array analysis of both probands was performed to detect shared regions of homozygosity which may harbor homozygous mutations in a gene causing their common features of abnormal pubertal development, alopecia, and variable cognitive delay. Our patients shared multiple homozygous genomic regions; ten shared regions were >1 Mb in length and constituted 0.99% of the genome. DCAF17, encoding a transmembrane nuclear protein of uncertain function, was the only gene identified in a homozygous region known to cause hypogonadotropic hypogonadism. DCAF17 mutations are associated with Woodhouse-Sakati syndrome, a rare disorder characterized by alopecia, hypogonadotropic hypogonadism, sensorineural hearing loss, diabetes mellitus, and extrapyramidal movements. Sequencing of the coding exons and flanking intronic regions of DCAF17 in the proband revealed homozygosity for a previously described founder mutation (c.436delC). Targeted DCAF17 sequencing of his affected sibling revealed the same homozygous mutation. This family illustrates the utility of SNP array testing in consanguineous families to efficiently and inexpensively identify regions of genomic homozygosity in which genetic candidates for recessive conditions can be identified. PMID:26664771

  18. Homozygous p.G61E mutation in a consanguineous Pakistani family with co-existence of juvenile-onset open angle glaucoma and primary congenital glaucoma.

    PubMed

    Bashir, Rasheeda; Tahir, Hafsa; Yousaf, Khazeema; Naz, Shagufta; Naz, Sadaf

    2015-10-10

    Glaucoma is one of the primary causes of visual impairment and blindness in the world. It is characterized by the damage to the optic nerve head and visual field loss. Variants in CYP1B1 are the most common cause of glaucoma in different world populations. We studied a consanguineous Pakistani family in which three affected individuals had a severe form of glaucoma with members in one generation diagnosed with juvenile-onset open angle glaucoma at 27 years of age, while the members of the next generation were affected with primary congenital glaucoma with onset at birth. Sequencing of CYP1B1 revealed a homozygous transition variant, c.182G>A, p.G61E which co-segregated with the disease phenotype. This variant has been previously reported to cause both recessively and dominantly inherited PCG and JOAG in different populations. However, this reported for the first time in Pakistani PCG and JOAG patients in a homozygous state. This is also the first ever report of a CYP1B1 variant segregating in a consanguineous family with co-existence of JOAG and PCG in two subsequent generations. This observation of different phenotypes due to an identical mutation suggests that primary congenital glaucoma and juvenile-onset open angle glaucoma can both be caused by homozygosity for the same mutation. It also indicates the reduced penetrance of the variant in those affected due to p.G61E mutation and further implies that modifiers have a role in controlling the time of onset of the disorder. PMID:26164761

  19. 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

  20. The alkylglycerol monooxygenase (AGMO) gene previously involved in autism also causes a novel syndromic form of primary microcephaly in a consanguineous Saudi family.

    PubMed

    Alrayes, Nuha; Mohamoud, Hussein Sheikh Ali; Ahmed, Saleem; Almramhi, Mona Mohammad; Shuaib, Taghreed Mohammad; Wang, Jun; Al-Aama, Jumana Yousuf; Everett, Kate; Nasir, Jamal; Jelani, Musharraf

    2016-04-15

    Autosomal recessive primary microcephaly (MCPH) refers to a genetically heterogeneous group of neurodevelopmental disorders in which patients exhibit a marked decrease in occipitofrontal head circumference at birth and a variable degree of intellectual disability. To date, 18 genes have been reported for MCPH worldwide. We enrolled a consanguineous family from Saudi Arabia presenting with primary microcephaly, developmental delay, short stature and intellectual disability. Whole exome sequencing (WES) with 100× coverage was performed on two affected siblings after defining common regions of homozygosity through genome-wide single nucleotide polymorphism (SNP) microarray genotyping. WES data analysis, confirmed by subsequent Sanger sequence validation, identified a novel homozygous deletion mutation (c.967delA; p.Glu324Lysfs12*) in exon 10 of the alkylglycerol monooxygenase (AGMO) gene on chromosome 7p21.2. Population screening of 178 ethnically matched control chromosomes and consultation of the Exome Aggregation Consortium database, containing 60,706 individuals' exomes worldwide, confirmed that this mutation was not present outside the family. To the best of our knowledge, this is the first evidence of an AGMO mutation underlying primary microcephaly and intellectual disability in humans. Our findings further expand the genetic heterogeneity of MCPH in familial cases. PMID:27000257

  1. 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…

  2. 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…

  3. 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. PMID:26205306

  4. Integration of sequence data from a Consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene.

    PubMed

    Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D; Mouassess, Faten; Achkar, Walid A L; Fulton, Robert S; Denny, Joshua C; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M; Pappas, Dimitrios A; Carroll, Robert J; Eyler, Anne E; Trynka, Gosia; Stahl, Eli A; Cui, Jing; Saxena, Richa; Coenen, Marieke J H; Guchelaar, Henk-Jan; Huizinga, Tom W J; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhão, Helena; Fonseca, João E; de Vries, Niek; Tak, Paul P; Moreland, Larry W; Bridges, S Louis; Miceli-Richard, Corinne; Choi, Hyon K; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A; Gregersen, Peter K; Mardis, Elaine R; Arayssi, Thurayya; Kazkaz, Layla A; Plenge, Robert M

    2014-01-01

    Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2 × 10(-6)). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. PMID:24520335

  5. Integration of Sequence Data from a Consanguineous Family with Genetic Data from an Outbred Population Identifies PLB1 as a Candidate Rheumatoid Arthritis Risk Gene

    PubMed Central

    Okada, Yukinori; Diogo, Dorothee; Greenberg, Jeffrey D.; Mouassess, Faten; Achkar, Walid A. L.; Fulton, Robert S.; Denny, Joshua C.; Gupta, Namrata; Mirel, Daniel; Gabriel, Stacy; Li, Gang; Kremer, Joel M.; Pappas, Dimitrios A.; Carroll, Robert J.; Eyler, Anne E.; Trynka, Gosia; Stahl, Eli A.; Cui, Jing; Saxena, Richa; Coenen, Marieke J. H.; Guchelaar, Henk-Jan; Huizinga, Tom W. J.; Dieudé, Philippe; Mariette, Xavier; Barton, Anne; Canhão, Helena; Fonseca, João E.; de Vries, Niek; Tak, Paul P.; Moreland, Larry W.; Bridges, S. Louis; Miceli-Richard, Corinne; Choi, Hyon K.; Kamatani, Yoichiro; Galan, Pilar; Lathrop, Mark; Raj, Towfique; De Jager, Philip L.; Raychaudhuri, Soumya; Worthington, Jane; Padyukov, Leonid; Klareskog, Lars; Siminovitch, Katherine A.; Gregersen, Peter K.; Mardis, Elaine R.; Arayssi, Thurayya; Kazkaz, Layla A.; Plenge, Robert M.

    2014-01-01

    Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P?=?0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF?=?0.042] and rs116541814 [MAF?=?0.021], combined P?=?3.2×10?6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P?=?0.049 for C-alpha test and P?=?0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. PMID:24520335

  6. Profiling ? Thalassemia Mutations in Consanguinity and Nonconsanguinity for Prenatal Screening and Awareness Programme

    PubMed Central

    Kumar, Ravindra; Arya, Vandana; Agarwal, Sarita

    2015-01-01

    Mutation spectrum varies significantly in different parts and different ethnic groups of India. Social factors such as preference to marry within the community and among 1st degree relatives (consanguinity) play an important role in impeding the gene pool of the disease within the community and so in society by and large. The present paper discusses the role of consanguinity in profiling of beta thalassemia mutation, and thus the approach for prenatal screening and prevention based awareness programme. Clinically diagnosed 516 cases of beta thalassemia were screened at molecular level. A detailed clinical Proforma was recorded with the information of origin of the family, ethnicity, and consanguinity. The present study reports that subjects originating from Uttar Pradesh, Uttarakhand, Bihar, and Jharkhand have c.92+5G>C and c.124_127delTTCT mutation as the commonest mutation compared to the subjects hailing from Madhya Pradesh and Chhattisgarh and Nepal where sickle mutation was found more common. In 40 consanguineous unions more common and specific beta mutations with higher rate of homozygosity have been reported. This consanguinity-based data helps not only in deciding target oriented prenatal diagnostic strategies but also in objective based awareness programmes in prevention of thalassemia major birth. PMID:26576156

  7. Profiling ? Thalassemia Mutations in Consanguinity and Nonconsanguinity for Prenatal Screening and Awareness Programme.

    PubMed

    Kumar, Ravindra; Arya, Vandana; Agarwal, Sarita

    2015-01-01

    Mutation spectrum varies significantly in different parts and different ethnic groups of India. Social factors such as preference to marry within the community and among 1st degree relatives (consanguinity) play an important role in impeding the gene pool of the disease within the community and so in society by and large. The present paper discusses the role of consanguinity in profiling of beta thalassemia mutation, and thus the approach for prenatal screening and prevention based awareness programme. Clinically diagnosed 516 cases of beta thalassemia were screened at molecular level. A detailed clinical Proforma was recorded with the information of origin of the family, ethnicity, and consanguinity. The present study reports that subjects originating from Uttar Pradesh, Uttarakhand, Bihar, and Jharkhand have c.92+5G>C and c.124_127delTTCT mutation as the commonest mutation compared to the subjects hailing from Madhya Pradesh and Chhattisgarh and Nepal where sickle mutation was found more common. In 40 consanguineous unions more common and specific beta mutations with higher rate of homozygosity have been reported. This consanguinity-based data helps not only in deciding target oriented prenatal diagnostic strategies but also in objective based awareness programmes in prevention of thalassemia major birth. PMID:26576156

  8. Marked parental consanguinity as a cause for increased major malformations in an Israeli Arab community.

    PubMed

    Jaber, L; Merlob, P; Bu, X; Rotter, J I; Shohat, M

    1992-09-01

    It is common among Israeli Arabs who live in the villages to prefer consanguineous marriages, particularly among first cousins. In addition, such villages are populated by a few (less than 20) original families, and inter-family/inter-village marriages are infrequent. The purpose of this study was to examine the consequences of such "consanguinity" in Taibe, a large Arab village, 30 km from Tel Aviv. Six hundred ten families were prospectively ascertained through infants who were routinely seen in the local "Well Baby Clinics." A significant increase in the incidence of major malformations was noted in relation to the closeness of the parental relationship. For the index cases group the prevalence of individuals with major malformations were 5.8% in the product of inter-village marriages, 8.3% in the intra-village non-related matings, 15.1% in the distant consanguineous group, and up to 15.8% in the progeny of first-cousin marriages (P less than 0.001). In the siblings of these index cases, the frequency of major malformations was 4.3%, 4.5%, 10.5%, and 10.3%, respectively. Analysis of the major malformations by each body system showed the same trend. The study demonstrates a marked high rate of consanguineous marriages, whose effect leads to a marked increase in major malformations and thus a prominent public health problem in such villages. This requires a unique genetic counseling approach. PMID:1519638

  9. Consanguinity and reproductive wastage in the Palestinian Territories.

    PubMed

    Assaf, Shireen; Khawaja, Marwan; DeJong, Jocelyn; Mahfoud, Ziad; Yunis, Khalid

    2009-03-01

    Many studies have found that consanguinity poses a threat to child mortality and health and can also pose a threat to offspring survival before birth. However, there are conflicting findings with some studies having found no increased risk on offspring survival associated with consanguinity. Data from a population-based survey conducted in 2004 in the Palestinian Territories was used to assess the risk of consanguinity on offspring survival. The analysis was conducted on 4418 women aged 15-49 who were asked whether or not they had experienced a stillbirth or a spontaneous abortion. These two outcomes were combined together for the analysis of reproductive wastage. Multivariable negative binomial regression was conducted to calculate the incidence risk ratios (IRR) for each region in the Palestinian Territories separately. The strongest risk factors for reproductive wastage, after controlling for other variables, were found to be consanguinity, age and parity with age presenting the highest IRRs. Standard of living, locality type, education level, women's employment and past intrauterine device use were not found to be significant risk factors for reproductive wastage. In the West Bank only first cousin level of consanguinity was found to be significant and 'hamola' level (or from same family clan) lost its significance after adjusting for other variables. In the Gaza Strip both the first cousin and 'hamola' levels of consanguinity were significant and presented almost equal IRRs of 1.3. In conclusion, consanguinity was found to be a significant risk factor for reproductive wastage. PMID:19159397

  10. 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.

  11. Novel homozygous, heterozygous and hemizygous FRMD7 gene mutations segregated in the same consanguineous family with congenital X-linked nystagmus

    PubMed Central

    Radhakrishna, Uppala; Ratnamala, Uppala; Deutsch, Samuel; Bartoloni, Lucia; Kuracha, Murali R; Singh, Raminder; Banwait, Jasjit; Bastola, Dhundy K; Johar, Kaid; Nath, Swapan K; Antonarakis, Stylianos E

    2012-01-01

    Congenital nystagmus (NYS) is characterized by bilateral, spontaneous, and involuntary movements of the eyeballs that most commonly presents between 2 and 6 months of life. To date, 44 different FRMD7 gene mutations have been found to be etiological factors for the NYS1 locus at Xq26-q27. The aim of this study was to find the FRMD7 gene mutations in a large eleven-generation Indian pedigree with 71 members who are affected by NYS. Mutation analysis of the entire coding region and splice junctions of the FRMD7 gene revealed a novel missense mutation, c.A917G, predicts a substitution of Arg for Gln at codon 305 (Q305R) within exon 10 of FRMD7. The mutation was detected in hemizygous males, and in homozygous and heterozygous states in affected female members of the family. This mutation was not detected in unaffected members of the family or in 100 unrelated control subjects. This mutation was found to be at a highly conserved residue within the FERM-adjacent domain in affected members of the family. Structure prediction and energetic analysis of wild-type FRMD7 compared with mutant (Q305R) revealed that this change in amino acid led to a change in secondary structure predicted to be an energetically unstable protein. The present study represents the first confirmation of FRMD7 gene mutations in a multigenerational Indian family and expands the mutation spectrum for this locus. PMID:22490987

  12. NKX2-5 mutations in an inbred consanguineous population: genetic and phenotypic diversity.

    PubMed

    Abou Hassan, Ossama K; Fahed, Akl C; Batrawi, Manal; Arabi, Mariam; Refaat, Marwan M; DePalma, Steven R; Seidman, J G; Seidman, Christine E; Bitar, Fadi F; Nemer, Georges M

    2015-01-01

    NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype-phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. We hypothesized that studying the role of NKX2-5 in inbred populations with homogeneous genetic backgrounds and high consanguinity rates such as Lebanon could help closing this gap. We sequenced NKX2-5 in 188 index CHD cases (25 with ASD). Five variants (three segregated in families) were detected in eleven families including the previously documented p.R25C variant, which was found in seven patients from different families, and in one healthy individual. In 3/5 familial dominant ASD cases, we identified an NKX2-5 mutation. In addition to the heterogeneity of NKX2-5 mutations, a diversity of phenotypes occurred within the families with predominant ASD and AV block. We did in fact identify a large prevalence of Sudden Cardiac Death (SCD) in families with truncating mutations, and two patients with coronary sinus disease. NKX2-5 is thus responsible for dominant familial ASD even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population. PMID:25742962

  13. Association studies in consanguineous populations

    SciTech Connect

    Genin, E.; Clerget-Darpous, F.

    1996-04-01

    To study the genetic determinism of multifactorial diseases in large panmictic populations, a strategy consists in looking for an association with markers closely linked to candidate genes. A distribution of marker genotypes different in patients and controls may indicate that the candidate gene is involved in the disease. In panmictic populations, the power to detect the role of a candidate gene depends on the gametic disequilibrium with the marker locus. In consanguineous populations, we show that it depends on the inbreeding coefficient F as well. Inbreeding increases the power to detect the role of a recessive or quasi-recessive disease-susceptibility factor. The gain in power turns out to be greater for small values of the gametic disequilibrium. Moreover, even in the absence of gametic disequilibrium, the presence of inbreeding may allow to detect the role of a recessive factor. Ignoring inbreeding when it exists may lead to reject falsely a recessive model if the mode of inheritance is inferred on the distribution of genotypes among patients. 5 refs., 6 figs., 1 tab.

  14. Is there a significant trend in prevalence of consanguineous marriage in Tehran? A review of three generations.

    PubMed

    Akrami, Seyed Mohammad; Montazeri, Vahideh; Shomali, Somaieh Rashid; Heshmat, Ramin; Larijani, Bagher

    2009-02-01

    Consanguineous marriage is a common practice in Iran. The present study surveyed the trend in consanguineous marriage across three generations of Iranians. Index cases, consisting of 400 individuals attending the diabetes and osteoporosis clinic in Shariati Hospital, were interviewed. Data on consanguinity status for 1789 marriages within the index cases' families were obtained. Generation 1 consisted of marriages contracted before 1948, Generation 2 consisted of marriages contracted between 1949 and 1978, and Generation 3 consisted of marriages contracted after 1979. Prevalence of consanguineous marriage within these three generations was 8.8%, 16.6% and 19%, respectively, and represented a significant trend (p < 0.001). First cousin marriage was the most common type of consanguinity (69%). Socioeconomic level of families was not significantly related to having a consanguineous marriage. These data suggest that premarital genetic counseling and mass media efforts are needed to increase public awareness about genetic risks associated with consanguineous marriage. PMID:18843527

  15. Changing profile of couples seeking genetic counseling for consanguinity in Australia.

    PubMed

    Port, Katrina E; Mountain, Helen; Nelson, John; Bittles, Alan H

    2005-01-15

    Consanguineous marriage is rare in most Western countries and, for example, in the USA it may be subject to regulation by both civil legislation and religious prescription. This is not the case in many regions of Asia and Africa where marriage within the family is strongly favored. Since the 1970s there has been widespread migration to North America, Western Europe, and Australasia from communities which encourage consanguineous marriage. To assess the effect of this trend on a genetic counseling program, the records of 302 couples referred to Genetic Services of Western Australia for consanguinity counseling were abstracted for the period 1975-2001. Overall, a family history of genetic disease or a previously affected child was reported in 28.8% of cases. Premarital or prepregnancy counseling on grounds of consanguinity was sought by 41.0% of couples, and a further 18.2% of consanguineous couples had been referred because of a consanguineous pregnancy. In 7.6% of cases a relationship closer than first cousin was involved. Through time there was a significant increase in the numbers of consanguineous consultants, and their patterns of religious affiliation and ethnic origin widened markedly. Although effectively excluded from entry to Australia prior to 1975, couples of Asian origin accounted for 25.5% of all consanguineous consultants. With ongoing migration, changes in the ethnic profiles and the specific counseling requirements of consanguineous couples can be expected to continue and probably accelerate. PMID:15558724

  16. Consanguinity on Robinson Crusoe Island, an isolated Chilean population.

    PubMed

    Villanueva, Pia; Fernández, Maria A; De Barbieri, Zulema; Palomino, Hernán

    2014-07-01

    The population of Robinson Crusoe Island is estimated at 633 inhabitants. The current population has a common origin from the first eight families who colonized the island at the end of the 19th century. The objective of this study was to determine the rates of consanguinity, the average coefficients of inbreeding, the types of consanguineous marriages and the inbreeding evolution between 1900 and 2000 on the island. All marriages registered on the island, from the last colonization until 2000 (417 in total), were included in the analysis. In addition, extended genealogies were obtained. The consanguinity rate was 14.9% and the average coefficient of inbreeding (?) 54.05 × 10(-4). The most frequent type of consanguineous marriages was between second cousins, followed by first cousins. The average value of the first/second cousin ratio was 1.11. The population of Robinson Crusoe Island has a high rate of inbreeding. The unique characteristic of the island - its small current population, originating from just a few families, with small rate of gene flow - could explain the observed high and increasing consanguinity. PMID:23931260

  17. Genetics and psychotic disorders: A fresh look at consanguinity.

    PubMed

    Guermouche, Aicha Dahdouh; Taleb, Mohammed; Blecha, Lisa; Benyamina, Amine

    2016-02-01

    Consanguineous unions refer to marriages between related individuals who share a common ancestor. These unions are still commonplace in certain regions of the world such as the southern coast of the Mediterranean, throughout the Middle East and South-East Asia. According to available data, couples of second cousins or closer and their offspring currently represent 10.4% of the world's population, thus resulting in increased frequencies of autosomal recessive disorders. Furthermore, consanguinity may be implicated in the increased frequency of multifactorial pathologies such as mental disorders. The few existing epidemiological studies in consanguineous and/or geographically isolated populations confirm that there is a significant association between consanguinity and mental disorders and a higher risk of schizophrenia or bipolar disorders among offspring from consanguineous couples. There exists a strong and complex genetic component in the predisposition to psychotic disorders that has been confirmed in numerous studies. However, the genetic basis of these disorders remains poorly understood. GWAS studies (Genome Wide Association Studies) over the past 10 years have identified a few weak associations, thus refuting the "common diseases-common variants" hypothesis. A model implicating numerous rare variants has been supported by the recent discovery of CNVs (Copy Number Variants) and their statistically significant association with psychiatric disorders such as schizophrenia, bipolar disorders and autism. The study of consanguineous families may contribute to identifying rare variants in homogenous populations who have conserved certain alleles. Major developments in molecular biology techniques would facilitate these studies as well as contributing to identifying major genes. These results emphasize the need for genetic counseling in high-risk communities and the importance of implementing preventive actions and raising awareness concerning the risk of consanguineous unions. PMID:26721321

  18. Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene.

    PubMed

    Ouechtati, Farah; Merdassi, Ahlem; Bouyacoub, Yosra; Largueche, Leila; Derouiche, Kaouther; Ouragini, Houyem; Nouira, Sonia; Tiab, Leila; Baklouti, Karim; Rebai, Ahmed; Schorderet, Daniel F; Munier, Francis L; Zografos, Leonidas; Abdelhak, Sonia; El Matri, Leila

    2011-01-01

    Complete achromatopsia is a rare autosomal recessive disease associated with CNGA3, CNGB3, GNAT2 and PDE6C mutations. This retinal disorder is characterized by complete loss of color discrimination due to the absence or alteration of the cones function. The purpose of the present study was the clinical and the genetic characterization of achromatopsia in a large consanguineous Tunisian family. Ophthalmic evaluation included a full clinical examination, color vision testing and electroretinography. Linkage analysis using microsatellite markers flanking CNGA3, CNGB3, GNAT2 and PDE6C genes was performed. Mutations were screened by direct sequencing. A total of 12 individuals were diagnosed with congenital complete achromatopsia. They are members of six nuclear consanguineous families belonging to the same large consanguineous family. Linkage analysis revealed linkage to GNAT2. Mutational screening of GNAT2 revealed three intronic variations c.119-69G>C, c.161+66A>T and c.875-31G>C that co-segregated with a novel mutation p.R313X. An identical GNAT2 haplotype segregating with this mutation was identified, indicating a founder mutation. All patients were homozygous for the p.R313X mutation. This is the first report of the clinical and genetic investigation of complete achromatopsia in North Africa and the largest family with recessive achromatopsia involving GNAT2; thus, providing a unique opportunity for genotype-phenotype correlation for this extremely rare condition. PMID:21107338

  19. A Novel Aberrant Splice Site Mutation in RAB23 Leads to an Eight Nucleotide Deletion in the mRNA and Is Responsible for Carpenter Syndrome in a Consanguineous Emirati Family

    PubMed Central

    Ben-Salem, S.; Begum, M.A.; Ali, B.R.; Al-Gazali, L.

    2013-01-01

    Carpenter syndrome is caused by mutations in the RAB23 gene that encodes a small GTPase of the Rab subfamily of proteins. Rab proteins are known to be involved in the regulation of cellular trafficking and signal transduction. Currently, only few mutations in RAB23 have been reported in patients with Carpenter syndrome. In this paper, we report the clinical features, molecular and functional analysis of 2 children from an Emirati consanguineous family with this syndrome. The affected children exhibit the typical features including craniosynostosis, typical facial appearance, polysyndactyly, and obesity. Molecular analysis of the RAB23 gene revealed a homozygous mutation affecting the first nucleotide of the acceptor splice site of exon 5 (c.482-1G>A). This mutation affects the authentic mRNA splicing and activates a cryptic acceptor site within exon 5. Thus, the erroneous splicing results in an eight nucleotide deletion, followed by a frameshift and premature termination codon at position 161 (p.V161fsX3). Due to the loss of the C-terminally prenylatable cysteine residue, the truncated protein will probably fail to associate with the target cellular membranes due to the absence of the necessary lipid modification. The p.V161fsX3 extends the spectrum of RAB23 mutations and points to the crucial role of prenylation in the pathogenesis of Carpenter syndrome within this family. PMID:23599695

  20. Consanguineous marriages in the United Arab Emirates.

    PubMed

    al-Gazali, L I; Bener, A; Abdulrazzaq, Y M; Micallef, R; al-Khayat, A I; Gaber, T

    1997-10-01

    This study examines the frequency of consanguineous marriage and the coefficient of inbreeding in the United Arab Emirates (UAE). The study was conducted in Al Ain and Dubai cities between October 1994 and March 1995. A sample of 2033 married UAE females aged 15 years and over participated. The degree of consanguinity between each female and her spouse, and the degree of consanguinity between their parents were recorded. The rate of consanguinity in the present generation was high (50.5%) with a coefficient of inbreeding of 0.0222. The commonest type of consanguineous marriage was between first cousins (26.2%). Double first cousin marriages were common (3.5%) compared to other populations. The consanguinity rate in the UAE has increased from 39% to 50.5% in one generation. The level of consanguinity was higher in Al Ain (54.2%) than in Dubai (40%). PMID:9881148

  1. Consanguinity in Lebanon: prevalence, distribution and determinants.

    PubMed

    Barbour, Bernadette; Salameh, Pascale

    2009-07-01

    The union of individuals with a common ancestor may lead to serious health consequences in their offspring. Consanguinity is high in Middle Eastern communities; it was around 26% in 1988. The objective of this study was to determine the prevalence of consanguinity in Beirut and other Lebanese regions, and its associated factors in different subgroups. The cross-sectional study was performed on a convenience sample of married women in Lebanon. The women were administered a standardized questionnaire in a face-to-face interview by independent enquirers. Among 1556 women, the overall prevalence of consanguineous marriages was 35.5%, and the consanguinity coefficient was 0.020; 968 marriages (62.2%) were not consanguineous, 492 (31.6%) were first cousin, 61 (3.9%) were second cousin and 36 (2.3%) had lower degrees of consanguinity. Beirut suburb dwelling, low education subgroups, women working in the home and non-Christian religion presented the highest rates of consanguinity (p<0.05). Consanguinity is associated with couples' nulliparity and child chronic morbidity. Factors that could affect consanguinity are having consanguineous parents, having a favourable opinion towards consanguinity, choosing a spouse for religious reasons, particularly in Islam, woman having a low education, woman working in the home and women thinking that consanguinity would not lead to serious diseases. Consanguinity is therefore still a prevailing problem in Lebanon. Specific health education, and genetic counselling in particular, are suggested to explain the consequences of consanguinity to the general population and to help couples make informed choices. PMID:19175949

  2. Consanguinity and reproductive health among Arabs.

    PubMed

    Tadmouri, Ghazi O; Nair, Pratibha; Obeid, Tasneem; Al Ali, Mahmoud T; Al Khaja, Najib; Hamamy, Hanan A

    2009-01-01

    Consanguineous marriages have been practiced since the early existence of modern humans. Until now consanguinity is widely practiced in several global communities with variable rates depending on religion, culture, and geography. Arab populations have a long tradition of consanguinity due to socio-cultural factors. Many Arab countries display some of the highest rates of consanguineous marriages in the world, and specifically first cousin marriages which may reach 25-30% of all marriages. In some countries like Qatar, Yemen, and UAE, consanguinity rates are increasing in the current generation. Research among Arabs and worldwide has indicated that consanguinity could have an effect on some reproductive health parameters such as postnatal mortality and rates of congenital malformations. The association of consanguinity with other reproductive health parameters, such as fertility and fetal wastage, is controversial. The main impact of consanguinity, however, is an increase in the rate of homozygotes for autosomal recessive genetic disorders. Worldwide, known dominant disorders are more numerous than known recessive disorders. However, data on genetic disorders in Arab populations as extracted from the Catalogue of Transmission Genetics in Arabs (CTGA) database indicate a relative abundance of recessive disorders in the region that is clearly associated with the practice of consanguinity. PMID:19811666

  3. Consanguinity and Birth Defects in the Jerusalem Perinatal Study Cohort

    PubMed Central

    Harlap, S.; Kleinhaus, K.; Perrin, M.C.; Calderon-Margalit, R.; Paltiel, O.; Deutsch, L.; Manor, O.; Tiram, E.; Yanetz, R.; Friedlander, Y.

    2008-01-01

    Background While parental consanguinity is known to increase the risk of birth defects in offspring, it is hard to quantify this risk in populations where consanguinity is prevalent. Methods To support ongoing studies of cancer and of psychiatric disease, we studied relationships of consanguinity to 1,053 major birth defects in 29,815 offspring, born in 1964–1976. To adjust for confounding variables (geographic origin, social class and hospital), we constructed logistic regression models, using GEE to take into account correlations between sibs. Odds ratios (ORs) and 95% confidence limits were estimated in comparison to a reference group of offspring with grandfathers born in different countries. Results With 10.1% of offspring having consanguineous parents, the adjusted OR for major birth defect was 1.41 (1.12–1.74). Offspring of marriages between uncles-nieces, first cousins and more distant relatives showed adjusted ORs of 2.36 (0.98–5.68), 1.59 (1.22–2.07) and 1.20 (0.89–1.59) respectively. For descendents of grandfathers born in the same country, but not known to be related, the OR was 1.05 (0.91–1.21); these showed increased risk associated with ancestries in Western Asia (1.27, 1.04–1.55, p < 0.02) or Europe (1.13, 0.79–1.80). Conclusions A strong association of consanguinity with poverty and low education points to the need to avoid exposure to environmental hazards in these families. PMID:18493143

  4. Consanguinity and prereproductive mortality in the Utah Mormon population.

    PubMed

    Jorde, L B

    2001-01-01

    To test the effects of parental consanguinity on mortality among offspring, inbreeding coefficients were estimated for 303,675 members of the Utah Mormon population who were born between 1847 and 1945. Although consanguinity has been relatively rare in this population, the large sample size permitted the identification of more than 3,500 inbred offspring. Among the offspring of unrelated parents, 13.2% died before the age of 16. Significant elevations in prereproductive mortality were seen among the offspring of first-cousin marriages (22%) and among the offspring of closer unions (32%). The cor- responding relative risks are 1.70 (95% confidence limits = 1.52, 1.91) and 2.41 (95% confidence limits = 1.59, 3.41), respectively. Other categories of relationship did not produce significant elevations in offspring mortality. Similar results were obtained when a case-control approach was used to remove the effects of socioeconomic variation. Consistent with many other studies of populations with low consanguinity rates, this population experienced a relatively high absolute increase in mortality among the offspring of first-cousin marriages (9%). Preliminary evidence is offered for the hypothesis that mortality differentials are larger in populations with low inbreeding and low mortality because nongenetic causes of death do not obscure the effects of consanguinity. PMID:11474206

  5. Consanguineous marriage and reproductive risk: attitudes and understanding of ethnic groups practising consanguinity in Western society.

    PubMed

    Teeuw, Marieke E; Loukili, Ghariba; Bartels, Edien Ac; ten Kate, Leo P; Cornel, Martina C; Henneman, Lidewij

    2014-04-01

    Consanguineous couples should be adequately informed about their increased reproductive risk and possibilities for genetic counselling. Information may only be effective if it meets the needs of the target group. This study aimed to gain more insight into: (1) attitudes of people belonging to ethnic groups in Western society towards consanguinity and their understanding of risk for offspring; and (2) their attitudes regarding reproductive information targeted at consanguineous couples. Dutch Moroccans and Turks were invited to complete an online questionnaire by snowball sampling and by placing a link on two popular Dutch Moroccan/Turkish forum websites between September and October 2011. The questionnaire was completed by 201 individuals who were, on average, neither positive nor negative towards consanguinity. Respondents with a consanguineous partner were more positive, estimated the risk for the offspring lower and were less positive about the provision of risk information to consanguineous couples when compared with respondents without a consanguineous partner. Participants of Turkish origin had a more negative attitude towards consanguinity and estimated the reproductive risk higher than Moroccan participants. More than half of the respondents thought that information should be given before marriage, whereas only 10% thought it should never be provided. The general practitioner was most often mentioned (54%) as the designated professional to inform people. Information about genetic risks related to consanguinity should be offered early, preferably before marriage. The diversity of the target population requires various strategies to disseminate information and reach consanguineous couples with the offer of genetic counselling. PMID:23921534

  6. On some novel aspects of consanguineous marriages.

    PubMed

    Denic, S; Nagelkerke, N; Agarwal, M M

    2011-01-01

    Consanguineous marriages, often viewed as incestuous and objectionable, are more widespread than commonly perceived. They integrate multiple facets of human adaptation: economic, cultural and genetic. The widely touted explanation for the origin and persistence of consanguinity is that it provides many socioeconomic benefits; however, this view may be too simplistic. The bias against consanguinity may preclude an objective understanding of this sociobiological puzzle. Inbreeding increases the speed of selection of beneficial recessive and co-dominant alleles, e.g. those that protect against diseases. In populations endemic with malaria, the prevalence of consanguineous marriages and the frequency of alleles protective against malaria are both very high. Thus, consanguinity could theoretically increase the relative fitness of a population under specific ecological conditions; sometimes, the overall genetic benefits may exceed genetic costs of inbreeding. We discuss some recent evidence from studies on inbreeding along with the reasons responsible for the mating strategy found in some human populations. We contend that a better appreciation of our inherent biases and potential genetic benefits of inbreeding in specific ecological conditions would help us to appreciate the wider picture of consanguinity. PMID:21150168

  7. First steps in exploring prospective exome sequencing of consanguineous couples.

    PubMed

    Teeuw, Marieke; Waisfisz, Quinten; Zwijnenburg, Petra J G; Sistermans, Erik A; Weiss, Marjan M; Henneman, Lidewij; ten Kate, Leo P; Cornel, Martina C; Meijers-Heijboer, Hanne

    2014-01-01

    Consanguinity is one of the most frequent risk factors for congenital disorders. In theory, prospective exome sequencing of consanguineous couples could identify couples who both are carriers of autosomal recessive diseases, and empower such couples to make informed reproductive decisions. To investigate this, we sent blood samples to our laboratory of four pairs of consanguineous parents having one or more children affected by an autosomal recessive disorder, without revealing any diagnostic information. The study was restricted to find identical, previously described, or evidently pathogenic mutations in both parents of each couple, in over 400 genes known to result in severe autosomal recessive disorders. Out of the six autosomal recessive disorders known to the four couples studied, two were correctly identified. Carrier status of one not previously known autosomal recessive disorder was discovered. As expected, given the pipeline used, large deletions, mutations in genes not present in the gene list, mutations outside the exons and consensus splice sites, and mutations that were not evidently pathogenic and previously not reported, were not identified. The restriction to detecting only couples with identical mutations diminishes the risk of revealing unsolicited findings and shortens the time needed for analysis, but also results in missing couples with different mutations in the same gene. In addition to the proposed pipeline, couples should be offered testing for carrier status of frequent disorders that can present themselves by large deletions, non-exonic mutations or compound heterozygous mutations (e.g. thalassemia, spinal muscular atrophy, cystic fibrosis). Even though sensitivity is reduced, offering exome sequencing prospectively will increase reproductive options for consanguineous couples. PMID:25281896

  8. 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. PMID:12674831

  9. Consanguinity and disorders of sex development.

    PubMed

    Bashamboo, Anu; McElreavey, Ken

    2014-01-01

    Disorders of sex development (DSD) are defined as 'congenital conditions in which the development of chromosomal, gonadal, or anatomical sex is atypical' [Lee et al., Pediatrics 2006;118:e488-e500]. Studies conducted in Western countries, with low rates of consanguinity, show that truly ambiguous genitalia have an estimated incidence of 1:5,000 births. There are indications that the prevalence of DSD is higher in endogamous communities. The incidence of ambiguous genitalia in Saudi Arabia has been estimated at 1:2,500 live births; whilst in Egypt, it has been estimated at 1:3,000 live births. This may be due in part to an increase in disorders of androgen synthesis associated with 46,XX DSD. There is clearly a need for further studies to address the frequency of DSD in communities with high levels of consanguinity. This will be challenging, as an accurate diagnosis is difficult and expensive even in specialized centres. In developing countries with high levels of consanguinity, these limitations can be compounded by cultural, social and religious factors. Overall there is an indication that consanguinity may lead to an increase in incidences of both 46,XY and 46,XX DSD, and a co-ordinated study of populations with higher incidences of consanguinity/endogamy is needed to resolve this. PMID:25060274

  10. 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. PMID:25060282

  11. Is parental consanguinity associated with reduced ovarian reserve?

    PubMed

    Seher, Tanja; Thiering, Elisabeth; Al Azemi, Majdah; Heinrich, Joachim; Schmidt-Weber, Carsten B; Kivlahan, Coleen; Gutermuth, Jan; Fatemi, Human M

    2015-09-01

    This observational study assessed whether women descending from consanguineous unions have reduced ovarian reserve compared with daughters of non-consanguine couples. Two hundred and ninety-one women (?39 years) were treated in a tertiary care centre in Kuwait. Women underwent a complete anamnesis, including an evaluation of the possible presence of parental consanguinity, transvaginal ultrasound on day 2/3 of the cycle to obtain the antral follicle count (AFC), determination of serum concentrations of FSH, LH, oestradiol and in case of low ovarian reserve (AFC < 9) anti-Müllerian hormone (AMH). The median AFC of non-consanguineous daughters was 11, while daughters from consanguineous parents displayed a significantly lower median AFC (7; P < 0?0001). FSH was slightly higher in the consanguineous patients, while LH and oestradiol concentrations did not vary between groups. In total, 29.9% of consanguineous patients had an AFC ? 9, compared with 63.9% of non-consanguineous patients. Consanguineous patients did not exhibit an age-dependent AFC-decline and displayed reduced AFC and AMH concentrations. The multivariate analysis revealed female consanguinity, as well as surgical history in non-consanguineous women, as strong positive predictors of low ovarian reserve. Parental consanguinity is strongly associated with reduced ovarian reserve. Future studies should evaluate a possible association between parental consanguinity and infertility. PMID:26206281

  12. Large Constituent Families Help Children Parse Compounds

    ERIC Educational Resources Information Center

    Krott, Andrea; Nicoladis, Elena

    2005-01-01

    The family size of the constituents of compound words, or the number of compounds sharing the constituents, has been shown to affect adults' access to compound words in the mental lexicon. The present study was designed to see if family size would affect children's segmentation of compounds. Twenty-five English-speaking children between 3;7 and…

  13. 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

  14. Clinical and molecular analysis of a large family with three distinct phenotypes of progressive muscular dystrophy.

    PubMed

    Illarioshkin, S N; Ivanova-Smolenskaya, I A; Tanaka, H; Vereshchagin, N V; Markova, E D; Poleshchuk, V V; Lozhnikova, S M; Sukhorukov, V S; Limborska, S A; Slominsky, P A; Bulayeva, K B; Tsuji, S

    1996-12-01

    We describe a unique six-generation, highly consanguineous family originating from an isolated mountainous village in the Russian province of Daghestan. Three separate clinical phenotypes of progressive muscular dystrophy were identified in this large family. Seven patients developed a classical limb-girdle variant of muscular dystrophy (LGMD), with disease onset at 15-30 years and loss of ambulation within a 25-year course. The second group included three patients with a slowly progressive distal myopathy first manifested in the late teens and confined to the tibial and calf muscles. Each of these two phenotypes segregated independently as an autosomal recessive trait, and muscle biopsies showed non-specific myopathic changes. Lastly, two male siblings exhibited an atypical variant of Duchenne muscular dystrophy confirmed by detection of a deletion in the dystrophin gene. To clarify the molecular basis of the polymorphic autosomal recessive form of muscular dystrophy in this kindred, we performed molecular genetic studies on 67 family members and obtained significant evidence for linkage to chromosome 2p. A maximum pairwise lod (logarithm of odds) score of 5.64 was achieved at the zero recombination fraction (i.e. at theta = 0.00) for locus D2S291; multipoint linkage analysis confirmed the most likely location of a mutant gene near D2S291. The patients with LGMD and those with the distal muscular dystrophy phenotype share a common affected homozygous haplotype associated with the same founder chromosome; key recombinants defined D2S286 and D2S292 to be the closest loci flanking the mutant gene. Remarkably, two clinically distinct forms of autosomal recessive muscular dystrophy, LGMD type 2B (LGMD2B) and Miyoshi myopathy, were recently mapped to the same locus. We suggest that all three chromosome 2p-linked conditions may represent allelic disorders, i.e. different phenotypic expressions of a single gene. PMID:9009996

  15. Attitude of Saudi Arabian adults towards consanguineous marriage

    PubMed Central

    Alharbi, Omar A.; Al-Shaia, Walaa A.; Al-Hamam, Abdulaziz A.; Al-Marzoug, Hala M.; Ahmed, Anwar E.; Bagha, Muhammed

    2015-01-01

    Background: Research on the attitudes of Saudi adults towards consanguinity is scarce. The study aimed to explore the attitudes towards consanguinity and its associations with socio-demographic characteristics in a sample of Saudi adults. Methods: A cross-sectional study was conducted using a self-administered questionnaire. A total of 386 outpatient waiting-area attendees at King Abdul-Aziz Medical City-Riyadh were included. Participants were asked about their socio-demographic characteristics, attitude towards consanguinity and the reasons behind this. Results: The positive attitude towards consanguinity among the study respondents was 48.1% with 95% confidence interval (42.91–53.33%). Social and traditional culture (59.9%) were found to be the predominant reasons for favoring consanguinity in Saudi Arabia. Evidence against a positive attitude towards consanguinity was noted in respondents who received medical information about consanguinity versus those who had not received medical information (42.3% vs. 57%, p-value = 0.008). According to the multivariate logistic model, the odds of a positive attitude towards consanguinity were 2 times higher for males (adjusted odds ratio [aOR]: 2.2; 95% CI: 1.147, 4.290) and 4.1 times higher in respondents in consanguineous marriages (aOR: 4.1; 95% CI: 2.350, 7.156). The odds of a positive attitude towards consanguinity were 50% less in respondents who received health information on consanguinity compared to those who had not received health information about consanguinity (aOR: 0.50; 95% CI: 0.253, 0.863). Conclusion: One in every two Saudi adults favors consanguinity however, Saudi men and women differ in their attitudes towards consanguinity. Receiving health information on consanguinity was associated with a negative attitude towards this practice. PMID:26835408

  16. 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. PMID:16688753

  17. Parental consanguinity and the Majewski syndrome.

    PubMed Central

    Black, I L; Fitzsimmons, J; Fitzsimmons, E; Thomas, A J

    1982-01-01

    We report a female infant with the Majewski syndrome, one of a group of conditions characterised by short ribs, polydactyly, dwarfism, and early neonatal death. This syndrome seems to be extremely rare, with only five well documented cases reported and, including this case, nine recorded in all. The Majewski syndrome is considered to be recessively inherited, and this report adds further support to this hypothesis, as the infant was born to consanguineous parents. Images PMID:7077625

  18. 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

  19. 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. PMID:26363620

  20. Is consanguineous marriage religiously encouraged? Islamic and Iranian considerations.

    PubMed

    Akrami, Seyed Mohammad; Osati, Zahra

    2007-03-01

    Consanguineous marriage has had considerable attention as a causative factor in the prevalence of genetic disorders. Iran, with its majority Muslim population, has a high rate of consanguineous marriage. In Iranian tradition, first cousin marriage is an acceptable and appreciated custom. However, there seems to be no encouragement of consanguineous marriage in the Islamic context; it is merely mentioned as a traditional and common custom. This paper may help medical professionals providing premarital genetic counselling, who are regularly asked about consanguineous marriage, especially in Islamic communities. Increased public awareness via the mass media would seem to be a priority. PMID:17059617

  1. Consanguinity as an Adjunct Diagnostic Tool.

    PubMed

    Srivastava, Priyanka; Saxena, Deepti; Joshi, Stephen; Phadke, Shubha R

    2016-03-01

    History of consanguinity is important in monogenic disorders as it supports autosomal recessive mode of inheritance. This case report illustrates the use of homozygosity mapping using single nucleotide polymorphism (SNP) microarray data to identify the causative gene in a case with Warburg Micro syndrome (WARBM). This syndrome has non-specific features like microcephaly and cataract; etiological diagnosis based on clinical features is not possible. Four causative genes are known for WARBM syndrome. In such a situation of autosomal recessive disorders of heterogeneous etiologies, SNP microarray and homozygosity mapping is a useful and cost effective strategy. PMID:26138576

  2. Little Brother Joins the Large Family

    NASA Astrophysics Data System (ADS)

    2006-12-01

    On the night of 15 December 2006, the fourth and last-to-be-installed VLTI Auxiliary Telescope (AT4) obtained its 'First Light'. The first images demonstrate that AT4 will be able to deliver the excellent image quality already delivered by the first three ATs. It will soon join its siblings to perform routinely interferometric measurements. ESO PR Photo 51a/06 ESO PR Photo 51a/06 VLT Auxiliary Telescope The VLT is composed of four 8.2-m Unit Telescope (Antu, Kueyen, Melipal and Yepun). They have been progressively put into service together with a vast suite of the most advanced astronomical instruments and are operated every night in the year. Contrary to other large astronomical telescopes, the VLT was designed from the beginning with the use of interferometry as a major goal. The VLT Interferometer (VLTI) combines starlight captured by two or three 8.2- VLT Unit Telescopes, dramatically increasing the spatial resolution and showing fine details of a large variety of celestial objects. ESO PR Photo 51b/06 ESO PR Photo 51b/06 One AT Under the Sky However, most of the time the large telescopes are used for other research purposes. They are therefore only available for interferometric observations during a limited number of nights every year. Thus, in order to exploit the VLTI each night and to achieve the full potential of this unique setup, some other (smaller), dedicated telescopes were included into the overall VLT concept. These telescopes, known as the VLTI Auxiliary Telescopes (ATs), are mounted on tracks and can be placed at precisely defined "parking" observing positions on the observatory platform. From these positions, their light beams are fed into the same common focal point via a complex system of reflecting mirrors mounted in an underground system of tunnels. The Auxiliary Telescopes are real technological jewels. They are placed in ultra-compact enclosures, complete with all necessary electronics, an air conditioning system and cooling liquid for thermal control, compressed air for enclosure seals, a hydraulic plant for opening the dome shells, etc. Each AT is also fitted with a transporter that lifts the telescope and relocates it from one station to another. It moves around with its own housing on the top of Paranal, almost like a snail. The VLTI is arguably the world's most advanced optical device of this type. It has already demonstrated its powerful capabilities by addressing several key scientific issues, such as determining the size and the shape of a variety of stars (ESO PR 22/02, PR 14/03, PR 31/03, and PR 09/06), measuring distances to stars (ESO PR 25/04), probing the innermost regions of the proto-planetary discs around young stars (ESO PR 27/04 and PR 35/06) or making the first detection by infrared interferometry of an extragalactic object (ESO PR 17/03).

  3. Autosomal dominant stationary night-blindness. A large family rediscovered.

    PubMed

    Rosenberg, T; Haim, M; Piczenik, Y; Simonsen, S E

    1991-12-01

    In 1909, 2 years after the famous publication by Nettleship, a large family with congenital stationary night-blindness of the 'Nougaret type' was published by the Danish district surgeon, Sigurd Rambusch. In 1990 the 'Rambusch family', still resident in the original area, was sought out and rediscovered, at which time the reconstructed part of the pedigree comprised more than 200 affected persons in 11 generations. Dark adaptometry and electroretinography were performed on a few affected family members, including a descendant with a uniocular affection. The pedigree is presented and recordings of dark adaptation courses and electroretinographical responses from a few family members are demonstrated. PMID:1789082

  4. Consanguinity trends and correlates in the Palestinian Territories.

    PubMed

    Assaf, Shireen; Khawaja, Marwan

    2009-01-01

    Secondary analysis of the trends and correlates of consanguinity in the Palestinian Territories was conducted using data from two separate surveys in 1995 and 2004. The analysis was conducted on ever-married women aged 15-54 who were asked about their relation to their husband in both surveys. A total of 16,197 women in 1995 and 4971 women in 2004 were successfully interviewed. Consanguinity was found to be widely practised in the Palestinian Territories with rates of total consanguinity reaching 45% of all marriages in 2004. Analysis was conducted with the data from the two surveys combined and this indicated that consanguinity was significantly decreasing with time after controlling for other variables. Age of the women, their age at marriage, region and locality type they lived in and their standard of living were all found to be significant predictors of consanguinity. The education level of the women was not found to be significant. After controlling for the survey year, women's labour force status was also found to be a non-significant predictor of consanguinity. Although consanguinity was found to be significantly decreasing slowly with time after controlling for other variables, the future trends of consanguinity are not known due to the unstable political situation in the territories, which could have a direct effect on marriage patterns. PMID:18549512

  5. A community-based study of mucopolysaccharidosis type VI in Brazil: the influence of founder effect, endogamy and consanguinity.

    PubMed

    Costa-Motta, Fabiana Moura; Bender, Fernanda; Acosta, Angelina; Abé-Sandes, Kiyoko; Machado, Taísa; Bomfim, Thaís; Boa Sorte, Tatiana; da Silva, Danniel; Bittles, Alan; Giugliani, Roberto; Leistner-Segal, Sandra

    2014-01-01

    Mucopolysaccharidosis type VI (MPS VI - Maroteaux-Lamy syndrome) is a globally rare lysosomal storage disease caused by a deficiency of arylsulfatase B. However, in Monte Santo, a poor and isolated rural region in Northeast Brazil with large family sizes and high rates of community endogamy and parental consanguinity (? = 0.00483), 9 living and 4 now deceased individuals in 11 kindreds have been diagnosed with MPS VI, all with the same p.H178L missense founder mutation. A further 33 deceased persons have been identified by family members as exhibiting the disease phenotype. Detailed pedigrees were constructed for the 13 genomically confirmed MPS VI patients, with blood samples collected from 236 unaffected family members to determine the prevalence of the p.H178L mutation. A total of 98 (20.8%) mutant alleles and 374 (79.2%) normal alleles were identified, with 41.5% of the individuals heterozygous for the p.H178L mutation and 58.5% homozygous for the normal allele. A significant number of other family members with a 50 or 25% chance of being heterozygous for the p.H178L mutation were unavailable for testing. The data indicate a compelling case for community-based neonatal screening in conjunction with further initiatives among MPS VI family members to promote genetic education and genetic counselling. PMID:25060283

  6. 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. PMID:15183745

  7. Airfoil family design for large offshore wind turbine blades

    NASA Astrophysics Data System (ADS)

    Méndez, B.; Munduate, X.; San Miguel, U.

    2014-06-01

    Wind turbine blades size has scaled-up during last years due to wind turbine platform increase especially for offshore applications. The EOLIA project 2007-2010 (Spanish Goverment funded project) was focused on the design of large offshore wind turbines for deep waters. The project was managed by ACCIONA Energia and the wind turbine technology was designed by ACCIONA Windpower. The project included the design of a wind turbine airfoil family especially conceived for large offshore wind turbine blades, in the order of 5MW machine. Large offshore wind turbines suffer high extreme loads due to their size, in addition the lack of noise restrictions allow higher tip speeds. Consequently, the airfoils presented in this work are designed for high Reynolds numbers with the main goal of reducing blade loads and mantainig power production. The new airfoil family was designed in collaboration with CENER (Spanish National Renewable Energy Centre). The airfoil family was designed using a evolutionary algorithm based optimization tool with different objectives, both aerodynamic and structural, coupled with an airfoil geometry generation tool. Force coefficients of the designed airfoil were obtained using the panel code XFOIL in which the boundary layer/inviscid flow coupling is ineracted via surface transpiration model. The desing methodology includes a novel technique to define the objective functions based on normalizing the functions using weight parameters created from data of airfoils used as reference. Four airfoils have been designed, here three of them will be presented, with relative thickness of 18%, 21%, 25%, which have been verified with the in-house CFD code, Wind Multi Block WMB, and later validated with wind tunnel experiments. Some of the objectives for the designed airfoils concern the aerodynamic behavior (high efficiency and lift, high tangential coefficient, insensitivity to rough conditions, etc.), others concern the geometry (good for structural design, compatibility for the different airfoil family members, etc.) and with the ultimate objective that the airfoils will reduce the blade loads. In this paper the whole airfoil design process and the main characteristics of the airfoil family are described. Some force coefficients for the design Reynolds number are also presented. The new designed airfoils have been studied with computational calculations (panel method code and CFD) and also in a wind tunnel experimental campaign. Some of these results will be also presented in this paper.

  8. Complex genetic background in a large family with Brugada syndrome

    PubMed Central

    Saber, Siamak; Amarouch, Mohamed?Yassine; Fazelifar, Amir?Farjam; Haghjoo, Majid; Emkanjoo, Zahra; Alizadeh, Abolfath; Houshmand, Massoud; Gavrilenko, Alexander V.; Abriel, Hugues; Zaklyazminskaya, Elena V.

    2015-01-01

    Abstract The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST?segment elevation in V1–V3 leads and negative T wave on standard ECG. BrS patients are at risk of sudden cardiac death (SCD) due to ventricular tachyarrhythmia. At least 17 genes have been proposed to be linked to BrS, although recent findings suggested a polygenic background. Mutations in SCN5A, the gene coding for the cardiac sodium channel Nav1.5, have been found in 15–30% of index cases. Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) in SCN5A. By performing whole?cell patch?clamp experiments using HEK293 cells expressing wild?type (WT) or p.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant?induced alterations lead to a loss of function of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation. Additional next generation sequencing analyses revealed the p.R25W mutation in KCNH2 gene in SCN5A?negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN5A genetic variant. PMID:25626866

  9. Complex genetic background in a large family with Brugada syndrome.

    PubMed

    Saber, Siamak; Amarouch, Mohamed-Yassine; Fazelifar, Amir-Farjam; Haghjoo, Majid; Emkanjoo, Zahra; Alizadeh, Abolfath; Houshmand, Massoud; Gavrilenko, Alexander V; Abriel, Hugues; Zaklyazminskaya, Elena V

    2015-01-01

    The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST-segment elevation in V1-V3 leads and negative T wave on standard ECG. BrS patients are at risk of sudden cardiac death (SCD) due to ventricular tachyarrhythmia. At least 17 genes have been proposed to be linked to BrS, although recent findings suggested a polygenic background. Mutations in SCN5A, the gene coding for the cardiac sodium channel Nav1.5, have been found in 15-30% of index cases. Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) in SCN5A. By performing whole-cell patch-clamp experiments using HEK293 cells expressing wild-type (WT) or p.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant-induced alterations lead to a loss of function of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation. Additional next generation sequencing analyses revealed the p.R25W mutation in KCNH2 gene in SCN5A-negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN5A genetic variant. PMID:25626866

  10. Kenny-Caffey syndrome in two sibs born to consanguineous parents: evidence for an autosomal recessive variant.

    PubMed

    Franceschini, P; Testa, A; Bogetti, G; Girardo, E; Guala, A; Lopez-Bell, G; Buzio, G; Ferrario, E; Piccato, E

    1992-01-01

    We report on 2 sibs with manifestations of the Kenny-Caffey syndrome born to normal, consanguineous parents. Clinical manifestations included dwarfism, internal cortical thickening and medullary stenosis of tubular bones, poorly ossified skull bones, and hypocalcemia. The younger of the two died during a tonic convulsion. The older had neonatal hypoparathyroidism and is now a short intelligent, 1-year-old child. This family gives new support to the existence of an autosomal recessive variant of the syndrome. PMID:1308349

  11. KIC 8462852: Transit of a Large Comet Family

    NASA Astrophysics Data System (ADS)

    Bodman, Eva H. L.; Quillen, Alice

    2016-03-01

    We investigate the plausibility of a cometary source of the unusual transits observed in the KIC 8462852 light curve. A single comet of similar size to those in our solar system produces a transit depth of the order of 10‑3 lasting less than a day which is much smaller and shorter than the largest dip observed (∼ 20% for ∼3 days), but a large, closely traveling cluster of comets can fit the observed depths and durations. We find that a series of large comet swarms, with all except one on the same orbit, provides a good fit for the KIC 8462852 data during Quarters 16 and 17, but does not explain the large dip observed during Quarter 8. However, the transit dips only loosely constrain the orbits and can be fit by swarms with periastrons differing by a factor of 10. To reach a transit depth of ∼0.2, the comets need to be in a close group of ∼30, if they are ∼100 km in radius or in a group of ∼300 if they are ∼10 km in radius. The total number of comets required to fit all of the dips is ∼70 ∼ 100 km or ∼700 ∼ 10 km comets. A single comet family from a tidally disrupted Ceres-sized progenitor or the start of a Late Heavy Bombardment period explains the last ∼60 days of the unusual KIC 8462852 light curve.

  12. A large family of filled skutterudites stabilized by electron count.

    PubMed

    Luo, Huixia; Krizan, Jason W; Muechler, Lukas; Haldolaarachchige, Neel; Klimczuk, Tomasz; Xie, Weiwei; Fuccillo, Michael K; Felser, Claudia; Cava, Robert J

    2015-01-01

    The Zintl concept is important in solid-state chemistry to explain how some compounds that combine electropositive and main group elements can be stable at formulas that at their simplest level do not make any sense. The electronegative elements in such compounds form a polyatomic electron-accepting molecule inside the solid, a 'polyanion', that fills its available energy states with electrons from the electropositive elements to obey fundamental electron-counting rules. Here we use this concept to discover a large family of filled skutterudites based on the group 9 transition metals Co, Rh, and Ir, the alkali, alkaline-earth, and rare-earth elements, and Sb4 polyanions. Forty-three new filled skutterudites are reported, with 63 compositional variations--results that can be extended to the synthesis of hundreds of additional new compounds. Many interesting electronic and magnetic properties can be expected in future studies of these new compounds. PMID:25744553

  13. A large family of filled skutterudites stabilized by electron count

    NASA Astrophysics Data System (ADS)

    Luo, Huixia; Krizan, Jason W.; Muechler, Lukas; Haldolaarachchige, Neel; Klimczuk, Tomasz; Xie, Weiwei; Fuccillo, Michael K.; Felser, Claudia; Cava, Robert J.

    2015-03-01

    The Zintl concept is important in solid-state chemistry to explain how some compounds that combine electropositive and main group elements can be stable at formulas that at their simplest level do not make any sense. The electronegative elements in such compounds form a polyatomic electron-accepting molecule inside the solid, a ‘polyanion’, that fills its available energy states with electrons from the electropositive elements to obey fundamental electron-counting rules. Here we use this concept to discover a large family of filled skutterudites based on the group 9 transition metals Co, Rh, and Ir, the alkali, alkaline-earth, and rare-earth elements, and Sb4 polyanions. Forty-three new filled skutterudites are reported, with 63 compositional variations—results that can be extended to the synthesis of hundreds of additional new compounds. Many interesting electronic and magnetic properties can be expected in future studies of these new compounds.

  14. Familial pattern of large vestibular aqueduct syndrome in a Chinese family

    PubMed Central

    Hazmi, Mohd; Ab Aziz, A.; Asma, A.

    2013-01-01

    Large Vestibular Aqueduct Syndrome (LVAS) is the most common radiographic malformation in children with early onset of hearing loss. Usually its occurrence is non-familial, however intriguingly a portion of patients with LVAS is found to have evidence of genetic predisposition. We described cases of LVAS in two siblings of a Chinese family. The elder sister first presented with reduced hearing since childhood and her brother has a similar complaint upon further questioning. Their hearing test showed bilateral sensorineural hearing loss (SNHL) and computed tomography (CT) of temporal bone showed enlarged vestibular aqueduct in both patients. We described an approach to diagnosis of LVAS and highlight the importance of hearing assessment in genetic link hearing loss.

  15. Filtering for compound heterozygous sequence variants in non-consanguineous pedigrees.

    PubMed

    Kamphans, Tom; Sabri, Peggy; Zhu, Na; Heinrich, Verena; Mundlos, Stefan; Robinson, Peter N; Parkhomchuk, Dmitri; Krawitz, Peter M

    2013-01-01

    The identification of disease-causing mutations in next-generation sequencing (NGS) data requires efficient filtering techniques. In patients with rare recessive diseases, compound heterozygosity of pathogenic mutations is the most likely inheritance model if the parents are non-consanguineous. We developed a web-based compound heterozygous filter that is suited for data from NGS projects and that is easy to use for non-bioinformaticians. We analyzed the power of compound heterozygous mutation filtering by deriving background distributions for healthy individuals from different ethnicities and studied the effectiveness in trios as well as more complex pedigree structures. While usually more then 30 genes harbor potential compound heterozygotes in single exomes, this number can be markedly reduced with every additional member of the pedigree that is included in the analysis. In a real data set with exomes of four family members, two sisters affected by Mabry syndrome and their healthy parents, the disease-causing gene PIGO, which harbors the pathogenic compound heterozygous variants, could be readily identified. Compound heterozygous filtering is an efficient means to reduce the number of candidate mutations in studies aiming at identifying recessive disease genes in non-consanguineous families. A web-server is provided to make this filtering strategy available at www.gene-talk.de. PMID:23940540

  16. 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. PMID:23619998

  17. The Perceptions and Views on Family Interaction and Relationships of Middle Children from Large Families: An Informal Mini Survey.

    ERIC Educational Resources Information Center

    Hall, Elena C. Thomas

    In Adler's Theory of Individual Psychology the significance of birth order position in the family constellation depends on the interpretation given to it by the child, which in turn influences his character. This study surveyed the perceptions of middle children in large families. Subjects (N=13) were middle children in families of more than five…

  18. Identification of a novel large CYP17A1 deletion by MLPA analysis in a family with classic 17?-hydroxylase deficiency.

    PubMed

    Turkkahraman, Doga; Guran, Tulay; Ivison, Hannah; Griffin, Aliesha; Vijzelaar, Raymon; Krone, Nils

    2015-01-01

    Steroid 17?-hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia caused by mutations in the 17?-hydroxylase ( CYP17A1) gene. CYP17A1 is a key enzyme in the biosynthesis of adrenal and gonadal steroid hormones facilitating both 17?-hydroxylase and 17,20-lyase activities. We characterized a partial CYP17A1 deletion in a Kurdish family with 17OHD by multiplex ligation-dependent probe amplification (MLPA). The index patient presented with amenorrhea and lack of pubertal development. Investigations established the diagnosis of 46,XY disorder of sex development (DSD). She is the daughter of consanguineous parents and has 2 sisters with similar clinical presentation. All patients showed biochemical signs of primary adrenal and gonadal insufficiency. The molecular genetic analysis by PCR suggested a deletion spanning exons 1–6 of the CYP17A1 gene. MLPA analysis confirmed the large partial CYP17A1 deletion in patients and parents in homozygous and heterozygous state, respectively. This is the first report employing MLPA for mutation analysis to detect a deletion of CYP17A1 spanning multiple exons in 3 patients with classic 17OHD. Therefore, it is important to consider large partial CYP17A1 deletions in 17OHD in addition to point mutations in cases where no segregation analysis is possible to determine the correct genotype. PMID:25765894

  19. Large quinacrine study comes under fire from family planners.

    PubMed

    1994-04-01

    A large study among 31,781 women, in 24 provinces of Vietnam, who underwent nonsurgical female sterilization via insertion of 2 doses of quinacrine 30 days apart has various flaws, according to many family planning specialists and researchers. The authors of the study based their findings on just 11,686 women and then extrapolated the results to all 31,781 women. Study providers did not follow a standard protocol. They used data from just 1 province (Namha) to determine the ectopic pregnancy rate (0.89/1000 woman years of use). Study authors are in the process of doing a separate analysis of ectopic pregnancy rates among all 24 provinces. Yet, it may not represent true rates because of the other inconsistencies in the study. Women may have died from ectopic pregnancy, but the researchers would not know this, since the women lived in rural areas. The medical director of the Association for Voluntary Surgical Contraception objects to the study because quinacrine has not gone through an acceptable and thorough regulatory review process. The study authors said that since the least skilled and experienced clinicians had the highest failure rate, and the most skilled and experienced clinicians had the lowest failure rate (17.2% vs. 5.3%), improved skills and more experience of inserting by clinicians would reduce the failure rate. Later analysis of the data by another group found, however, that failures continued despite the size of the series of women, suggesting that the clinician is consistently not performing the procedure correctly. The group attributes failures to other causes (e.g., in utero blood interfering with the action of quinacrine). Other experts attribute the failures to the technology. Since Vietnam has had an aggressive national population program, and a provider secretly inserted quinacrine in a woman in Vietnam recently during a routine exam, family planners fear that women may be forced to accept the quinacrine method. PMID:12318750

  20. Reproductive wastage and developmental disorders in relation to consanguinity in south India.

    PubMed

    Asha Bai, P V; John, T J; Subramaniam, V R

    1981-09-01

    The effect of consanguinity on fertility, reproductive loss and developmental disorders were studied in 156 consanguineous marriages in comparison with 221 non-consanguineous marriages. Although fertility was greater (P less than 0.05) in consanguineous than in non-consanguineous marriages, the number of living children were approximately equal in both groups, on account of increased child mortality in the former (P less than 0.05). The frequencies of abortion and stillbirth were (also) approximately equal in both groups. Developmental anomalies were significantly more frequent (P less than 0.001) among the offspring of consanguineous parents. These results indicate the continued presence of deleterious genes in this population, in spite of the practice of consanguinity over many generations. PMID:7314241

  1. Assessing the influence of consanguinity on congenital heart disease.

    PubMed

    Bittles, Alan H

    2011-07-01

    Numerous articles have been published linking consanguineous marriage to an elevated prevalence of congenital heart disease, with ventricular septal defects and atrial septal defects the most commonly cited disorders. While initially persuasive, on closer examination many of these studies have fundamental shortcomings in their design and in the recruitment of study subjects and controls. Improved matching of cases and controls, to include recognition of the long-established community boundaries within which most marriages are contracted, and the assessment of consanguinity within specific levels and types of marital union would improve and help to focus the study outcomes. At the same time, major discrepancies between studies in their reported prevalence and types of congenital heart disease suggest an urgent need for greater standardization in the classification and reporting of these disorders. PMID:21976867

  2. Does consanguinity affect the severity of pre-eclampsia?

    PubMed

    Badria, L Francis; Amarin, Z O

    2003-06-01

    To determine whether consanguinity is more likely to be associated with severe forms of pre-eclampsia/eclampsia. Presuming a pure genetic contribution, we speculated that consanguineous marriages would increase the occurrence of severe forms of pre-eclampsia/eclampsia, through an expected increased chance for homozygosity to the putative gene. The study is a clinical case series on pre-eclamptic/eclamptic primiparae delivered at Princess Badea Teaching Hospital, which is a tertiary referral center. The internationally accepted definitions for hypertension, proteinuria, mild and severe pre-eclampsia were adopted. The study included 77 primiparae. The incidence of consanguinity in the studied sample was 38%. Of them, 28 (36.4%) had mild pre-eclampsia, 45 (58.4%) had severe pre-eclampsia and four (5.2%) had eclampsia. There was no statistically significant difference in the occurrence of severe pre-eclampsia/eclampsia between primiparae married to a first cousin or a relative other than a first cousin and primiparae married to a non-relative, odds ratio 1.1 (95% CI 0.33-3.87), P value 0.94, odds ratio 2.6 (95% CI 0.45-27.6), P value 0.30, respectively. Also, there was no statistically significant difference in occurrence of severe pre-eclampsia/eclampsia between primiparae whose parents are first cousins or relatives other than a first cousin and primiparae whose parents are non-relatives, odds ratio 1.3 (95% CI 0.36-4.72), P value 0.81, odds ratio 1.61 (95% CI 0.23-18.4), P value 0.70, respectively. Our study did not support a causal relationship between consanguinity and the occurrence of severe pre-eclampsia/eclampsia. The role of more complex genetic, immunologic, metabolic, hemostatic or, possibly yet, other unknown factors have to be explored. PMID:12768302

  3. Consanguinity and late fertility: spatial analysis reveals positive association patterns.

    PubMed

    Lisa, Antonella; Astolfi, Paola; Zei, Gianna; Tentoni, Stefania

    2015-01-01

    The role of consanguinity on human complex traits is an important and controversial issue. In this work we focused on the Sardinian population and examined the effect of consanguineous unions on late female fertility. During the last century the island has been characterized by a high incidence of marriages between relatives, favoured by socio economic conditions and geographical isolation, and by high fertility despite a widespread tendency to delay reproduction. Through spatial analysis techniques, we explored the geographical heterogeneity of consanguinity and late fertility, and identified in Central-Eastern Sardinia a common area with an excess of both traits, where the traits are positively associated. We found that their association did not significantly affect women's fertility in the area, despite the expected negative role of both traits. Intriguingly, this critical zone corresponds well to areas reported by previous studies as being peculiar for a high frequency of centenarians and for lower risk in pregnancy outcome. The proposed approach can be generally exploited to identify target populations on which socioeconomic, biodemographic and genetic data can be collected at the individual level, and deeper analyses carried out to disentangle the determinants of complex biological traits and to investigate their association. PMID:25441534

  4. 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. PMID:26627887

  5. Interplay of Socio-economic Factors, Consanguinity, Fertility, and Offspring Mortality in Monastir, Tunisia

    PubMed Central

    Kerkeni, Emna; Monastiri, Kamel; Seket, Besma; Guediche, Mohamed Neji; Ben Cheikh, Hassen

    2007-01-01

    Aim To assess the association among social status, prevalence of consanguineous marriages, and the effects of consanguinity on reproductive behavior and mortality in Tunisia. Methods The study included data on a total of 1741 live-births born from November 1989 to October 1990 in the maternity ward of the University-Hospital Fattouma Bourguiba of Monastir, Tunisia. After delivery, women filled out a questionnaire on the age of the parents at marriage, the number of pregnancies and abortions, the number of neonatal and post-neonatal deaths, and deaths of children under 5 years. Three categories of marriages were distinguished as follows: marriages between first cousins, marriages between cousins of other degree, and non consanguineous marriages. Results Consanguineous marriages represented 432 (24.81%) of the unions. Most consanguineous marriages were contracted between first cousins (n?=?303; 70.13%). Consanguineous couples had a lower age at marriage and a higher fertility index than non-consanguineous couples. The rates of spontaneous abortions and stillbirths were not correlated with consanguinity. However, higher rates of neonatal and post-neonatal deaths, and deaths of children younger than 5 years were observed in consanguineous couples. Conclusion Fertility index and mortality, especially in the first year of life, were significantly higher in consanguineous marriages. This important socio-economical factor needs to be considered in assessing equity on health in specific social and cultural contexts. PMID:17948956

  6. Inheritance of quantitative dermatoglyphic traits with asymmetry and diversity in Muzeina Bedouin tribe: a small isolated and consanguineous population from South Sinai.

    PubMed

    Karmakar, Bibha; Malkin, Ida; Kobyliansky, Eugene

    2014-06-01

    The genetic factors contribute significantly to the determination of dermatoglyphic traits is well established. However, the controversies in views and findings of this issue are still inconclusive. The present study is an attempt to evaluate the inheritance of quantitative dermatoglyphic traits with asymmetry (DA and FA) and diversity (Div) through sibling correlations. Data include 218 individuals from (88 families) in a small isolate, the nomadic tribe Muzeina with a high degree of consanguinity (0.09) from South Sinai. Statistical analyses include sibling correlations, cross-correlations and genetic correlation (GC)--a ratio of sibling cross-correlation between traits divided on square root of the both traits sibling correlation product. The familial correlation coefficients for quantitative dermatoglyphic traits are perhaps expected lower in such a small isolated and consanguineous population than our previous studied in Indian populations and Chuvashian populations from Russia. These results indicate a simpler genetic basis due to high degree (0.09 inbreeding coefficient) of consanguinity in Muzeina Bedouin tribe. There is no evidence of major gene involvement, although a little genetic effect obtained from familial correlations on asymmetry (DA and FA) and diversity (Div) traits through sibling correlations. The significant interaction between sexes was found, which contradicts with the other populations perhaps due to high level of consanguinity. Lower correlation coefficients than in other non-consanguineous populations for quantitative dermatoglyphic traits indicate a simpler genetic basis due to high degree of inbreeding coefficient (0.09) in Muzeina. Dermatoglyphic asymmetry and diversity traits may be due to environmental factors rather than dominance in Bedouins, although a little genetic effect was found suggests a measure of developmental instability in human (FA). PMID:25144975

  7. 'Silent' carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient.

    PubMed

    Camus, D; Shinar, Y; Aamar, S; Langevitz, P; Ben-Zvi, I; Livneh, A; Lidar, M

    2012-09-01

    The presence of two mutations in the familial Mediterranean fever gene, without overt familial Mediterranean fever (FMF), designated as phenotype III, predisposes to developing 'silent' AA amyloidosis, recognized as phenotype II, due to the absence of medical supervision and colchicine prophylaxis. We sought to determine the prevalence of phenotype III in large families with only one subject affected with FMF, in order to assess the population at risk for transformation to phenotype II. A total of seven large families were recruited for the study. Siblings were screened for MEFV mutations and underwent a clinical interview to assess for unrecognized FMF manifestations. Phenotype III, most commonly associated with a V726A/E148Q genotype, was detected in 10% of siblings of index cases from informative families, corresponding to a 10-fold increase in comparison to the expected rate in the general population (p < 0.01). Unnoticed 'FMF-like' manifestations were detected among two siblings in the five families in which the index case was heterozygous, but in none of the siblings of the homozygous index cases. The enrichment for phenotype III and detection of occult FMF in large families, in which only a single member is afflicted with FMF, mandates routine clinical evaluation and genetic screening of siblings. PMID:21995303

  8. The practice of consanguineous marriage in Oman: prevalence, trends and determinants.

    PubMed

    Islam, M Mazharul

    2012-09-01

    The practice of consanguineous marriage has been the culturally preferred form of marriage in most Arab and the Middle Eastern countries, including Oman, but due to a paucity of population-based data in the past there is a dearth of information about its form and dynamics in Oman. Recent national-level surveys allow this gap to be filled. This paper examines the prevalence, trends and determinants of consanguineous marriages in Oman using data from the 2000 Oman National Health Survey. The results indicate a very high prevalence of consanguineous marriage in Oman, as more than half (52%) of marriages are consanguineous. First cousin unions are the most common type of consanguineous unions, constituting 39% of all marriages and 75% of all consanguineous marriages. The study observed various patterns of consanguinity, some of them common with other Arab nations, and some unique in nature. Women's age at marriage, employment, place of childhood residence and geographical region appear to be significant determinants of consanguineous marriages. Consanguineous marriage shows a strong association with marital stability, early age at marriage and early-age childbearing. There has been no appreciable change in the prevalence of consanguineous unions in Oman over the last four decades despite massive socioeconomic development and modernization. However, recent marriage cohorts show slight declining trends. The results suggest that consanguinity is likely to remain stable in the future or decline at a slow rate. Specific health education and genetic counselling should be followed in line with WHO recommendations to minimize the negative health consequences of consanguinity for child health. PMID:22317781

  9. Effect of consanguinity on Argentinean Angus beef DNA traceability.

    PubMed

    Baldo, A; Rogberg-Muñoz, A; Prando, A; Mello Cesar, A S; Lirón, J P; Sorarrain, N; Ramelli, P; Posik, D M; Pofcher, E; Ripoli, M V; Beretta, E; Peral-García, P; Vaca, R; Mariani, P; Giovambattista, G

    2010-08-01

    Since the 1990s several authors have envisaged the use of DNA to certify meat origin. Two major parameters must be assessed before a DNA based traceability protocol can be implemented in the food chain: (i) the information content of a DNA marker set in a specific livestock breed or group of breeds; (ii) the minimum number of DNA markers needed to obtain a statistically acceptable match probability. The objective of the present work was to establish the effect of different levels of inbreeding in the matching efficiency, and the minimum number of microsatellite markers needed, in a DNA based meat traceability program, starting from an 11-microsatellite marker panel. Samples were obtained from beef production farms in South America, where animals are typically bred under pasture-based extensive conditions. Three groups of animals with different consanguinity rates were sampled. Exclusion power (Q) was higher than 0.999998 and match probability lower than 3.01E-08, for the whole set of markers within each group. Both values were affected by consanguinity. To reach a two mismatch criteria exclusion power (Q(2)) of 99.99, six markers were needed in unrelated animals whereas seven markers were needed in related animals. To reach Q(2)=99.9999, 8 and 10 microsatellite markers, respectively, were needed. In general, one or two more microsatellite markers were needed to identify consanguineous animals. This study proved the DNA marker set used to be suitable for the identification of the meat from all slaughtered animals in Argentina, per week, month, and year. PMID:20416796

  10. Broad scan linkage analysis in a large Tourette family pedigree

    SciTech Connect

    Peiffer, A.; Leppert, M.; Wetering, B.J.M. van der

    1994-09-01

    Attempts to find a gene causing Tourette syndrome (TS) using linkage analysis have been unsuccessful even though as much as 65% of the autosomal genetic map has been excluded by the pooled results from several laboratories collaborating worldwide. One reason for this failure may be the misclassification of affection status of marry-in spouses. Specifically, we have found that six unrelated spouses in our Utah TS pedigree suffer from TS, obsessive-compulsive disorder or chronic motor tics. In light of these findings we decided to conduct a complete genomic scan from this Utah kindred with polymorphic markers in three related sibships in which there was no assortative mating. A linkage study assuming autosomal dominant inheritance was done using tetranucleotide repeat markers developed at the University of Utah. We selected markers that were less than 300 bp in size and that gave a heterozygosity of over 70% upon analysis in 4 CEPH families. Results to date with 95 markers run at an interval of 30 cM (covering 61% of the genome) show no evidence of linkage. We intend to extend the coverage to 100% of the genome. Pending completion of this scan, failure to provide evidence of linkage in our TS pedigree might then be attributed to phenotypic misclassification or erroneous assumptions regarding the genetic model of transmission.

  11. Fertility Related Attitudes of Minority Mothers with Large and Small Families.

    ERIC Educational Resources Information Center

    Linn, Margaret W.; And Others

    The relationship between certain attitudes and the levels of fertility in five cultural groups was explored in this study. The group studied were blacks, Cubans, American Indians, migrant Chicanos, and white Protestants. Mothers, aged 35-45, with one or two children (small family) or five children (large family) were compared. Attitudes measured…

  12. [Consanguineous marriages, inbreeding and its effects in the Taimyr Nganasans].

    PubMed

    Gol'tsova, T V

    1981-01-01

    Genealogy, marriage structure, inbreeding and its effects in Taimyr Nganasans have been studied in detail. The population size in 715. 223 pairs were analysed. Uncle-niece and first cousin marriages were absent. Marriage frequency of second cousins and more remote relatives is 20.0%. Average inbreeding coefficient of the population is 0.0022 with some variation among three subpopulations (0.0015-0.0027). Consanguineous marriages are characterized by lower average number of livebirths, living children, stillbirths and miscarriages. There are some difficulties in the interpretation of the differences received because of a higher incidence of repeated marriages between relatives; 6 cases of hereditary diseases were registered among the offsprings of nonconsanguineous marriages, including two cases with one parent inbred. PMID:7195855

  13. Malaysia: where big is still better. For Malays, large families are part of the plan.

    PubMed

    1993-11-01

    The benefits of various-sized families in Malaysia were discussed by several women and supplemented with official statements on family planning (FP). The Director of the National Population and Family Development, Dr. Raj Karim, advised that maternal health is jeopardized when women have more than five children. About 30% of reproductive age women in Malaysia have five or more children. A Federation of FP Associations spokesperson agreed that women should be advised of the dangers of bearing over five children, of the importance of spacing births two to four years apart, and of the ideal age of childbearing (21-39 years). The government lacks an official policy on family size. The government position is, however, compatible with Islamic teachings on spacing in order to protect the health of the mother and child. Islamic law does not permit sterilization or abortion. The "fatwas" of Islamic teaching may have been misconstrued by those not using any form of contraception. Dr. Karim, who has five children, reported that having a large family can be difficult for a woman with a job, a career, and a husband or when both parents work. Most Malays desire large families. The average Malay family size was 4.1 children in 1990; Malaysian Chinese have fertility of 2.3 children and Malaysian Indians have 2.6 children. People say that the benefits outweigh the hardships of a large family. PMID:12287219

  14. Finnish type of familial amyloidosis: cosegregation of Asp187----Asn mutation of gelsolin with the disease in three large families.

    PubMed Central

    Hiltunen, T; Kiuru, S; Hongell, V; Heliö, T; Palo, J; Peltonen, L

    1991-01-01

    Familial amyloidosis of Finnish type (FAF) is one of the familial amyloidotic polyneuropathy (FAP) syndromes, a group of inherited disorders characterized by extracellular accumulation of amyloid and by clinical symptoms and signs of polyneuropathy. FAF, an autosomal dominant trait, belongs to those rare monogenic disorders which occur with increased frequency in the Finnish population: only single FAF cases have been reported from other populations. In most types of FAP syndromes the accumulating protein is a transthyretin variant. However, recent evidence has suggested that the amyloid peptides in FAF are related to gelsolin, an actin modulating protein. The gelsolin fragments isolated from at least one patient with amyloidosis have been reported to have an amino acid substitution, with asparagine replacing aspartic acid at position 187 of the plasma gelsolin. In this study allele-specific oligonucleotides were used to analyze three large FAF families with multiple affected individuals as well as healthy family members. We found the corresponding G-A mutation in nucleotide 654 of the plasma gelsolin gene to cosegregate with the disease. The result was confirmed by sequencing and strongly suggests that the mutation has caused all the FAF cases of these families. Since the disease is clustered in restricted areas on the southern coast of Finland, this mutation most probably causes the majority, if not all, of FAF cases in Finland. Images Figure 2 PMID:1652889

  15. Internal organization of large protein families: relationship between the sequence, structure and function based clustering

    PubMed Central

    Cai, Xiao-hui; Jaroszewski, Lukasz; Wooley, John; Godzik, Adam

    2011-01-01

    The protein universe can be organized in families that group proteins sharing common ancestry. Such families display variable levels of structural and functional divergence, from homogenous families, where all members have the same function and very similar structure, to very divergent families, where large variations in function and structure are observed. For practical purposes of structure and function prediction, it would be beneficial to identify sub-groups of proteins with highly similar structures (iso-structural) and/or functions (iso-functional) within divergent protein families. We compared three algorithms in their ability to cluster large protein families and discuss whether any of these methods could reliably identify such iso-structural or iso-functional groups. We show that clustering using profile-sequence and profile-profile comparison methods closely reproduces clusters based on similarities between 3D structures or clusters of proteins with similar biological functions. In contrast, the still commonly used sequence-based methods with fixed thresholds result in vast overestimates of structural and functional diversity in protein families. As a result, these methods also overestimate the number of protein structures that have to be determined to fully characterize structural space of such families. The fact that one can build reliable models based on apparently distantly related templates is crucial for extracting maximal amount of information from new sequencing projects. PMID:21671455

  16. Marfan syndrome in a large family: response of family members to a screening programme.

    PubMed Central

    Bridges, A B; Faed, M; Boxer, M; Gray, J R; Bundy, C; Murray, A

    1992-01-01

    Reaction to medical, social, and genetic implications of Marfan syndrome was evaluated by means of two questionnaires, the first after various tests before discussion of the diagnosis, the second after full discussion of the patient's diagnosis. Thirty-seven members of a family known to be at risk for Marfan syndrome attended for both questionnaires. All patients claimed to be satisfied with the way they were informed of the results of screening; 41% of patients were more worried about their health and 48% were more worried about the future after diagnosis. Apart from 50% of the smokers reducing or stopping their intake of cigarettes there were only very minor changes in lifestyle over the first month despite the increased level of expressed anxiety. If a definitive screening test was available, 96% of patients claimed they would have chosen it, 45% felt it would have an influence on their future plans, and 78% would choose to use a method of prenatal diagnosis for Marfan syndrome if it were available. PMID:1613770

  17. Consanguinity and endogamy in the Netherlands: demographic and medical genetic aspects.

    PubMed

    Ten Kate, Leo P; Teeuw, Marieke E; Henneman, Lidewij; Cornel, Martina C

    2014-01-01

    This paper reviews what is currently known about the presence of consanguinity and endogamy in the Netherlands, in the past and today, and concludes with a discussion of medical genetic aspects. First geographic characteristics, the demographic history, the genetic make-up of the native population, legal aspects and the public opinion are reviewed. Then data on the prevalence of consanguinity in the native population are presented for marriages since 1840, followed by data on consanguineous marriages among immigrants from countries with a tradition of close-kin marriages. It is estimated that approximately 1% of at-risk consanguineous couples are referred to clinical genetic centres for prospective genetic counselling in the Netherlands. This picture will change dramatically if and when next-generation sequencing is introduced to identify couples at ? 25% risk prospectively. PMID:25060279

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

    PubMed

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

    2014-01-01

    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. PMID:24995749

  19. Vici syndrome in siblings born to consanguineous parents.

    PubMed

    Tasdemir, Sener; Sahin, Ibrahim; Cay?r, Atilla; Yuce, Ihsan; Ceylaner, Serdar; Tatar, Abdulgani

    2016-01-01

    Vici syndrome (OMIM 242840) is a rare syndrome and since its initial description by Vici et al. [1988], only 29 cases have been reported. We describe two brothers from healthy consanguineous Turkish parents with psychomotor delay, congenital bilateral cataracts, high palate, long philtrum, micrognathia, fair hair, and skin. They both had general hypotonia and elevated muscle enzymes. Magnetic resonance imaging (MRI) of the brain confirmed agenesis of corpus callosum in both patients. Secundum type atrial septal defect (in Patient 1) and mild mitral, tricuspid, and pulmonary insufficiency (in Patient 2) were detected by echocardiographic examination. Immunological studies were normal, as were chromosome karyotype analyses (46, XY). Both children had bilateral cutaneous syndactyly between second and third toes and also bilateral sensorineural hearing loss. Patient 1 had poor feeding and regurgitation necessitating a feeding tube; mild laryngomalacia was subsequently detected by bronchoscopy. Mutation analysis in patient 2 showed a homozygous p.R2483* (c.7447C?>?T) mutation in EPG5 gene. We report a summary of the clinical findings in our patients and 29 cases from the literature. © 2015 Wiley Periodicals, Inc. PMID:26395118

  20. Classic Kaposi sarcoma in 3 unrelated Turkish children born to consanguineous kindreds.

    PubMed

    Sahin, Gürses; Palanduz, Ayse; Aydogan, Gonul; Cassar, Olivier; Ertem, A Ulya; Telhan, Leyla; Canpolat, Nur; Jouanguy, Emmanuelle; Picard, Capucine; Gessain, Antoine; Abel, Laurent; Casanova, Jean-Laurent; Plancoulaine, Sabine

    2010-03-01

    Infection by human herpesvirus 8 (HHV-8) in childhood is common in the Mediterranean basin; however, classic Kaposi sarcoma (KS) is exceedingly rare in children not infected with HIV and not receiving immunosuppression, with only 30 cases having been reported since 1960. We recently reported 2 children with autosomal and X-linked recessive primary immunodeficiencies underlying KS in a context of multiple clinical manifestations. These reports suggested that classic KS in otherwise healthy children might also result from inborn errors of immunity more specific to HHV-8. In this article, we describe 3 unrelated Turkish children with classic KS born to first-cousin parents. The first patient, a girl, developed KS at 2 years of age with disseminated cutaneous and mucosal lesions. The clinical course progressed rapidly, and the patient died within 3 months despite treatment with vincristine. The other 2 children developed a milder form of KS at the age of 9 years, with multiple cutaneous lesions. A boy treated with interferon alpha therapy for 12 months is now in full remission at the age of 14, 2 years after treatment. The second girl is currently stabilized with etoposide, which was begun 4 months ago. None of the 3 children had any relevant familial history or other clinical features. The occurrence of classic KS in 3 unrelated Turkish children, each born to consanguineous parents, strongly suggests that autosomal recessive predisposition may drive the rare occurrence of HHV-8-associated classic KS in children. PMID:20156905

  1. Creating a Family-Like Atmosphere in Child Care Settings: All the More Difficult in Large Child Care Centers.

    ERIC Educational Resources Information Center

    Whitehead, Linda C.; Ginsberg, Stacey I.

    1999-01-01

    Presents suggestions for creating family-like programs in large child-care centers in three areas: (1) physical environment, incorporating cozy spaces, beauty, and space for family interaction; (2) caregiving climate, such as sharing home photographs, and serving meals family style; and (3) family involvement, including regular conversations with…

  2. Has consanguinity any impact on occurrence of pre-eclampsia and eclampsia?

    PubMed

    Badria, L F; Abu-Heija, A; Zayed, F; Ziadeh, S M; Alchalabi, H

    2001-07-01

    In this study we tested the hypothesis of an association between consanguinity and pre-eclampsia/eclampsia. This is a case-control study conducted at Princess Badea Teaching Hospital, Irbid-Jordan during the period May 1997-April 1998. The study population were Jordanian women delivered at Princess Badea Teaching Hospital with or without hypertensive disorders of pregnancy. The total number was 208 pre-eclamptic/eclamptic women (76 primiparous and 132 multiparous) and 618 randomly selected non-hypertensive women. In primiparous as well as multiparous women, it was evident that neither consanguinity nor the degree of the relationship to the husband in consanguineous marriages had an impact on the incidence of preeclampsia/eclampsia. However, comparing the incidence of consanguinity between pre-eclamptic/eclamptic and non-hypertensive, multiparous women married to a relative other than first cousin, the P value was 0.0248, which we explained as chance incidence. When we compared the incidence of consanguineous marriages as a whole between pre-eclamptic/eclamptic and non-hypertensive, multiparous women, there was no evidence of any impact of consanguinity on the incidence of pre-eclampsia/eclampsia. PMID:12521826

  3. Large-scale mitochondrial DNA deletion underlying familial multiple system atrophy of the cerebellar subtype.

    PubMed

    Alsemari, Abdulaziz; Al-Hindi, Hindi Nasser

    2016-02-01

    A family with mitochondrial inheritance of multiple system atrophy of the cerebellar subtype. MRI brain shows significant cerebellar atrophy with mild pontine atrophy and the classical hot cross bun sign in Pons. The muscle biopsy was indicative of mitochondrial myopathy. Mitochondrial DNA analysis revealed a low-level large mtDNA deletion, m.3264_1607del12806 bp. PMID:26862402

  4. 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. PMID:19895726

  5. Genetic heterogeneity in psoriasis vulgaris based on linkage analyses of a large family material

    SciTech Connect

    Wahlstroem, J.; Swanbeck, G.; Inerot, A.

    1994-09-01

    Information on psoriasis among parents and siblings in 14,008 families has been collected. On the basis of this material, evidence for monogenetic autosomal recessive inheritance of psoriasis has recently been presented. Indications from more than one type of non-pustular psoriasis has been obtained from the population genetic data. Molecular genetic linkage analysis of psoriasis to a number of polymorphic genetic markers for a large number of families has been made. It is apparent that there is genetic heterogeneity in a psoriasis population with regard to psoriasis genes. Using the computer program Linkage 5.0 and a formula for heterogeneity, a lodscore over 3.0 for one locus has been obtained. This locus has further been confirmed by several other markers in the vicinity. The locus found is linked to slightly over half of the families, indicating that there are more genetically independent types of psoriasis. The age at onset of those families that are apparently linked to this locus have a slightly higher age at onset than those not linked to that locus but with a considerable overlap. In spite of close coverage of the whole chromosomes number 6 and 17, no linkage has been found in this regions. This indicates that neither the HLA region nor the region earlier found to be involved in one family with psoriasis are primarily involved in our families.

  6. Combined genetic and imaging diagnosis for two large Chinese families affected with Pelizaeus-Merzbacher disease.

    PubMed

    Lv, Y; Cao, L H; Pang, H; Lu, L N; Li, J L; Fu, Y; Qi, S L; Luo, Y; Li-Ling, J

    2012-01-01

    Pelizaeus-Merzbacher disease (PMD) is a rare X-linked recessive disorder characterized by nystagmus, impaired motor development, ataxia, and progressive spasticity. Genetically defective or altered levels of proteolipid protein (PLP1) or gap-junction alpha protein 12 gene have been found to be a common cause. Here we report on two large Han Chinese families affected with this disease. The probands of both families had produced sons featuring cerebral palsy that had never been correctly diagnosed. PMD was suspected after careful analysis of family history and clinical features. Three rounds of molecular testing, including RT-PCR, genetics linkage and SRY sequence analyses, in combination with fetal ultrasound and magnetic resonance imaging, confirmed the diagnosis. In Family 1, in addition to two patients, three carriers were identified, including one who was not yet married. Genetic testing indicated that a fetus did not have the disease. A healthy girl was born later. In Family 2, two patients and two carriers were identified, while a fetus was genetically normal. A healthy girl was born later. We concluded that by combining genetic testing and imaging, awareness of the symptoms of PMD and understanding of its molecular biology, there is great benefit for families that are at risk for producing offspring affected with this severe disease. PMID:22911587

  7. Large, rapidly evolving gene families are at the forefront of host-parasite interactions in Apicomplexa.

    PubMed

    Reid, Adam J

    2015-02-01

    The Apicomplexa is a phylum of parasitic protozoa, which includes the malaria parasite Plasmodium, amongst other species that can devastate human and animal health. The past decade has seen the release of genome sequences for many of the most important apicomplexan species, providing an excellent basis for improving our understanding of their biology. One of the key features of each genome is a unique set of large, variant gene families. Although closely related species share the same families, even different types of malaria parasite have distinct families. In some species they tend to be found at the ends of chromosomes, which may facilitate aspects of gene expression regulation and generation of sequence diversity. In others they are scattered apparently randomly across chromosomes. For some families there is evidence they are involved in antigenic variation, immune regulation and immune evasion. For others there are no known functions. Even where function is unknown these families are most often predicted to be exposed to the host, contain much sequence diversity and evolve rapidly. Based on these properties it is clear that they are at the forefront of host-parasite interactions. In this review I compare and contrast the genomic context, gene structure, gene expression, protein localization and function of these families across different species. PMID:25257746

  8. Identification of a novel FBN1 gene mutation in a large Pakistani family with Marfan syndrome

    PubMed Central

    Micheal, Shazia; Khan, Muhammad Imran; Akhtar, Farah; Weiss, Marjan M.; Islam, Farah; Ali, Mehmood; Qamar, Raheel; Maugeri, Alessandra

    2012-01-01

    Purpose To describe a novel mutation in the fibrillin-1 (FBN1) gene in a large Pakistani family with autosomal dominant Marfan syndrome (MFS). Methods Blood samples were collected of 11 family members affected with Marfan syndrome, and DNA was isolated by phenol-extraction. The coding exons of FBN1 were analyzed by polymerase chain reaction (PCR) and direct sequencing. One hundred-thirty controls were screened for a mutation in the FBN1 gene that was identified in this family by restriction fragment length polymorphism (RFLP) analysis. Results A novel heterozygous missense mutation c.2368T>A; p.Cys790Ser was observed in exon 19. This mutation substitutes a highly conserved cysteine residue by serine in a calcium binding epidermal growth factor-like domain (cbEGF) of FBN1. This mutation was present in all affected members and absent from unaffected individuals of the family in addition to 130 healthy Pakistani controls. Interestingly all affected family members presented with ectopia lentis, myopia and glaucoma, but lacked the cardinal cardiovascular features of MFS. Conclusions This is a first report of a mutation in FBN1 in MFS patients of Pakistani origin. The identification of a FBN1 mutation in this family confirms the diagnosis of MFS patients and expands the worldwide spectrum of FBN1 mutations. PMID:22876116

  9. Bombay blood group: Is prevalence decreasing with urbanization and the decreasing rate of consanguineous marriage

    PubMed Central

    Mallick, Sujata; Kotasthane, Dhananjay S.; Chowdhury, Puskar S.; Sarkar, Sonali

    2015-01-01

    Context: Bombay blood group although rare is found to be more prevalent in the Western and Southern states of India, believed to be associated with consanguineous marriage. Aims: To estimate the prevalence of the Bombay blood group (Oh) in the urban population of Puducherry. To find the effect of urbanization on consanguineous marriage and to establish whether consanguinity plays a part in the prevalence of Oh group. To compare Oh group prevalence with that of other neighboring states, where population is not predominantly urban. Settings and Design: This is a descriptive study in a tertiary care hospital in Puducherry, over a period of 6 years. Materials and Methods: All blood samples showing ‘O’ group were tested with anti-H lectin. Specialized tests like Adsorption Elution Technique, inhibition assay for determination of secretor status were performed on Oh positive cases. Any history of consanguineous marriage was recorded. Statistical Analysis Used: All variables were categorical variable and percentage and proportions were calculated manually. Results: Analysis of the results of 35,497 study subjects showed that the most common group was ‘O’ group constituting 14,164 (39.90%) of subjects. Only three “Oh” that is, Bombay phenotype (0.008%) were detected. Consanguinity was observed in two cases (66.66%). Conclusions: This study shows the prevalence of Bombay blood group representing the urban population of Puducherry, to be high (0.008%) and associated with consanguineous marriage (66.66%). Thus, consanguinity is still an important risk factor present, even in an urban population in Southern India. PMID:26420929

  10. Evaluating the feasibility of using candidate DNA barcodes in discriminating species of the large Asteraceae family

    PubMed Central

    2010-01-01

    Background Five DNA regions, namely, rbcL, matK, ITS, ITS2, and psbA-trnH, have been recommended as primary DNA barcodes for plants. Studies evaluating these regions for species identification in the large plant taxon, which includes a large number of closely related species, have rarely been reported. Results The feasibility of using the five proposed DNA regions was tested for discriminating plant species within Asteraceae, the largest family of flowering plants. Among these markers, ITS2 was the most useful in terms of universality, sequence variation, and identification capability in the Asteraceae family. The species discriminating power of ITS2 was also explored in a large pool of 3,490 Asteraceae sequences that represent 2,315 species belonging to 494 different genera. The result shows that ITS2 correctly identified 76.4% and 97.4% of plant samples at the species and genus levels, respectively. In addition, ITS2 displayed a variable ability to discriminate related species within different genera. Conclusions ITS2 is the best DNA barcode for the Asteraceae family. This approach significantly broadens the application of DNA barcoding to resolve classification problems in the family Asteraceae at the genera and species levels. PMID:20977734

  11. [Family investigation and clinical genetic analysis of a large pedigree with congenital stationary night blindness].

    PubMed

    Fei, Y J

    1992-05-01

    A large pedigree of congenital stationary night blindness (CSNB) was investigated by both the family method and the family history method, and the diagnosis was confirmed by dark adaptation and full-field electroretinogram tests. There were 57 affected members of 7 successive generations in the pedigree which showed typical autosomal dominant inheritance with a complete gene penetrance. Based on this study and other sources, the genetic aspect and the clinical manifestations of CSNB, especially the characteristics of dark adaptation and electroretinogram, were discussed. PMID:1286605

  12. 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

  13. Large French-Canadian family with Lewy body parkinsonism: exclusion of known loci.

    PubMed

    Grimes, David A; Grimes, J David; Racacho, Lem; Scoggan, Kylie A; Han, Fabin; Schwarz, Betty Anne; Woulfe, John; Bulman, Dennise

    2002-11-01

    The identification of rare, large families with Parkinson's disease (PD) has provided important clues that have contributed to our understanding of this complex disorder. We have identified a large French-Canadian kindred that spans five generations consisting of more than 90 individuals. A total of 65 individuals now have been examined, had venous blood drawn, and DNA extracted. Two-point and multipoint linkage analysis was performed to assess linkage to known PD genes or loci. Within the third and fourth generations of this family there are 10 living, plus 3 deceased members with well-documented levodopa responsive parkinsonism. Autopsy results on 1 member demonstrated the loss of pigmented neurons in the substantia nigra and the presence of alpha-synuclein positive Lewy bodies. Four of the PD patients have prominent postural and kinetic tremors that preceded their parkinsonism by up to 10 years. Two other individuals within the family have prominent isolated postural and kinetic tremors without parkinsonism. The alpha-synuclein(4q21.3-23), Parkin(6q25.2-27), PARK3 (2p13), PARK4, and ubiquitin carboxy terminal hydrolase-L1 (4p14-16.3) and PARK6 and PARK7 (1p35-36) loci were excluded in this kindred using closely linked markers. The clinical and pathological features of this family are consistent with the diagnosis of PD. This family further demonstrates the known genetic heterogeneity in PD and is large enough that a genome-wide screen has been undertaken in an effort to identify a novel PD gene. PMID:12465058

  14. Identification of a rhodopsin gene mutation in a large family with autosomal dominant retinitis pigmentosa

    PubMed Central

    Yu, Xinping; Shi, Wei; Cheng, Lulu; Wang, Yanfang; Chen, Ding; Hu, Xuting; Xu, Jinling; Xu, Limin; Wu, Yaming; Qu, Jia; Gu, Feng

    2016-01-01

    Retinitis pigmentosa (RP) is a genetically highly heterogeneous retinal disease and one of the leading causes of blindness in the world. Next-generation sequencing technology has enormous potential for determining the genetic etiology of RP. We sought to identify the underlying genetic defect in a 35-year-old male from an autosomal-dominant RP family with 14 affected individuals. By capturing next-generation sequencing (CNGS) of 144 genes associated with retinal diseases, we identified eight novel DNA variants; however, none of them cosegregated for all the members of the family. Further analysis of the CNGS data led to identification of a recurrent missense mutation (c.403C?>?T, p.R135W) in the rhodopsin (RHO) gene, which cosegregated with all affected individuals in the family and was not observed in any of the unaffected family members. The p.R135W mutation has a reference single nucleotide polymorphism (SNP) ID (rs104893775), and it appears to be responsible for the disease in this large family. This study highlights the importance of examining NGS data with reference SNP IDs. Thus, our study is important for data analysis of NGS-based clinical genetic diagnoses. PMID:26794436

  15. A large multigene family codes for the polypeptides of the crystalline trichocyst matrix in Paramecium.

    PubMed Central

    Madeddu, L; Gautier, M C; Vayssié, L; Houari, A; Sperling, L

    1995-01-01

    The secretory granules (trichocysts) of Paramecium are characterized by a highly constrained shape that reflects the crystalline organization of their protein contents. Yet the crystalline trichocyst content is composed not of a single protein but of a family of related polypeptides that derive from a family of precursors by protein processing. In this paper we show that a multigene family, of unusually large size for a unicellular organism, codes for these proteins. The family is organized in subfamilies; each subfamily codes for proteins with different primary structures, but within the subfamilies several genes code for nearly identical proteins. For one subfamily, we have obtained direct evidence that the different members are coexpressed. The three subfamilies we have characterized are located on different macronuclear chromosomes. Typical 23-29 nucleotide Paramecium introns are found in one of the regions studied and the intron sequences are more variable than the surrounding coding sequences, providing gene-specific markers. We suggest that this multigene family may have evolved to assure a microheterogeneity of structural proteins necessary for morphogenesis of a complex secretory granule core with a constrained shape and dynamic properties: genetic analysis has shown that correct assembly of the crystalline core is necessary for trichocyst function. Images PMID:7579685

  16. Clinical and linkage study of a large family with simple ectopia lentis linked to FBN1

    SciTech Connect

    Edwards, M.J.; Roberts, J.; Partington, M.W.; Colley, P.W.; Hollway, G.E.; Kozman, H.M.; Mulley, J.C.

    1994-10-15

    Simple ectopia lentis (EL) was studied in a large family, by clinical examination and analysis of linkage to markers in the region of FBN1, the gene for fibrillin which causes Marfan syndrome on chromosome 15. No patient had clinical or echocardiographic evidence of Marfan syndrome, although there was a trend towards relatively longer measurements of height; lower segment; arm span; middle finger, hand, and foot length in the affected members of the family, compared with unaffected sibs of the same sex. Analysis of linkage to intragenic FBN1 markers was inconclusive because they were relatively uninformative. Construction of a multipoint background map from the CEPH reference families identified microsatellite markers linked closely to FBN1 which could demonstrate linkage of EL in this family to the FBN1 region. LINKMAP analysis detected a multipoint lod score of 5.68 at D15S119, a marker approximately 6 cM distal to FBN1, and a multipoint lod score of 5.04 at FBN1. The EL gene in this family is likely to be allelic to Marfan syndrome, and molecular characterization of the FBN1 mutation should now be possible. 25 refs., 6 figs., 2 tabs.

  17. Identification of a rhodopsin gene mutation in a large family with autosomal dominant retinitis pigmentosa.

    PubMed

    Yu, Xinping; Shi, Wei; Cheng, Lulu; Wang, Yanfang; Chen, Ding; Hu, Xuting; Xu, Jinling; Xu, Limin; Wu, Yaming; Qu, Jia; Gu, Feng

    2016-01-01

    Retinitis pigmentosa (RP) is a genetically highly heterogeneous retinal disease and one of the leading causes of blindness in the world. Next-generation sequencing technology has enormous potential for determining the genetic etiology of RP. We sought to identify the underlying genetic defect in a 35-year-old male from an autosomal-dominant RP family with 14 affected individuals. By capturing next-generation sequencing (CNGS) of 144 genes associated with retinal diseases, we identified eight novel DNA variants; however, none of them cosegregated for all the members of the family. Further analysis of the CNGS data led to identification of a recurrent missense mutation (c.403C?>?T, p.R135W) in the rhodopsin (RHO) gene, which cosegregated with all affected individuals in the family and was not observed in any of the unaffected family members. The p.R135W mutation has a reference single nucleotide polymorphism (SNP) ID (rs104893775), and it appears to be responsible for the disease in this large family. This study highlights the importance of examining NGS data with reference SNP IDs. Thus, our study is important for data analysis of NGS-based clinical genetic diagnoses. PMID:26794436

  18. Clinical expression of developmental coordination disorder in a large Canadian family.

    PubMed

    Gaines, Robin; Collins, David; Boycott, Kym; Missiuna, Cheryl; Delaat, Denise; Soucie, Helen

    2008-11-01

    Previous studies of the phenotype of developmental coordination disorder (DCD) have largely concentrated on population-based samples. The present study reports on an in-depth examination of a large Canadian family with eight children, after three children who were suspected to have DCD were referred for evaluation. Subsequently, five of the six children whose motor impairments could be measured, and the mother, met the diagnostic criteria for DCD as per the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders - fourth edition. The family members diagnosed with DCD showed remarkably similar profiles of motor difficulties. Additionally, the five children diagnosed with DCD had current speech articulation difficulties, with four of them having visited speech/language pathologists; the mother had a lateral lisp. More in-depth testing for three children revealed intact intellectual, academic and language comprehension skills. Three of the children diagnosed with DCD were obese. The present report highlights familial clustering of DCD and the presence of comorbid conditions in the affected children. PMID:19436536

  19. Towards identification of an epilepsy gene in a large family with idiopathic generalized epilepsy

    SciTech Connect

    Roussear, M.; Lopes-Cendes, I.; Berkovic, S.F.

    1994-09-01

    To identify the disease gene in a large, multiplex family segregating an autosomal dominant form of idiopathic generalized epilepsy (IGE). The IGEs have been recognized for several decades as being genetically determined. However, large pedigrees with a clear Mendelian inheritance are not commonly available. This, and the presence of locus heterogeneity have been obstacles to the identification of linkage in several IGE syndromes. We have identified a large IGE kindred with fifty-eight living individuals, including 26 affecteds, showing a clear autosomal dominant inheritance with incomplete penetrance. Forty-fur informative individuals, including 23 affecteds, were selected for the linkage studies. We have chosen 200 polymorphic microsatellite markers, about 20 cM apart, throughout the human autosomes as a genome-search linkage strategy. To date, 47 markers, representing 30% of the human genome, have been excluded for linkage in the Australian kindred. As our study progresses, we will report up-to-date results.

  20. Penetrance and clinical consequences of a gross SDHB deletion in a large family

    PubMed Central

    Solis, DC; Burnichon, N; Timmers, HJLM; Raygada, MJ; Kozupa, A; Merino, MJ; Makey, D; Adams, KT; Venisse, A; Gimenez-Roqueplo, A-P; Pacak, K

    2016-01-01

    Mutations in the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) are inherited in an autosomal dominant manner and are associated with hereditary paraganglioma (PGL) and pheochromocytoma. The phenotype of patients with SDHB point mutations has been previously described. However, the phenotype and penetrance of gross SDHB deletions have not been well characterized as they are rarely described. The objective was to describe the phenotype and estimate the penetrance of an exon 1 large SDHB deletion in one kindred. A retrospective and prospective study of 41 relatives across five generations was carried out. The main outcome measures were genetic testing, clinical presentations, plasma catecholamines and their O-methylated metabolites. Of the 41 mutation carriers identified, 11 were diagnosed with PGL, 12 were found to be healthy carriers after evaluation, and 18 were reportedly healthy based on family history accounts. The penetrance of PGL related to the exon 1 large SDHB deletion in this family was estimated to be 35% by age 40. Variable expressivity of the phenotype associated with a large exon 1 SDHB deletion was observed, including low penetrance, diverse primary PGL tumor locations, and malignant potential. PMID:19389109

  1. Impact of consanguinity on cardio-metabolic health and other diseases: findings from an Afro-Indian tribal community.

    PubMed

    Bhasin, Prerna; Kapoor, Satwanti

    2015-04-01

    Numerous anthropological reports have indicated consanguineous marriage in populous Asian countries, but the overall impact of first cousin marriage on survival and health of specific communities has rarely been reported. The aim of the study was to estimate risks for various complex diseases in the progeny of consanguineous parents. A cross-sectional study was conducted among 222 women among Siddis, a particularly vulnerable tribal group in the state of Gujarat, India, who are Sunni Muslims by faith. The Siddis are not part of the original Negrito element of India. They are descendants of Africans from Northeast and East Africa who were brought to India as slaves, soldiers, or servants. The degree of consanguinity between each female and her spouse and the degree of consanguinity between their parents and proband's grandparents were recorded with the help of pedigrees. The results showed that the rate of consanguinity in the present generation was 49 % (N?=?109), higher than preceding generations. A significant association was observed between women's age, educational level, occupational status, consanguineous parents, and consanguinity. Socioeconomic status and consanguinity showed U-shaped associations. Nearly three times odds for cardio-metabolic risks (2.65 odds ratio (OR) for heart diseases, 2.44 OR for diabetes mellitus, and 2.62 OR for hypertension) have been contracted in the progeny of consanguineous marriage in the parental generation. The risk of cardio-metabolic diseases is higher in offspring of consanguineous couples, and there is a significant increase in the prevalence of common adult diseases. PMID:25524067

  2. 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…

  3. The multiple occurrence of myeloma and asymptomatic paraproteinaemia within one family

    PubMed Central

    Meijers, Katharina A. E.; de Leeuw, B.; Voormolen-Kálova, Milena

    1972-01-01

    Case histories are described of three patients who died of myeloma and of three persons with asymptomatic paraproteinaemia. They were first and second degree relatives in two generations of a Dutch family without consanguinity. PMID:4567645

  4. Identification of a GJA3 Mutation in a Large Family with Bilateral Congenital Cataract.

    PubMed

    Li, Bin; Liu, Yuying; Liu, Yaning; Guo, Hui; Hu, Zhengmao; Xia, Kun; Jin, Xuemin

    2016-03-01

    The congenital cataract has been a clinically important cause of impaired vision development, making up about 10% of the cases of childhood blindness. Mutations of more than 40 genes have been identified causing congenital cataract with Mendelian inheritance, which indicated that it has an extremely high genetic heterogeneity. In this study, we recruited a large congenital cataract family and identified a missense mutation (c.143A>G: p.E48G) within gap junction protein alpha-3 (GJA3) gene in the proband using whole exome sequencing. Subsequent Sanger sequencing of this mutation in all family members revealed that this mutation cosegregated with the phenotype in the family with full penetrance. Our study identified a mutation in GJA3 that correlated with congenital cataract phenotype, which was not reported previously, and would be of benefit to the diagnosis of this genetic disorder. This finding expands the mutation spectrum of GJA3 and provides useful information for further study of the molecular pathogenesis of congenital cataract. PMID:26683566

  5. Premature ovarian failure and FMR1 premutation co-segregation in a large Brazilian family.

    PubMed

    Machado-Ferreira, M C; Costa-Lima, M A; Boy, R T; Esteves, G S; Pimentel, M M G

    2002-08-01

    Fragile X syndrome is the most common form of inherited mental retardation in men. The molecular mechanism underlying the disease is an amplification of a polymorphic trinucleotide repeat (CGG)n located at 5' end of FMR1 which promotes transcriptional silencing of the gene. Four different classes of alleles could be distinguished in the population based on the size of the repeat, however only large amplifications over 200 CGG are associated with the disease. In the past decade several authors have associated premutated alleles, which harbor expansions from 61 to 200 repeats, with the occurrence of premature ovarian failure (POF). In this work we describe a large Brazilian family in which a POF/premutated woman has transmitted to five out of seven daughters a FMR1 premutated allele. From these five women with premutations, three have experienced premature ovarian failure. Our data clearly indicate a co-segregation pattern of inheritance between POF and fragile X premutation. PMID:12119565

  6. The influence of admixture and consanguinity on population genetic diversity in Middle East.

    PubMed

    Yang, Xiong; Al-Bustan, Suzanne; Feng, Qidi; Guo, Wei; Ma, Zhiming; Marafie, Makia; Jacob, Sindhu; Al-Mulla, Fahd; Xu, Shuhua

    2014-11-01

    The Middle East (ME) is an important crossroad where modern humans migrated 'out of Africa' and spread into Europe and Asia. After the initial peopling and long-term isolation leading to well-differentiated populations, the ME also had a crucial role in subsequent human migrations among Africa, Europe and Asia; thus, recent population admixture has been common in the ME. On the other hand, consanguinity, a well-known practice in the ME, often reduces genetic diversity and works in opposition to admixture. Here, we explored the degree to which admixture and consanguinity jointly affected genetic diversity in ME populations. Genome-wide single-nucleotide polymorphism data were generated in two representative ME populations (Arabian and Iranian), with comparisons made with populations worldwide. Our results revealed an overall higher genetic diversity in both ME populations relative to other non-African populations. We identified a much larger number of long runs of homozygosity in ME populations than in any other populations, which was most likely attributed to high levels of consanguineous marriages that significantly decreased both individual and population heterozygosity. Additionally, we were able to distinguish African, European and Asian ancestries in ME populations and quantify the impact of admixture and consanguinity with statistical approaches. Interestingly, genomic regions with significantly excessive ancestry from individual source populations are functionally enriched in olfactory pathways, which were suspected to be under natural selection. Our findings suggest that genetic admixture, consanguinity and natural selection have collectively shaped the genetic diversity of ME populations, which has important implications in both evolutionary studies and medical practices. PMID:25253659

  7. Clinical presentation and mutation analysis of VHL disease in a large Chinese family.

    PubMed

    Zhang, Qing; Li, De-Ling; Kang, Peng; Ji, Nan; Yang, Jun; Liu, Wei-Ming; Zhang, Li-Wei; Jia, Gui-Jun

    2015-11-01

    Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited neoplastic disorder characterized by marked phenotypic variability and age-dependent penetrance. This disease is caused by germline mutations in the VHL tumor suppressor gene. Systematic physical examinations, imaging assessments and molecular genetic tests for the VHL gene were performed in a large Chinese VHL family. The examined Chinese VHL family, which has 25 members from four generations, including 7 diagnosed VHL patients and 2 asymptomatic mutation carriers. The average ages of first onset for generations I, II, and III were 37, 30 and 16, respectively. The male:female ratio among VHL patients was 6:1. Molecular genetic investigations detected the c.433C>T [p.Q145X] nonsense mutation in the VHL gene. Molecular modeling of the VHL-ElonginC- ElonginB-HIF-1? complex predicted that the p.Q145X mutation markedly alters the L7 loop structure of the ?-domain of the VHL protein (pVHL), destabilizes the VHL-HIF-1?complex, and induces the truncation of pVHL. We speculate that the p.Q145X nonsense mutation leads to relatively obvious familial aggregation. This mutation causes the type I phenotype of VHL disease and is associated with a high risk of retinal and central nervous system (CNS) hemangioblastomas (HGBs) and visceral cysts, but a low risk of renal cell carcinoma. Moreover, within a VHL family, the average ages of first onset became younger in successive generations, and the CNS HGBs are more likely to occur in male patients. PMID:26341373

  8. Evolutionary mechanisms driving the evolution of a large polydnavirus gene family coding for protein tyrosine phosphatases

    PubMed Central

    2012-01-01

    Background Gene duplications have been proposed to be the main mechanism involved in genome evolution and in acquisition of new functions. Polydnaviruses (PDVs), symbiotic viruses associated with parasitoid wasps, are ideal model systems to study mechanisms of gene duplications given that PDV genomes consist of virulence genes organized into multigene families. In these systems the viral genome is integrated in a wasp chromosome as a provirus and virus particles containing circular double-stranded DNA are injected into the parasitoids’ hosts and are essential for parasitism success. The viral virulence factors, organized in gene families, are required collectively to induce host immune suppression and developmental arrest. The gene family which encodes protein tyrosine phosphatases (PTPs) has undergone spectacular expansion in several PDV genomes with up to 42 genes. Results Here, we present strong indications that PTP gene family expansion occurred via classical mechanisms: by duplication of large segments of the chromosomally integrated form of the virus sequences (segmental duplication), by tandem duplications within this form and by dispersed duplications. We also propose a novel duplication mechanism specific to PDVs that involves viral circle reintegration into the wasp genome. The PTP copies produced were shown to undergo conservative evolution along with episodes of adaptive evolution. In particular recently produced copies have undergone positive selection in sites most likely involved in defining substrate selectivity. Conclusion The results provide evidence about the dynamic nature of polydnavirus proviral genomes. Classical and PDV-specific duplication mechanisms have been involved in the production of new gene copies. Selection pressures associated with antagonistic interactions with parasitized hosts have shaped these genes used to manipulate lepidopteran physiology with evidence for positive selection involved in adaptation to host targets. PMID:23270369

  9. A large and functionally diverse family of Fad2 genes in safflower (Carthamus tinctorius L.)

    PubMed Central

    2013-01-01

    Background The application and nutritional value of vegetable oil is highly dependent on its fatty acid composition, especially the relative proportion of its two major fatty acids, i.e oleic acid and linoleic acid. Microsomal oleoyl phosphatidylcholine desaturase encoded by FAD2 gene is known to introduce a double bond at the ?12 position of an oleic acid on phosphatidylcholine and convert it to linoleic acid. The known plant FAD2 enzymes are encoded by small gene families consisting of 1-4 members. In addition to the classic oleate ?12-desaturation activity, functional variants of FAD2 that are capable of undertaking additional or alternative acyl modifications have also been reported in a limited number of plant species. In this study, our objective was to identify FAD2 genes from safflower and analyse their differential expression profile and potentially diversified functionality. Results We report here the characterization and functional expression of an exceptionally large FAD2 gene family from safflower, and the temporal and spatial expression profiles of these genes as revealed through Real-Time quantitative PCR. The diversified functionalities of some of the safflower FAD2 gene family members were demonstrated by ectopic expression in yeast and transient expression in Nicotiana benthamiana leaves. CtFAD2-1 and CtFAD2-10 were demonstrated to be oleate desaturases specifically expressed in developing seeds and flower head, respectively, while CtFAD2-2 appears to have relatively low oleate desaturation activity throughout the plant. CtFAD2-5 and CtFAD2-8 are specifically expressed in root tissues, while CtFAD2-3, 4, 6, 7 are mostly expressed in the cotyledons and hypocotyls in young safflower seedlings. CtFAD2-9 was found to encode a novel desaturase operating on C16:1 substrate. CtFAD2-11 is a tri-functional enzyme able to introduce a carbon double bond in either cis or trans configuration, or a carbon triple (acetylenic) bond at the ?12 position. Conclusions In this study, we isolated an unusually large FAD2 gene family with 11 members from safflower. The seed expressed FAD2 oleate ?12 desaturase genes identified in this study will provide candidate targets to manipulate the oleic acid level in safflower seed oil. Further, the divergent FAD2 enzymes with novel functionality could be used to produce rare fatty acids, such as crepenynic acid, in genetically engineered crop plants that are precursors for economically important phytoalexins and oleochemical products. PMID:23289946

  10. Serrated polyposis: Colonic phenotype, extra-colonic features and familial risk in a large cohort

    PubMed Central

    Jasperson, Kory W.; Kanth, Priyanka; Kirchhoff, Anne C.; Huismann, Darcy; Gammon, Amanda; Kohlmann, Wendy; Burt, Randall W.; Samadder, N. Jewel

    2013-01-01

    BACKGROUND Serrated polyposis is a poorly understood and likely under-diagnosed condition. Little is known regarding the colorectal cancer risk, extra-colonic phenotype, and etiology of serrated polyposis. OBJECTIVE The aim of this study is to describe the clinical and family history features of a large cohort of individuals with serrated polyposis. DESIGN This is a retrospective cohort study from two prospectively collected registries. PATIENTS Patients meeting the updated 2010 World Health Organization criteria for serrated polyposis. MAIN OUTCOME MEASURES We report descriptive statistics for clinical and family history factors. RESULTS A total of 52 individuals met criteria for serrated polyposis. Of these, one had Lynch syndrome and was not included in the statistical analyses. Median age at serrated polyposis diagnosis was 51 years (range 18–77). Twenty four (47%) were male and 25 (49%) had a history of smoking. Two-hundred sixty-eight lower endoscopic procedures were performed; 42 (82%) had colorectal adenomas, 8 (16%) had a personal history of colorectal cancer (only one was diagnosed during follow-up), 12 (24%) had extra-colonic tumors (4 had more than one primary tumor), and 19 (37%) reported a family history of colorectal cancer. Esophagogastroduodenoscopy in 30 individuals revealed only one (3%) with unexplained gastroduodenal polyps. No association was found between colorectal cancer diagnosis and sex, age at serrated polyposis diagnosis, extra-colonic tumor, history of adenoma, or smoking status. LIMITATIONS This was a retrospective study with no comparison groups. CONCLUSIONS Gastroduodenal polyps are uncommon and likely not associated with serrated polyposis. Although extra-colonic tumors were common in our cohort, it is still unclear whether these are associated with serrated polyposis. Our data, along with previous studies, support an association between serrated polyposis and smoking. Further work is still needed to clarify the effect of smoking on polyp development/progression in serrated polyposis. PMID:24104994

  11. Transcriptome Sequencing of a Large Human Family Identifies the Impact of Rare Noncoding Variants

    PubMed Central

    Li, Xin; Battle, Alexis; Karczewski, Konrad J.; Zappala, Zach; Knowles, David A.; Smith, Kevin S.; Kukurba, Kim R.; Wu, Eric; Simon, Noah; Montgomery, Stephen B.

    2014-01-01

    Recent and rapid human population growth has led to an excess of rare genetic variants that are expected to contribute to an individual’s genetic burden of disease risk. To date, much of the focus has been on rare protein-coding variants, for which potential impact can be estimated from the genetic code, but determining the impact of rare noncoding variants has been more challenging. To improve our understanding of such variants, we combined high-quality genome sequencing and RNA sequencing data from a 17-individual, three-generation family to contrast expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) within this family to eQTLs and sQTLs within a population sample. Using this design, we found that eQTLs and sQTLs with large effects in the family were enriched with rare regulatory and splicing variants (minor allele frequency < 0.01). They were also more likely to influence essential genes and genes involved in complex disease. In addition, we tested the capacity of diverse noncoding annotation to predict the impact of rare noncoding variants. We found that distance to the transcription start site, evolutionary constraint, and epigenetic annotation were considerably more informative for predicting the impact of rare variants than for predicting the impact of common variants. These results highlight that rare noncoding variants are important contributors to individual gene-expression profiles and further demonstrate a significant capability for genomic annotation to predict the impact of rare noncoding variants. PMID:25192044

  12. A dominant form of congenital stationary night blindness (adCSNB) in a large Chinese family.

    PubMed

    Liu, X; Zhuang, S; Hu, S; Zhang, F; Lin, B; Li, X; Xu, D; Chen, S-H

    2005-05-01

    Summary A pedigree of congenital stationary night blindness (CSNB) is described in a large Chinese family. The clinical description, pedigree, dark adaptation and elctroretinogram (ERG) studies indicate that the patients have an autosomal dominant form (ad) of CSNB. The disorder has been transmitted through at least 12 generations with over 40 affected individuals identified. The ERG data reveal that affected persons have severely diminished b-wave responses to dim light, but normal a-wave and subnormal b-wave responses to maximum light stimuli. The dark adaptation curves of three patients show a monophase curve, typical for night blindness. We have excluded the five previously known mutations in the three genes (RHO, PDE6B and GNAT1) associated with adCSNB, and linkage studies have excluded tight linkage between the disease locus and markers associated with these three genes. Thus, this family has adCSNB caused by a different gene from the previously identified RHO, PDE6B, and GNAT1. PMID:15845035

  13. Functional Divergence of the Glutathione S-Transferase Supergene Family in Physcomitrella patens Reveals Complex Patterns of Large Gene Family Evolution in Land Plants1[W][OA

    PubMed Central

    Liu, Yan-Jing; Han, Xue-Min; Ren, Lin-Ling; Yang, Hai-Ling; Zeng, Qing-Yin

    2013-01-01

    Plant glutathione S-transferases (GSTs) are multifunctional proteins encoded by a large gene family that play major roles in the detoxification of xenobiotics and oxidative stress metabolism. To date, studies on the GST gene family have focused mainly on vascular plants (particularly agricultural plants). In contrast, little information is available on the molecular characteristics of this large gene family in nonvascular plants. In addition, the evolutionary patterns of this family in land plants remain unclear. In this study, we identified 37 GST genes from the whole genome of the moss Physcomitrella patens, a nonvascular representative of early land plants. The 37 P. patens GSTs were divided into 10 classes, including two new classes (hemerythrin and iota). However, no tau GSTs were identified, which represent the largest class among vascular plants. P. patens GST gene family members showed extensive functional divergence in their gene structures, gene expression responses to abiotic stressors, enzymatic characteristics, and the subcellular locations of the encoded proteins. A joint phylogenetic analysis of GSTs from P. patens and other higher vascular plants showed that different class GSTs had distinct duplication patterns during the evolution of land plants. By examining multiple characteristics, this study revealed complex patterns of evolutionary divergence among the GST gene family in land plants. PMID:23188805

  14. Functional divergence of the glutathione S-transferase supergene family in Physcomitrella patens reveals complex patterns of large gene family evolution in land plants.

    PubMed

    Liu, Yan-Jing; Han, Xue-Min; Ren, Lin-Ling; Yang, Hai-Ling; Zeng, Qing-Yin

    2013-02-01

    Plant glutathione S-transferases (GSTs) are multifunctional proteins encoded by a large gene family that play major roles in the detoxification of xenobiotics and oxidative stress metabolism. To date, studies on the GST gene family have focused mainly on vascular plants (particularly agricultural plants). In contrast, little information is available on the molecular characteristics of this large gene family in nonvascular plants. In addition, the evolutionary patterns of this family in land plants remain unclear. In this study, we identified 37 GST genes from the whole genome of the moss Physcomitrella patens, a nonvascular representative of early land plants. The 37 P. patens GSTs were divided into 10 classes, including two new classes (hemerythrin and iota). However, no tau GSTs were identified, which represent the largest class among vascular plants. P. patens GST gene family members showed extensive functional divergence in their gene structures, gene expression responses to abiotic stressors, enzymatic characteristics, and the subcellular locations of the encoded proteins. A joint phylogenetic analysis of GSTs from P. patens and other higher vascular plants showed that different class GSTs had distinct duplication patterns during the evolution of land plants. By examining multiple characteristics, this study revealed complex patterns of evolutionary divergence among the GST gene family in land plants. PMID:23188805

  15. 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

  16. 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

  17. Institutional protocol to manage consanguinity detected by genetic testing in pregnancy in a minor.

    PubMed

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

    2015-03-01

    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

  18. The Role of Family Environment in Depressive Symptoms among University Students: A Large Sample Survey in China

    PubMed Central

    Yang, Yanjie; Chen, Lu; Qiu, Xiaohui; Qiao, Zhengxue; Zhou, Jiawei; Pan, Hui; Ban, Bo; Zhu, Xiongzhao; He, Jincai; Ding, Yongqing; Bai, Bing

    2015-01-01

    Objective To explore the relationship between family environment and depressive symptoms and to evaluate the influence of hard and soft family environmental factors on depression levels in a large sample of university students in China. Methods A multi-stage stratified sampling procedure was used to select 6,000 participants. The response rate was 88.8%, with 5,329 students completing the Beck Depression Inventory (BDI) and the Family Environment Scale Chinese Version (FES-CV), which was adapted for the Chinese population. Differences between the groups were tested for significance by the Student’s t-test; ANOVA was used to test continuous variables. The relationship between soft family environmental factors and BDI were tested by Pearson correlation analysis. Hierarchical linear regression analysis was conducted to model the effects of hard environmental factors and soft environmental factors on depression in university students. Results A total of 11.8% of students scored above the threshold of moderate depression(BDI?14). Hard family environmental factors such as parent relationship, family economic status, level of parental literacy and non-intact family structure were associated with depressive symptoms. The soft family environmental factors—conflict and control—were positively associated with depression, while cohesion was negatively related to depressive symptom after controlling for other important associates of depression. Hierarchical regression analysis indicated that the soft family environment correlates more strongly with depression than the hard family environment. Conclusions Soft family environmental factors—especially cohesion, conflict and control—appeared to play an important role in the occurrence of depressive symptoms. These findings underline the significance of the family environment as a source of risk factors for depression among university students in China and suggest that family-based interventions and improvement are very important to reduce depression among university students. PMID:26629694

  19. [Information should be given on consanguinity as a risk factor for congenital malformations].

    PubMed

    Cornel, Martina C; Houwink, Elisa J F; Houwink, Pieter E F

    2014-01-01

    In the Born in Bradford study, an increased risk for congenital anomalies was found in the Pakistani subpopulation of Bradford, where cousin marriage is relatively frequent. While consanguinity may be associated with a risk for congenital malformations, it does not prove a causal relationship. Whatever the case, high perinatal mortality as well as the high prevalence of congenital anomalies are good reasons for implementing the knowledge on reproductive risks that has been available for many years. Well-known risk factors include higher maternal age, that was associated with congenital anomalies in the British mothers. Further research in an intervention study may provide more data on whether the associations found are causal. Implementing preconception care should involve primary care physicians, who need both facilities and training. In the Netherlands, the high perinatal mortality, especially in some big cities, could profit from similar interventions. Dutch primary care physicians consider it their responsibility to discuss consanguinity with patients, although there is some reluctance because of anticipated religious and social value conflicts. Without information reaching the target populations, they may lack awareness and will not ask for information themselves. People from Dutch migrant groups would prefer to be informed about reproductive risks of consanguinity by their primary care physicians. PMID:24397975

  20. A novel mutation in the C7orf11 gene causes nonphotosensitive trichothiodystrophy in a multiplex highly consanguineous kindred.

    PubMed

    Pode-Shakked, Ben; Marek-Yagel, Dina; Greenberger, Shoshana; Pode-Shakked, Naomi; Pras, Elon; Barzilai, Aviv; Yassin, Saeed; Sidi, Yechezkel; Anikster, Yair

    2015-12-01

    Trichothiodystrophy (TTD), also known as sulfur-deficient brittle hair syndrome, is a rare autosomal recessive multisystem disorder, which manifests with brittle hair, mental retardation, ichthyosis and decreased fertility. Mutations in the TTDN1 (C7orf11) gene have been shown to cause a nonphotosensitive type of trichothiodystrophy. We report of a 19 years old male, born to consanguineous parents of Arab-Muslim descent, who presented due to severe renal failure, but exhibited additional unique features, including developmental delay, mental retardation, splenomegaly, pancytopenia, hypogonadism and brittle hair. Following the clinical diagnosis of nonphotosensitive TTD, sequencing of the coding exons of C7orf11 was performed and revealed the patient to be homozygous for a novel c.505dupA mutation. As the severe renal failure following which the proband was referred to our care is not typically characteristic of this disorder, its significance is discussed. Molecular diagnosis of this highly affected family should enable genetic counseling and prenatal diagnosis for future pregnancies. PMID:26518168

  1. Stimulation of lignocellulosic biomass hydrolysis by proteins of glycoside hydrolase family 61: structure and function of a large, enigmatic family.

    PubMed

    Harris, Paul V; Welner, Ditte; McFarland, K C; Re, Edward; Navarro Poulsen, Jens-Christian; Brown, Kimberly; Salbo, Rune; Ding, Hanshu; Vlasenko, Elena; Merino, Sandy; Xu, Feng; Cherry, Joel; Larsen, Sine; Lo Leggio, Leila

    2010-04-20

    Currently, the relatively high cost of enzymes such as glycoside hydrolases that catalyze cellulose hydrolysis represents a barrier to commercialization of a biorefinery capable of producing renewable transportable fuels such as ethanol from abundant lignocellulosic biomass. Among the many families of glycoside hydrolases that catalyze cellulose and hemicellulose hydrolysis, few are more enigmatic than family 61 (GH61), originally classified based on measurement of very weak endo-1,4-beta-d-glucanase activity in one family member. Here we show that certain GH61 proteins lack measurable hydrolytic activity by themselves but in the presence of various divalent metal ions can significantly reduce the total protein loading required to hydrolyze lignocellulosic biomass. We also solved the structure of one highly active GH61 protein and find that it is devoid of conserved, closely juxtaposed acidic side chains that could serve as general proton donor and nucleophile/base in a canonical hydrolytic reaction, and we conclude that the GH61 proteins are unlikely to be glycoside hydrolases. Structure-based mutagenesis shows the importance of several conserved residues for GH61 function. By incorporating the gene for one GH61 protein into a commercial Trichoderma reesei strain producing high levels of cellulolytic enzymes, we are able to reduce by 2-fold the total protein loading (and hence the cost) required to hydrolyze lignocellulosic biomass. PMID:20230050

  2. Moxidectin and the avermectins: Consanguinity but not identity

    PubMed Central

    Prichard, Roger; Ménez, Cécile; Lespine, Anne

    2012-01-01

    The avermectins and milbemycins contain a common macrocyclic lactone (ML) ring, but are fermentation products of different organisms. The principal structural difference is that avermectins have sugar groups at C13 of the macrocyclic ring, whereas the milbemycins are protonated at C13. Moxidectin (MOX), belonging to the milbemycin family, has other differences, including a methoxime at C23. The avermectins and MOX have broad-spectrum activity against nematodes and arthropods. They have similar but not identical, spectral ranges of activity and some avermectins and MOX have diverse formulations for great user flexibility. The longer half-life of MOX and its safety profile, allow MOX to be used in long-acting formulations. Some important differences between MOX and avermectins in interaction with various invertebrate ligand-gated ion channels are known and could be the basis of different efficacy and safety profiles. Modelling of IVM interaction with glutamate-gated ion channels suggest different interactions will occur with MOX. Similarly, profound differences between MOX and the avermectins are seen in interactions with ABC transporters in mammals and nematodes. These differences are important for pharmacokinetics, toxicity in animals with defective transporter expression, and probable mechanisms of resistance. Resistance to the avermectins has become widespread in parasites of some hosts and MOX resistance also exists and is increasing. There is some degree of cross-resistance between the avermectins and MOX, but avermectin resistance and MOX resistance are not identical. In many cases when resistance to avermectins is noticed, MOX produces a higher efficacy and quite often is fully effective at recommended dose rates. These similarities and differences should be appreciated for optimal decisions about parasite control, delaying, managing or reversing resistances, and also for appropriate anthelmintic combination. PMID:24533275

  3. Large BRCA1 and BRCA2 genomic rearrangements in Malaysian high risk breast-ovarian cancer families.

    PubMed

    Kang, Peter; Mariapun, Shivaani; Phuah, Sze Yee; Lim, Linda Shushan; Liu, Jianjun; Yoon, Sook-Yee; Thong, Meow Keong; Mohd Taib, Nur Aishah; Yip, Cheng Har; Teo, Soo-Hwang

    2010-11-01

    Early studies of genetic predisposition due to the BRCA1 and BRCA2 genes have focused largely on sequence alterations, but it has now emerged that 4-28% of inherited mutations in the BRCA genes may be due to large genomic rearrangements of these genes. However, to date, there have been relatively few studies of large genomic rearrangements in Asian populations. We have conducted a full sequencing and large genomic rearrangement analysis (using Multiplex Ligation-dependent Probe Amplification, MLPA) of 324 breast cancer patients who were selected from a multi-ethnic hospital-based cohort on the basis of age of onset of breast cancer and/or family history. Three unrelated individuals were found to have large genomic rearrangements: 2 in BRCA1 and 1 in BRCA2, which accounts for 2/24 (8%) of the total mutations detected in BRCA1 and 1/23 (4%) of the mutations in BRCA2 detected in this cohort. Notably, the family history of the individuals with these mutations is largely unremarkable suggesting that family history alone is a poor predictor of mutation status in Asian families. In conclusion, this study in a multi-ethnic (Malay, Chinese, Indian) cohort suggests that large genomic rearrangements are present at a low frequency but should nonetheless be included in the routine testing for BRCA1 and BRCA2. PMID:20617377

  4. Patient perception and knowledge of acetaminophen in a large family medicine service.

    PubMed

    Herndon, Christopher M; Dankenbring, Dawn M

    2014-06-01

    The use of acetaminophen is currently under increased scrutiny by the US Food and Drug Administration (FDA) due to the risk of intentional and more concerning, unintentional overdose-related hepatotoxicity. Acetaminophen is responsible for an estimated 48% of all acute liver failure diagnoses. The purpose of this study is to evaluate patient perception and knowledge of the safe use and potential toxicity of acetaminophen-containing products. The authors conducted a descriptive, 2-week study using a convenience sample from a large family medicine clinic waiting room. Survey questions assessed ability to identify acetaminophen, knowledge of the current recommended maximum daily dose, respondent acetaminophen use patterns, common adverse effects associated with acetaminophen, and respondent self-reported alcohol consumption. Acetaminophen safety information was provided to all persons regardless of participation in the study. Of the 102 patients who chose to participate, 79% recognized acetaminophen as a synonym of Tylenol, whereas only 9% identified APAP as a frequently used abbreviation. One third of respondents thought acetaminophen was synonymous with ibuprofen and naproxen. Approximately one fourth of patients correctly identified the then maximum recommended daily acetaminophen dose of 4 g. Seventy-eight percent of patients correctly identified hepatotoxicity as the most common serious adverse effect. We conclude that patient deficiencies in knowledge of acetaminophen recognition, dosing, and toxicity warrant public education by health professionals at all levels of interaction. Current initiatives are promising; however, further efforts are required. PMID:24813653

  5. Familial gigantiform cementoma: distinctive clinical features of a large Chinese pedigree.

    PubMed

    Wang, H W; Yu, M; Qin, X J; Zhang, C P

    2015-01-01

    Familial gigantiform cementoma is a rare benign fibrocemento-osseous lesion of the jaws that can cause severe facial deformity. It has an autosomal dominant mode of inheritance, but varies in its phenotype. It is more common in white, African, and East-Asian patients. Here we report what is to our knowledge the first distinctive Chinese family with familial gigantiform cementoma involving 4 generations and 13 patients, and which suggests that the tumour presents with 3 distinctive growth phrases. PMID:25284619

  6. Contribution of large genomic BRCA1 alterations to early-onset breast cancer selected for family history and tumour morphology: a report from The Breast Cancer Family Registry

    PubMed Central

    2011-01-01

    Introduction Selecting women affected with breast cancer who are most likely to carry a germline mutation in BRCA1 and applying the most appropriate test methodology remains challenging for cancer genetics services. We sought to test the value of selecting women for BRCA1 mutation testing on the basis of family history and/or breast tumour morphology criteria as well as the value of testing for large genomic alterations in BRCA1. Methods We studied women participating in the Breast Cancer Family Registry (BCFR), recruited via population-based sampling, who had been diagnosed with breast cancer before the age of 40 years who had a strong family history of breast or ovarian cancer (n = 187) and/or a first primary breast tumour with morphological features consistent with carrying a BRCA1 germline mutation (n = 133; 37 met both criteria). An additional 184 women diagnosed before the age of 40 years who had a strong family history of breast or ovarian cancer and who were not known to carry a germline BRCA1 mutation were selected from among women who had been recruited into the BCFR from clinical genetics services. These 467 women had been screened for BRCA1 germline mutations, and we expanded this testing to include a screen for large genomic BRCA1 alterations using Multiplex Ligation-dependent Probe Amplification. Results Twelve large genomic BRCA1 alterations were identified, including 10 (4%) of the 283 women selected from among the population-based sample. In total, 18 (12%), 18 (19%) and 16 (43%) BRCA1 mutations were identified in the population-based groups selected on the basis of family history only (n = 150), the group selected on the basis of tumour morphology only (n = 96) and meeting both criteria (n = 37), respectively. Conclusions Large genomic alterations accounted for 19% of all BRCA1 mutations identified. This study emphasises the value of combining information about family history, age at diagnosis and tumour morphology when selecting women for germline BRCA1 mutation testing as well as including a screen for large genomic alterations. PMID:21281505

  7. Nuclear DNA content of medullary thyroid carcinoma in a large family with the MEN-2A syndrome.

    PubMed

    Haak, H R; Cornelisse, C J; Goslings, B M; Fleuren, G J

    1991-04-01

    Flow cytometry of medullary thyroid carcinoma (MCT) was performed in a large family with the MEN-2A syndrome. Of 15 family members with MCT five patients (10-27 yr) were without lymph node metastases. Six patients had a normal pentagastrin test after operation. All patients are alive and free of symptoms of MCT 6-9 yr after total thyroidectomy and an ablative dose of 131-I. In 12 of the 15 patients with MCT flowcytometry of paraffin-embedded tissue could be performed. The majority of all tumors (n = 9) were classified as peridiploid. Metastatic tumor, 6 years after thyroidectomy, in one of the patients was diploid. Only two MCT were clearly aneuploid. In one patient the tumor was tetraploid. We conclude that the majority of the MCT patients in this family with the MEN-2A syndrome have no or limited ploidy aberrations in their tumors, which correlates well with the favourable prognosis of familial MCT. PMID:1677951

  8. Characterization of the p16 gene in the mouse: Evidence for a large gene family

    SciTech Connect

    Fountain, J.W.; Giendening, J.M.; Flores, J.F.

    1994-09-01

    The p16 gene product is an inhibitor of the cyclin-dependent kinase 4 (CDK4)/cyclin D complex. When uninhibited, the CDK4/cyclin D complex participates in the phosphorylation of the retinoblastoma (RB) protein and renders it inactive. Upon inactivation of the RB protein, transition from the G{sub 1} to the S phase of mitosis occurs and results in cellular proliferation. Thus, p16 is presumed to act as a negative regulator of cell growth by preventing the phosphorylation, and thereby subsequent inactivation, of RB by CDK4/cyclin D. Recently, the p16 gene (also known as the multiple tumor suppressor 1 (MTS1) gene) has been mapped to chromosome 9p21 and found to be deleted or mutated in a number of tumor cell lines. These findings support the role of p16 as a growth inhibitor or tumor suppressor gene and suggest that the mutation of this gene may have global implications in carcinogenesis. We have chosen to test the functional significance of p16 mutations in vivo through the generation of a mouse mutant for p16. In preparation for this undertaking, eight apparently independent (as judged by restriction enzyme digestion and differential hybridization) mouse genomic embryonic stem cell clones have been identified using exon 2 from the human p16 gene as a probe. The identification of these multiple nonoverlapping clones was not entirely surprising since the reduced stringency hybridization of a zoo blot with the same probe also revealed 10-15 positive EcoRI fragments in all species tested, including human, monkey, cow, dog, cat, rabbit, hamster, mouse, chicken and D. melanogaster. Taken together, these findings suggest that the p16 gene is a member of a large gene family. The location of these genomic clones, as well as their potential expression in the mouse, is currently under investigation.

  9. Family dinner and disordered eating behaviors in a large cohort of adolescents

    PubMed Central

    Haines, Jess; Gillman, Matthew W.; Rifas-Shiman, Sheryl; Field, Alison E.; Austin, S. Bryn

    2009-01-01

    We aimed to examine longitudinal associations between family dinner and disordered eating behaviors among adolescents. We studied 7535 females and 5913 males, 9 to 14 years of age in 1996. We performed multivariable logistic regression to assess the associations of previous year family dinner with 1-year incidence of each of 3 outcomes: purging, binge eating, and frequent dieting. Compared to those who ate family dinner “never or some days,” female adolescents who ate family dinner at least most days were less likely to initiate purging, binge eating, and frequent dieting. Estimates of association among males were similar in direction and magnitude, although lower frequency of the outcomes resulted in less precise estimates and fewer statistically significant results. PMID:20390605

  10. Cascade testing for carrier status in cystic fibrosis in a large family.

    PubMed

    Turner, G; Meagher, W; Willis, C; Colley, P

    1993-08-01

    The offer to determine carrier status for cystic fibrosis (CF) was made to the 230 descendants of a couple who were presumed to carry the delta F508 mutation. "Cascade testing" was employed, in which the mutation is followed from the oldest generation down. Compliance was over 75% and family members were relieved of the anxiety engendered by uncertainty. In one couple considering having a family, both partners were found to be carriers. PMID:8336615

  11. Tumor mapping in two large multigeneration families with CYLD mutations: Implications for patient management and tumor induction

    PubMed Central

    Rajan, N; Langtry, J A A; Ashworth, A; Roberts, C; Chapman, P; Burn, J; Trainer, A H

    2010-01-01

    Objective To comprehensively ascertain the extent and severity of clinical features in multiple affected individuals from two large families with proven heterozygous mutations in the CYLD locus and to correlate these findings with the three appendageal tumor predisposition syndromes, familial cylindromatosis (FC), Brooke-Spiegler syndrome (BSS), and multiple familial trichoepitheliomas (MFT) known to be associated with such germline mutations. Design Inter- and intra-familial observational study. Setting Tertiary genetic and dermatology referral centre. Participants 32 individuals were recruited from two large multigenerational families with CYLD mutations. Clinical details, history and tumor maps were obtained from all participants whilst 18 were further corroborated with detailed clinical examination. Main outcome measures Severity of tumor density, distribution and histology, associated medical conditions, patient symptoms and impact of disease on quality of life. Results We demonstrate a wide variation in clinical presentation seen in individuals from the same family. In addition, we provide clinical evidence that correlates with hormonally stimulated hair follicles being particularly vulnerable to loss of heterozygosity and tumor induction. Conclusion In view of our findings, we propose that the burden of disease at sites other than the head and neck is underreported in the literature, but impacts greatly on quality of life. The differentiation between the clinical diagnoses has little prognostic or clinical utility in genetic counselling even within individuals from the same family. Thus, we suggest an encompassing diagnosis of “CYLD cutaneous syndrome”. Finally, our results relating to the clinical distribution of tumors suggest hormonal factors may play an important role in tumor induction in these patients. PMID:19917957

  12. Structural, Functional, and Evolutionary Analysis of the Unusually Large Stilbene Synthase Gene Family in Grapevine1[W

    PubMed Central

    Parage, Claire; Tavares, Raquel; Réty, Stéphane; Baltenweck-Guyot, Raymonde; Poutaraud, Anne; Renault, Lauriane; Heintz, Dimitri; Lugan, Raphaël; Marais, Gabriel A.B.; Aubourg, Sébastien; Hugueney, Philippe

    2012-01-01

    Stilbenes are a small family of phenylpropanoids produced in a number of unrelated plant species, including grapevine (Vitis vinifera). In addition to their participation in defense mechanisms in plants, stilbenes, such as resveratrol, display important pharmacological properties and are postulated to be involved in the health benefits associated with a moderate consumption of red wine. Stilbene synthases (STSs), which catalyze the biosynthesis of the stilbene backbone, seem to have evolved from chalcone synthases (CHSs) several times independently in stilbene-producing plants. STS genes usually form small families of two to five closely related paralogs. By contrast, the sequence of grapevine reference genome (cv PN40024) has revealed an unusually large STS gene family. Here, we combine molecular evolution and structural and functional analyses to investigate further the high number of STS genes in grapevine. Our reannotation of the STS and CHS gene families yielded 48 STS genes, including at least 32 potentially functional ones. Functional characterization of nine genes representing most of the STS gene family diversity clearly indicated that these genes do encode for proteins with STS activity. Evolutionary analysis of the STS gene family revealed that both STS and CHS evolution are dominated by purifying selection, with no evidence for strong selection for new functions among STS genes. However, we found a few sites under different selection pressures in CHS and STS sequences, whose potential functional consequences are discussed using a structural model of a typical STS from grapevine that we developed. PMID:22961129

  13. Consanguinity and rare mutations outside of MCCC genes underlie nonspecific phenotypes of MCCD

    PubMed Central

    Shepard, Peter J.; Barshop, Bruce A.; Baumgartner, Matthias R.; Hansen, John-Bjarne; Jepsen, Kristen; Smith, Erin N.; Frazer, Kelly A.

    2015-01-01

    Purpose 3-Methylcrotonyl-CoA carboxylase deficiency (MCCD) is an autosomal recessive disorder of leucine catabolism that has a highly variable clinical phenotype, ranging from acute metabolic acidosis to nonspecific symptoms such as developmental delay, failure to thrive, hemiparesis, muscular hypotonia, and multiple sclerosis. Implementation of newborn screening for MCCD has resulted in broadening the range of phenotypic expression to include asymptomatic adults. The purpose of this study was to identify factors underlying the varying phenotypes of MCCD. Methods We performed exome sequencing on DNA from 33 cases and 108 healthy controls. We examined these data for associations between either MCC mutational status, genetic ancestry, or consanguinity and the absence or presence/specificity of clinical symptoms in MCCD cases. Results We determined that individuals with nonspecific clinical phenotypes are highly inbred compared with cases that are asymptomatic and healthy controls. For 5 of these 10 individuals, we discovered a homozygous damaging mutation in a disease gene that is likely to underlie their nonspecific clinical phenotypes previously attributed to MCCD. Conclusion Our study shows that nonspecific phenotypes attributed to MCCD are associated with consanguinity and are likely not due to mutations in the MCC enzyme but result from rare homozygous mutations in other disease genes. PMID:25356967

  14. Syndrome Keratitis-Ichtyosis-Deafness (KID) chez un enfant togolais issu d'un mariage consanguin

    PubMed Central

    Kombaté, Koussak; Saka, Bayaki; Landoh, Dadja Essoya; Mouhari-Toure, Abass; Akakpo, Séfako; Belei, Eric; Gnassingbé, Wanguena; Djibril, Mohaman Awalou; Tchangaï-Walla, Kissem; Pitché, Palokinam

    2015-01-01

    Le syndrome KID est une affection génétique rare associant kératite, ichtyose et surdité. Nous rapportons un cas dont la surdité s'est compliquée de mutisme chez un enfant togolais issu d'un mariage consanguin.Il s'agissait d'une fillette de 9 ans admise en dermatologie pour une peau sèche et une kératodermie palmoplantaire évoluant depuis l'enfance, une surdité sévère et un mutisme total évoluant depuis la naissance. Il n'y avait pas d'histoire familiale connue de syndrome KID. Les parents de cet enfant sont des cousins germains. A l'examen, on notait une kératodermie palmoplantaire typique en cuir grossier, une peau sèche ichtyosiforme finement squameuse avec un aspect pachydermique aux genoux et un aspect arlequin aux jambes. L'examen ophtalmologique avait noté une blépharo-conjonctivite, une xérophtalmie, une photophobie et une absence de sourcils. L'examen ORL avait objectivé une hypotrophie des pavillons des oreilles, une surdité sévère et un mutisme total. La particularité de cette observation réside dans la sévérité de l'atteinte auditive qui s'est compliquée de mutisme. Notre enfant étant née de parents consanguins sains, sans histoire familiale de KID, nous pensons que le mode de transmission est probablement sporadique. Une étude moléculaire du cas index et de ses parents, non réalisée à cause de notre plateau technique limité aurait pu le confirmer. PMID:26664520

  15. On the genetics of mandibular prognathism: analysis of large European noble families.

    PubMed Central

    Wolff, G; Wienker, T F; Sander, H

    1993-01-01

    Mandibular prognathism is assumed to be a polygenic trait in the vast majority of cases. In a few families, this phenotype and perhaps a syndrome with a broader spectrum of facial anomalies seems to be determined by a single dominant gene of very low frequency (McKusick No *176700). The phenotype is known to have occurred independently in several European noble families. We constructed a pedigree comprising 13 of these families with 409 members in 23 generations in which mandibular prognathism has been segregating. Obviously, the presumed dominant gene is not fully penetrant in the heterozygous state. Pedigree analysis using the Elston-Stewart algorithm yields a maximum likelihood estimate (MLE) of p = 0.955 (SE 0.038) of the penetrance parameter. Images PMID:8445614

  16. A large duplication in LIPH underlies autosomal recessive hypotrichosis simplex in four Middle Eastern families.

    PubMed

    Nahum, Sagi; Pasternack, Sandra M; Pforr, Jana; Indelman, Margarita; Wollnik, Bernd; Bergman, Reuven; Nöthen, Markus M; König, Arne; Khamaysi, Ziyad; Betz, Regina C; Sprecher, Eli

    2009-06-01

    Autosomal recessive hypotrichosis simplex (ARHS) manifests with paucity of hair appearing during early childhood. We assessed four affected families. We initially genotyped three of these families for a panel of microsatellite markers spanning all ARHS-associated loci and obtained data suggesting linkage to 3q27, encompassing LIPH, which had previously been shown to be associated with ARHS. Accordingly, a homozygous duplication mutation in exon 2 of this gene (c.280_369dup; p.Gly94_Lys123dup) was found to segregate with the disease in all the families. Through the identification of the first duplication mutation in the human LIPH gene, we provide further evidence supporting a role for the phospholipase signalling pathway in hair growth and differentiation. PMID:18820939

  17. Association between Secondary and Primary Sjögren's Syndrome in a Large Collection of Lupus Families.

    PubMed

    Aggarwal, Rachna; Anaya, Juan-Manuel; Koelsch, Kristi A; Kurien, Biji T; Scofield, R Hal

    2015-01-01

    Objective. Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) share clinical and immunogenetic features and may occur together. We undertook this study to determine the risk of primary SS among SLE-unaffected relatives of SLE patients and whether or not primary and secondary SS tended to occur in the same families. Methods. We collected clinical and serological data on 2694 SLE patients, 7390 SLE-unaffected relatives of the SLE patients, and 1470 matched controls. Results. Of the 2694 subjects with SLE, 548 had secondary SS, while 71 of their 7390 SLE-unaffected relatives had primary SS. None of the 1470 controls had SS as defined herein (p = 5 × 10(-5) compared to SLE-unaffected relatives). Of the 71 SLE-unaffected relatives with primary SS, 18 (25.3%) had an SLE-affected family member with secondary SS, while only 530 of the 7319 (7.2%) SLE-unaffected relatives without SS did so (p = 1 × 10(-8)). Conclusion. Among families identified for the presence of SLE, primary and secondary SS tend to occur within the same families. These results highlight the commonalities between these two forms of SS, which in fact correspond to the same disease. PMID:26246904

  18. The Bacterial Intimins and Invasins: A Large and Novel Family of Secreted Proteins

    PubMed Central

    Tsai, Jennifer C.; Yen, Ming-Ren; Castillo, Rostislav; Leyton, Denisse L.; Henderson, Ian R.; Saier, Milton H.

    2010-01-01

    Background Gram-negative bacteria have developed a limited repertoire of solutions for secreting proteins from the cytoplasmic compartment to the exterior of the cell. Amongst the spectrum of secreted proteins are the intimins and invasins (the Int/Inv family; TC# 1.B.54) which are characterized by an N-terminal ?-barrel domain and a C-terminal surface localized passenger domain. Despite the important role played by members of this family in diseases mediated by several species of the Enterobacteriaceae, there has been little appreciation for the distribution and diversity of these proteins amongst Gram-negative bacteria. Furthermore, there is little understanding of the molecular events governing secretion of these proteins to the extracellular milieu. Principal Findings In silico approaches were used to analyze the domain organization and diversity of members of this secretion family. Proteins belonging to this family are predominantly associated with organisms from the ?-proteobacteria. Whilst proteins from the Chlamydia, ?-, ?- and ?-proteobacteria possess ?-barrel domains and passenger domains of various sizes, Int/Inv proteins from the ?-proteobacteria, cyanobacteria and chlorobi possess only the predicted ?-barrel domains. Phylogenetic analyses revealed that with few exceptions these proteins cluster according to organismal type, indicating that divergence occurred contemporaneously with speciation, and that horizontal transfer was limited. Clustering patterns of the ?-barrel domains correlate well with those of the full-length proteins although the passenger domains do so with much less consistency. The modular subdomain design of the passenger domains suggests that subdomain duplication and deletion have occurred with high frequency over evolutionary time. However, all repeated subdomains are found in tandem, suggesting that subdomain shuffling occurred rarely if at all. Topological predictions for the ?-barrel domains are presented. Conclusion Based on our in silico analyses we present a model for the biogenesis of these proteins. This study is the first of its kind to describe this unusual family of bacterial adhesins. PMID:21203509

  19. Evolution of a large, conserved, and syntenic gene family in insects.

    PubMed

    Shah, Neethu; Dorer, Douglas R; Moriyama, Etsuko N; Christensen, Alan C

    2012-02-01

    The Osiris gene family, first described in Drosophila melanogaster, is clustered in the genomes of all Drosophila species sequenced to date. In D. melanogaster, it explains the enigmatic phenomenon of the triplo-lethal and haploinsufficient locus Tpl. The synteny of Osiris genes in flies is well conserved, and it is one of the largest syntenic blocks in the Drosophila group. By examining the genome sequences of other insects in a wide range of taxonomic orders, we show here that the gene family is well-conserved and syntenic not only in the diptera but across the holometabolous and hemimetabolous insects. Osiris gene homologs have also been found in the expressed sequence tag sequences of various other insects but are absent from all groups that are not insects, including crustacea and arachnids. It is clear that the gene family evolved by gene duplication and neofunctionalization very soon after the divergence of the insects from other arthropods but before the divergence of the insects from one another and that the sequences and synteny have been maintained by selection ever since. PMID:22384409

  20. bZIPs and WRKYs: two large transcription factor families executing two different functional strategies

    PubMed Central

    Llorca, Carles M.; Potschin, Maren; Zentgraf, Ulrike

    2014-01-01

    bZIPs and WRKYs are two important plant transcription factor (TF) families regulating diverse developmental and stress-related processes. Since a partial overlap in these biological processes is obvious, it can be speculated that they fulfill non-redundant functions in a complex regulatory network. Here, we focus on the regulatory mechanisms that are so far described for bZIPs and WRKYs. bZIP factors need to heterodimerize for DNA-binding and regulation of transcription, and based on a bioinformatics approach, bZIPs can build up more than the double of protein interactions than WRKYs. In contrast, an enrichment of the WRKY DNA-binding motifs can be found in WRKY promoters, a phenomenon which is not observed for the bZIP family. Thus, the two TF families follow two different functional strategies in which WRKYs regulate each other’s transcription in a transcriptional network whereas bZIP action relies on intensive heterodimerization. PMID:24817872

  1. Classic Case Report of Donohue Syndrome (Leprechaunism; OMIM *246200): The Impact of Consanguineous Mating.

    PubMed

    Nijim, Yousif; Awni, Youssef; Adawi, Amin; Bowirrat, Abdalla

    2016-02-01

    Donohue syndrome ([DS]; leprechaunism) describes a genetic autosomal recessive disorder that results from the presence of homozygous or compound heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2).Donohue syndrome is associated with a fatal congenital form of dwarfism with features of intrauterine and postnatal growth retardation, exaggerated hyperglycemia with hyperinsulinism and dysmorphic abnormalities.We present a case of DS owing to the rarity of this syndrome (1 case in every million births). We discuss how the disease presents, its genetic underpinning, and its prevention.The case was encountered in an Arab male born on 1 September, 2014, for consanguineous parents. The delivery was via cesarean section at 37 weeks gestation due to severe intrauterine growth restriction and nonprogress labor term. The patient was admitted to the Neonatal Intensive Care Unit due to infection, and jaundice. Dysmorphic features, abnormalities of the craniofacial region, low birth weight, skin abnormalities, abdominal distension and hypertrichosis were observed. Laboratory examinations showed, hyperinsulinism, increased C-peptide, thrombocytopenia, leucopenia, and anemia.The diagnosis of DS was done based on the combinations of typical dysmorphic characteristics, clinical evaluation, supported by genetic analysis and exaggerated biochemical results. Genetic diagnosis of DS was performed through analysis of DNA via polymerase chain reaction (PCR). A qualitative real-time PCR was used, to monitor the amplification of a targeted DNA molecule during the PCR. Other technique using sequencing of the INSR gene, which permits genetic diagnosis, counseling, and antenatal diagnoses in subsequent pregnancies, were also performed.Treatment of DS is supportive and requires the combined efforts of a multidisciplinary team, which include pediatricians, endocrinologists, dermatologists, and other health care professionals. Currently, treatment with recombinant insulin-like growth factor 1 demonstrates effectiveness, and a combination treatment with insulin-like growth factor binding protein 3 resulted in an increased lifespan.There is a scarcity of genetic information on DS among the Arab population. Consanguinity is one of underlying reasons for the appearance of rare genetic disorders. Inbreeding has long been considered a controversial phenomenon. Genetic counseling and overwhelming the alertness of the negative consequences of consanguinity on public health are warranted. PMID:26871809

  2. Assessment of amyloid β-protein precursor gene mutations in a large set of familial and sporadic Alzheimer disease cases

    PubMed Central

    Tanzi, Rudolph E.; Vaula, Giovanna; Romano, Donna M.; Mortilla, Marzia; Huang, Tricia L.; Tupler, Rossella G.; Wasco, Wilma; Hyman, Bradley T.; Haines, Jonathan L.; Jenkins, Barbara J.; Kalaitsidaki, Marianna; Warren, Andrew C.; McInnis, Melvin C.; Antonarakis, Stylianos E.; Karlinsky, Harry; Percy, Maire E.; Connor, Linda; Growdon, John; Crapper-McIachlan, Donald R.; Gusella, James F.; George-Hyslop, Peter H. St

    1992-01-01

    A genetic locus associated with familial Alzheimer disease (FAD) and a candidate gene, APP, encoding the amyloid protein precursor have both been assigned previously to chromosome 21, and, in a few FAD families, mutations of APP have been detected. However, obligate crossovers between APP and FAD have also been reported in several FAD pedigrees, including FAD4, a large kindred showing highly suggestive evidence for linkage of the disorder to chromosome 21. In case the apparent APP crossover in FAD4 actually represented an intragenic recombination event or segregation of different mutations in different family branches, we have performed a more detailed assessment of APP as a candidate gene in this family. The entire coding region of the APP gene was sequenced for FAD4 and for FAD1, a second large kindred. No mutations were found, indicating that, in at least one chromosome 21–linked FAD pedigree, the gene defect is not accounted for by a mutation in the known coding region of the APP gene. A total of 25 well-characterized early- and late-onset FAD pedigrees were typed for genetic linkage to APP, to assess the percentage of FAD families predicted to carry mutations in the APP gene. None of the FAD families yielded positive lod scores at a recombination fraction of 0.0. To estimate the overall prevalence of FAD-associated mutations in the βA4 domain of APP, we sequenced exons 16 and 17 in 30 (20 early- and 10 late-onset) FAD kindreds and in 11 sporadic AD cases, and we screened 56 FAD kindreds and 81 cases of sporadic AD for the presence of the originally reported FAD-associated mutation, APP717 Val→Ile (by BclI digestion). No APP gene mutations were found in any of the FAD families or sporadic-AD samples examined in this study, suggesting that the mutations in exons 16 and 17 are a rare cause of FAD. Overall, these data suggest that APP gene mutations account for a very small portion of FAD. ImagesFigure 1 PMID:1642228

  3. 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

  4. On the adaptive origins and maladaptive consequences of human inbreeding: parasite prevalence, immune functioning, and consanguineous marriage.

    PubMed

    Hoben, Ashley D; Buunk, Abraham P; Fincher, Corey L; Thornhill, Randy; Schaller, Mark

    2010-01-01

    We propose that consanguineous marriages arise adaptively in response to high parasite prevalence and function to maintain coadapted gene complexes and associated local adaptation that defend against local pathogens. Therefore, a greater prevalence of inbreeding by consanguineous marriage is expected in geographical regions that historically have had high levels of disease-causing parasites. Eventually such marriages may, under the contemporary high movement of people with modern transportation, jeopardize the immunity of those who practice inbreeding as this leads to an increased susceptibility to novel pathogens. Therefore, a greater frequency of inbreeding is expected to predict higher levels of contemporary mortality and morbidity from infectious diseases. This parasite model of human inbreeding was supported by an analysis involving 72 countries worldwide. We found that historically high levels of pathogen prevalence were related positively to the proportion of consanguineous marriages, and that a higher prevalence of such marriages was associated with higher contemporary mortality and morbidity due to pathogens. Our study addresses plausible alternative explanations. The results suggest that consanguineous marriage is an adaptive consequence of historical pathogen ecologies, but is maladaptive in contemporary disease ecologies. PMID:22947825

  5. Aspects of pre-eclamptic toxaemia of pregnancy, consanguinity, twinning in Ankara.

    PubMed Central

    Stevenson, A C; Say, B; Ustaoglu, S; Durmus, Z

    1976-01-01

    It appears that women classed as having pre-eclamptic toxaemia are less frequently consanguineous with their husbands than all other mothers and in particular those mothers classed as having pregnancies complicated by chronic hypertensive disease. Search revealed no evidence for possible biases which could have stimulated such findings. Further evidence is advanced suggesting that, though pre-eclamptic toxaemia is more common in all types of twin pregnancies than in single births, it is more common where the twins are dizygous than where they are monozygous. It is pointed out that both these findings would be expected if there was a contribution to the aetiology of pre-eclamptic toxaemia by maternal/fetal immunological incompatibility. However, if such a mechanism exists it is not always determined at the same gene locus. PMID:1271421

  6. Study of large inbred Friedreich ataxia families reveals a recombination between D9S15 and the disease locus

    SciTech Connect

    Belal, S.; Ben Hamida, C.; Hentati, F.; Ben Hamida, M. ); Panayides, K.; Ioannou, P.; MIddleton, L.T. ); Sirugo, G.; Koenig, S.; Mandel, J.L ); Beckmann, J. )

    1992-12-01

    Friedreich ataxia is a neurodegenerative disorder with autosomal recessive inheritance. Precise linkage mapping of the Friedreich ataxia locus (FRDA) in 9q13-q21 should lead to the isolation of the defective gene by positional cloning. The two closest DNA markers, D9S5 and D9S15, show very tight linkage to FRDA, making difficult the ordering of the three loci. The authors present a linkage study of three large Friedreich ataxia families of Tunisian origin, with several multiallelic markers around D9S5 and D9S15. Haplotype data were used to investigate genetic homogeneity of the disease in these geographically related families. A meiotic recombination was found in a nonaffected individual, which excludes a 150-kb segment, including D9S15, as a possible location for the Freidreich ataxia gene and which should orient the search in the D9S5 region. 16 refs., 1 fig., 1 tab.

  7. Maternal intrusiveness, family financial means, and anxiety across childhood in a large multiphase sample of community youth.

    PubMed

    Cooper-Vince, Christine E; Pincus, Donna B; Comer, Jonathan S

    2014-01-01

    Intrusive parenting has been positively associated with child anxiety, although examinations of this relationship to date have been largely confined to middle to upper middle class families and have rarely used longitudinal designs. With several leading interventions for child anxiety emphasizing the reduction of parental intrusiveness, it is critical to determine whether the links between parental intrusiveness and child anxiety broadly apply to families of all financial means, and whether parental intrusiveness prospectively predicts the development of child anxiety. This study employed latent growth curve analysis to evaluate the interactive effects of maternal intrusiveness and financial means on the developmental trajectory of child anxiety from 1st grade to age 15 in 1,121 children (50.7 % male) and their parents from the NICHD SECCYD. The overall model was found to provide good fit, revealing that early maternal intrusiveness and financial means did not impact individual trajectories of change in child anxiety, which were stable from 1st to 5th grade, and then decrease from 5th grade to age 15. Cross-sectional analyses also examined whether family financial means moderated contemporaneous relationships between maternal intrusiveness and child anxiety in 3rd and 5th grades. The relationship between maternal intrusiveness and child anxiety was moderated by family financial means for 1st graders, with stronger links found among children of lower family financial means, but not for 3rd and 5th graders. Neither maternal intrusiveness nor financial means in 1st grade predicted subsequent changes in anxiety across childhood. Findings help elucidate for whom and when maternal intrusiveness has the greatest link with child anxiety and can inform targeted treatment efforts. PMID:23929005

  8. Maternal intrusiveness, family financial means, and anxiety across childhood in a large multiphase sample of community youth

    PubMed Central

    Cooper-Vince, Christine E.; Pincus, Donna B.; Comer, Jonathan S.

    2013-01-01

    Intrusive parenting has been positively associated with child anxiety, although examinations of this relationship to date have been largely confined to middle to upper middle class families and have rarely used longitudinal designs. With several leading interventions for child anxiety emphasizing the reduction of parental intrusiveness, it is critical to determine whether the links between parental intrusiveness and child anxiety broadly apply to families of all financial means, and whether parental intrusiveness prospectively predicts the development of child anxiety. This study employed latent growth curve analysis to evaluate the interactive effects of maternal intrusiveness and financial means on the developmental trajectory of child anxiety from 1st grade to age 15 in 1,121 children (50.7% male) and their parents from the NICHD SECCYD. The overall model was found to provide good fit, revealing that early maternal intrusiveness and financial means did not impact individual trajectories of change in child anxiety, which were stable from 1st to 5th grade, and then decrease from 5th grade to age 15. Cross-sectional analyses also examined whether family financial means moderated contemporaneous relationships between maternal intrusiveness and child anxiety in 3rd and 5th grades. The relationship between maternal intrusiveness and child anxiety was moderated by family financial means for 1st graders, with stronger links found among children of lower family financial means, but not for 3rd and 5th graders. Neither maternal intrusiveness nor financial means in 1st grade predicted subsequent changes in anxiety across childhood. Findings help elucidate for whom and when maternal intrusiveness has the greatest link with child anxiety and can inform targeted treatment efforts. PMID:23929005

  9. Large distribution and high sequence identity of a Copia-type retrotransposon in angiosperm families.

    PubMed

    Dias, Elaine Silva; Hatt, Clémence; Hamon, Serge; Hamon, Perla; Rigoreau, Michel; Crouzillat, Dominique; Carareto, Claudia Marcia Aparecida; de Kochko, Alexandre; Guyot, Romain

    2015-09-01

    Retrotransposons are the main component of plant genomes. Recent studies have revealed the complexity of their evolutionary dynamics. Here, we have identified Copia25 in Coffea canephora, a new plant retrotransposon belonging to the Ty1-Copia superfamily. In the Coffea genomes analyzed, Copia25 is present in relatively low copy numbers and transcribed. Similarity sequence searches and PCR analyses show that this retrotransposon with LTRs (Long Terminal Repeats) is widely distributed among the Rubiaceae family and that it is also present in other distantly related species belonging to Asterids, Rosids and monocots. A particular situation is the high sequence identity found between the Copia25 sequences of Musa, a monocot, and Ixora, a dicot species (Rubiaceae). Our results reveal the complexity of the evolutionary dynamics of the ancient element Copia25 in angiosperm, involving several processes including sequence conservation, rapid turnover, stochastic losses and horizontal transfer. PMID:26245353

  10. Hereditary Sensory Autonomic Neuropathy II, a rare disease in a large Pakistani family.

    PubMed

    Arain, Fazal Manzoor; Chand, Prem

    2015-10-01

    Hereditary Sensory Autonomic Neuropathy II (HSAN II) is a rare genetic disorder, characterized by severe loss of pain, temperature and touch sensation. Injuries in these patients can progress to necrosis and shedding of digits and limbs. Here we report two cases of HSAN II belonging to a Pakistani family. Individual 1, a forty five year old man, had complete loss of pain sensation since birth. Self-mutilation and complication of injuries resulted in the shedding of all the digits and right foot and surgical amputation of left leg. Individual 2, a five year old girl,had delay in healing of wounds and self-mutilation. Examination showed a complete lack of pain sensation throughout her body and hyporeflexia. As the genetic cause of HSAN II is unknown, identification of more patients will allow further research on this disease and possibly develop a cure. PMID:26440849

  11. Exome sequencing of 75 individuals from multiply affected coeliac families and large scale resequencing follow up.

    PubMed

    Mistry, Vanisha; Bockett, Nicholas A; Levine, Adam P; Mirza, Muddassar M; Hunt, Karen A; Ciclitira, Paul J; Hummerich, Holger; Neuhausen, Susan L; Simpson, Michael A; Plagnol, Vincent; van Heel, David A

    2015-01-01

    Coeliac disease (CeD) is a highly heritable common autoimmune disease involving chronic small intestinal inflammation in response to dietary wheat. The human leukocyte antigen (HLA) region, and 40 newer regions identified by genome wide association studies (GWAS) and dense fine mapping, account for ?40% of the disease heritability. We hypothesized that in pedigrees with multiple individuals with CeD rare [minor allele frequency (MAF) <0.5%] mutations of larger effect size (odds ratios of ?2-5) might exist. We sequenced the exomes of 75 coeliac individuals of European ancestry from 55 multiply affected families. We selected interesting variants and genes for further follow up using a combination of: an assessment of shared variants between related subjects, a model-free linkage test, and gene burden tests for multiple, potentially causal, variants. We next performed highly multiplexed amplicon resequencing of all RefSeq exons from 24 candidate genes selected on the basis of the exome sequencing data in 2,248 unrelated coeliac cases and 2,230 controls. 1,335 variants with a 99.9% genotyping call rate were observed in 4,478 samples, of which 939 were present in coding regions of 24 genes (Ti/Tv 2.99). 91.7% of coding variants were rare (MAF <0.5%) and 60% were novel. Gene burden tests performed on rare functional variants identified no significant associations (p<1×10(-3)) in the resequenced candidate genes. Our strategy of sequencing multiply affected families with deep follow up of candidate genes has not identified any new CeD risk mutations. PMID:25635822

  12. Exome Sequencing of 75 Individuals from Multiply Affected Coeliac Families and Large Scale Resequencing Follow Up

    PubMed Central

    Mistry, Vanisha; Bockett, Nicholas A.; Levine, Adam P.; Mirza, Muddassar M.; Hunt, Karen A.; Ciclitira, Paul J.; Hummerich, Holger; Neuhausen, Susan L.; Simpson, Michael A.; Plagnol, Vincent; van Heel, David A.

    2015-01-01

    Coeliac disease (CeD) is a highly heritable common autoimmune disease involving chronic small intestinal inflammation in response to dietary wheat. The human leukocyte antigen (HLA) region, and 40 newer regions identified by genome wide association studies (GWAS) and dense fine mapping, account for ∼40% of the disease heritability. We hypothesized that in pedigrees with multiple individuals with CeD rare [minor allele frequency (MAF) <0.5%] mutations of larger effect size (odds ratios of ∼ 2–5) might exist. We sequenced the exomes of 75 coeliac individuals of European ancestry from 55 multiply affected families. We selected interesting variants and genes for further follow up using a combination of: an assessment of shared variants between related subjects, a model-free linkage test, and gene burden tests for multiple, potentially causal, variants. We next performed highly multiplexed amplicon resequencing of all RefSeq exons from 24 candidate genes selected on the basis of the exome sequencing data in 2,248 unrelated coeliac cases and 2,230 controls. 1,335 variants with a 99.9% genotyping call rate were observed in 4,478 samples, of which 939 were present in coding regions of 24 genes (Ti/Tv 2.99). 91.7% of coding variants were rare (MAF <0.5%) and 60% were novel. Gene burden tests performed on rare functional variants identified no significant associations (p<1×10−3) in the resequenced candidate genes. Our strategy of sequencing multiply affected families with deep follow up of candidate genes has not identified any new CeD risk mutations. PMID:25635822

  13. Age distribution of human gene families shows significant roles of both large- and small-scale duplications in vertebrate evolution.

    PubMed

    Gu, Xun; Wang, Yufeng; Gu, Jianying

    2002-06-01

    The classical (two-round) hypothesis of vertebrate genome duplication proposes two successive whole-genome duplication(s) (polyploidizations) predating the origin of fishes, a view now being seriously challenged. As the debate largely concerns the relative merits of the 'big-bang mode' theory (large-scale duplication) and the 'continuous mode' theory (constant creation by small-scale duplications), we tested whether a significant proportion of paralogous genes in the contemporary human genome was indeed generated in the early stage of vertebrate evolution. After an extensive search of major databases, we dated 1,739 gene duplication events from the phylogenetic analysis of 749 vertebrate gene families. We found a pattern characterized by two waves (I, II) and an ancient component. Wave I represents a recent gene family expansion by tandem or segmental duplications, whereas wave II, a rapid paralogous gene increase in the early stage of vertebrate evolution, supports the idea of genome duplication(s) (the big-bang mode). Further analysis indicated that large- and small-scale gene duplications both make a significant contribution during the early stage of vertebrate evolution to build the current hierarchy of the human proteome. PMID:12032571

  14. A systematic search for linkage with nonsyndromic recessive deafness in two large Middle Eastern inbred kindreds excludes more than 30% of the genome

    SciTech Connect

    Weiss, S.; Korostishevsky, M.; Frydman, M.

    1994-09-01

    It has been estimated that as many as 35 loci may individually cause autosomal recessive non-syndromic deafness. The extreme genetic heterogeneity, limited clinical differentiation and phenotypic assortative mating in many western countries make many families unsuitable for genetic linkage studies. Recently the first of those loci was mapped (to 13q) in two consanguineous families from northern Tunisia. We are studying two large highly consanguineous Middle Eastern kindreds (a total of 26 deaf in 98 sampled individuals). Examination in each family showed no evidence of clinical heterogeneity and indicated an uncomplicated profound bilateral sensorineural deafness. We have been able to exclude the 13q locus as the cause of deafness in each kindred and have also excluded such `candidate` loci as regions as those causing Usher`s syndrome type 1 (11q13)(11p), Usher`s syndrome type II (1q32-q41), Waardenburg syndrome type I (2q37), branchio-oto-renal syndrome (8q12-q13), Monge`s deafness (5q31), and Treacher Collins syndrome (5q31.3-q33.3). To date, no lod scores greater than 1 have been obtained in either kindred using 150 RFLT`s, VNTR`s and highly polymorphic microsatellite markers (CA repeats and tetranucleotides). By Morton`s criterion a minimum of 30% of the autosomal genome can be excluded for each kindred separately.

  15. Molecular analysis of recombination in a family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion

    SciTech Connect

    Shashi, V.; Golden, W.L.; Allinson, P.S.

    1996-06-01

    It has been demonstrated in animal studies that, in animals heterozygous for pericentric chromosomal inversions, loop formation is greatly reduced during meiosis. This results in absence of recombination within the inverted segment, with recombination seen only outside the inversion. A recent study in yeast has shown that telomeres, rather than centromeres, lead in chromosome movement just prior to meiosis and may be involved in promoting recombination. We studied by cytogenetic analysis and DNA polymorphisms the nature of meiotic recombination in a three-generation family with a large pericentric X chromosome inversion, inv(X)(p21.1q26), in which Duchenne muscular dystrophy (DMD) was cosegregating with the inversion. On DNA analysis there was no evidence of meiotic recombination between the inverted and normal X chromosomes in the inverted segment. Recombination was seen at the telomeric regions, Xp22 and Xq27-28. No deletion or point mutation was found on analysis of the DMD gene. On the basis of the FISH results, we believe that the X inversion is the mutation responsible for DMD in this family. Our results indicate that (1) pericentric X chromosome inversions result in reduction of recombination between the normal and inverted X chromosomes; (2) meiotic X chromosome pairing in these individuals is likely initiated at the telomeres; and (3) in this family DMD is caused by the pericentric inversion. 50 refs., 7 figs., 1 tab.

  16. Molecular analysis of recombination in a family with Duchenne muscular dystrophy and a large pericentric X chromosome inversion.

    PubMed Central

    Shashi, V.; Golden, W. L.; Allinson, P. S.; Blanton, S. H.; von Kap-Herr, C.; Kelly, T. E.

    1996-01-01

    It has been demonstrated in animal studies that, in animals heterozygous for pericentric chromosomal inversions, loop formation is greatly reduced during meiosis. This results in absence of recombination within the inverted segment, with recombination seen only outside the inversion. A recent study in yeast has shown that telomeres, rather than centromeres, lead in chromosome movement just prior to meiosis and may be involved in promoting recombination. We studied by cytogenetic analysis and DNA polymorphisms the nature of meiotic recombination in a three-generation family with a large pericentric X chromosome inversion, inv(X)(p21.1q26), in which Duchenne muscular dystrophy (DMD) was cosegregating with the inversion. On DNA analysis there was no evidence of meiotic recombination between the inverted and normal X chromosomes in the inverted segment. Recombination was seen at the telomeric regions, Xp22 and Xq27-28. No deletion or point mutation was found on analysis of the DMD gene. On the basis of the FISH results, we believe that the X inversion is the mutation responsible for DMD in this family. Our results indicate that (1) pericentric X chromosome inversions result in reduction of recombination between the normal and inverted X chromosomes; (2) meiotic X chromosome pairing in these individuals is likely initiated at the telomeres; and (3) in this family DMD is caused by the pericentric inversion. Images Figure 2 Figure 5 Figure 6 Figure 7 PMID:8651300

  17. A large Italian family with Gilles de la Tourette syndrome: clinical study and analysis of the SLITRK1 gene.

    PubMed

    Fabbrini, Giovanni; Pasquini, Massimo; Aurilia, Cinzia; Berardelli, Isabella; Breedveld, Guido; Oostra, Ben A; Bonifati, Vincenzo; Berardelli, Alfredo

    2007-11-15

    Our objective was to report the clinical characteristics and to investigate the role of SLITRK1 gene in a large Italian family with Tourette syndrome (TS). The diagnosis of TS and chronic motor tics (CMT) was made according to "The Tourette Syndrome Classification Study Group" (1993). Psychiatric diagnoses were made by administering the Structured Clinical Interview for DSM and the Yale-Brown Obsessive Compulsive Scale. Genetic study included direct sequencing and copy number analysis of the SLITRK1 gene, and haplotype analysis. We found tics or other behavioral manifestations in 15 subjects. Of these, 5 received a diagnosis of definite TS, 5 were classified as having definite CMT, 2 had definite nonspecific tic disorder, and 3 patients had obsessive-compulsive disorder without motor or phonic tics. Tics mainly involved the craniocervical district. Many patients with tics had coexisting psychiatric disorders, especially obsessive-compulsive disorder, performed poorly at school and had social problems. Direct sequencing and copy number analysis of the SLITRK1 gene, and haplotype analysis suggested that the SLITRK1 locus was not involved in this family. In conclusion, the distinctive clinical features in this family are the motor tics mainly involving the face and the neck and the severe coexisting psychiatric disorders. The negative results of the SLITRK1 analysis point to genetic heterogeneity in TS. PMID:17712845

  18. The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma

    PubMed Central

    Lesueur, F; de Lichy, M; Barrois, M; Durand, G; Bombled, J; Avril, M-F; Chompret, A; Boitier, F; Lenoir, G M; Bressac-de Paillerets, B

    2008-01-01

    Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16INK4a and p14ARF. Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene. PMID:18612309

  19. The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.

    PubMed

    Lesueur, F; de Lichy, M; Barrois, M; Durand, G; Bombled, J; Avril, M-F; Chompret, A; Boitier, F; Lenoir, G M; Bressac-de Paillerets, B; Baccard, Monique; Bachollet, Bertrand; Berthet, Pascaline; Bonadona, Valérie; Bonnetblanc, Jean-Marie; Caron, Olivier; Chevrant-Breton, Jacqueline; Cuny, Jean-François; Dalle, Stéphane; Delaunay, Michèle; Demange, Liliane; De Quatrebarbes, Julie; Doré, Jean-François; Frénay, Marc; Fricker, Jean-Pierre; Gauthier-Villars, Marion; Gesta, Paul; Giraud, Sophie; Gorry, Philippe; Grange, Florent; Green, Andrew; Huiart, Laetitia; Janin, Nicolas; Joly, Pascal; Kérob, Delphine; Lasset, Christine; Leroux, Dominique; Limacher, Jean-Marc; Longy, Michel; Mansard, Sandrine; Marrou, Karine; Martin-Denavit, Tanguy; Mateus, Christine; Maubec, Eve; Olivier-Faivre, Laurence; Orlandini, Vincent; Pujol, Pascal; Sassolas, Bruno; Stoppa-Lyonnet, Dominique; Thomas, Luc; Vabres, Pierre; Venat, Laurence; Wierzbicka, Ewa; Zattara, Hélène

    2008-07-22

    Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene. PMID:18612309

  20. High incidence of large deletions in the PMS2 gene in Spanish Lynch syndrome families.

    PubMed

    Brea-Fernández, A J; Cameselle-Teijeiro, J M; Alenda, C; Fernández-Rozadilla, C; Cubiella, J; Clofent, J; Reñé, J M; Anido, U; Milá, M; Balaguer, F; Castells, A; Castellvi-Bel, S; Jover, R; Carracedo, A; Ruiz-Ponte, C

    2014-06-01

    Lynch syndrome (LS) is caused by germline mutations in one of the four mismatch repair (MMR) genes. Defects in this pathway lead to microsatellite instability (MSI) in DNA tumors, which constitutes the molecular hallmark of this disease. Selection of patients for genetic testing in LS is usually based on fulfillment of diagnostic clinical criteria (i.e. Amsterdam criteria or the revised Bethesda guidelines). However, following these criteria PMS2 mutations have probably been underestimated as their penetrances appear to be lower than those of the other MMR genes. The use of universal MMR study-based strategies, using MSI testing and immunohistochemical (IHC) staining, is being one proposed alternative. Besides, germline mutation detection in PMS2 is complicated by the presence of highly homologous pseudogenes. Nevertheless, specific amplification of PMS2 by long-range polymerase chain reaction (PCR) and the improvement of the analysis of large deletions/duplications by multiplex ligation-dependent probe amplification (MLPA) overcome this difficulty. By using both approaches, we analyzed 19 PMS2-suspected carriers who have been selected by clinical or universal strategies and found five large deletions and one frameshift mutation in PMS2 in six patients (31%). Owing to the high incidence of large deletions found in our cohort, we recommend MLPA analysis as the first-line method for searching germline mutations in PMS2. PMID:23837913

  1. A novel homozygous splicing mutation of CASC5 causes primary microcephaly in a large Pakistani family.

    PubMed

    Szczepanski, Sandra; Hussain, Muhammad Sajid; Sur, Ilknur; Altmüller, Janine; Thiele, Holger; Abdullah, Uzma; Waseem, Syeda Seema; Moawia, Abubakar; Nürnberg, Gudrun; Noegel, Angelika Anna; Baig, Shahid Mahmood; Nürnberg, Peter

    2016-02-01

    Primary microcephaly is a disorder characterized by a small head and brain associated with impaired cognitive capabilities. Mutations in 13 different genes encoding centrosomal proteins and cell cycle regulators have been reported to cause the disease. CASC5, a gene encoding a protein important for kinetochore formation and proper chromosome segregation during mitosis, has been suggested to be associated with primary microcephaly-4 (MCPH4). This was based on one mutation only and circumstantial functional evidence. By combining homozygosity mapping and whole-exome sequencing in an MCPH family from Pakistan, we identified a second mutation (NM_170589.4;c.6673-19T>A) in CASC5. This mutation induced skipping of exon 25 of CASC5 resulting in a frameshift and the introduction of a premature stop codon (p.Met2225Ilefs*7). The C-terminally truncated protein lacks 118 amino acids that encompass the region responsible for the interaction with the hMIS12 complex, which is essential for proper chromosome alignment and segregation. Furthermore, we showed a down-regulation of CASC5 mRNA and reduction of the amount of CASC5 protein by quantitative RT-PCR and western blot analysis, respectively. As a further sign of functional deficits, we observed dispersed dots of CASC5 immunoreactive material outside the metaphase plate of dividing patient fibroblasts. Normally, CASC5 is a component of the kinetochore of metaphase chromosomes. A higher mitotic index in patient cells indicated a mitotic arrest in the cells carrying the mutation. We also observed lobulated and fragmented nuclei as well as micronuclei in the patient cells. Moreover, we detected an altered DNA damage response with higher levels of ?H2AX and 53BP1 in mutant as compared to control fibroblasts. Our findings substantiate the proposed role of CASC5 for primary microcephaly and suggest that it also might be relevant for genome stability. PMID:26621532

  2. Genome-Wide Linkage Analysis of Cardiovascular Disease Biomarkers in a Large, Multigenerational Family

    PubMed Central

    Hauser, Elizabeth; Li, Yi-Ju; Thompson, Dana K.; Johnson, Jessica; Chen, Hsiang-Cheng; Nelson, Sarah; Haynes, Carol; Gregory, Simon G.; Kraus, Virginia B.; Shah, Svati H.

    2013-01-01

    Given the importance of cardiovascular disease (CVD) to public health and the demonstrated heritability of both disease status and its related risk factors, identifying the genetic variation underlying these susceptibilities is a critical step in understanding the pathogenesis of CVD and informing prevention and treatment strategies. Although one can look for genetic variation underlying susceptibility to CVD per se, it can be difficult to define the disease phenotype for such a qualitative analysis and CVD itself represents a convergence of diverse etiologic pathways. Alternatively, one can study the genetics of intermediate traits that are known risk factors for CVD, which can be measured quantitatively. Using the latter strategy, we have measured 21 cardiovascular-related biomarkers in an extended multigenerational pedigree, the CARRIAGE family (Carolinas Region Interaction of Aging, Genes, and Environment). These biomarkers belong to inflammatory and immune, connective tissue, lipid, and hemostasis pathways. Of these, 18 met our quality control standards. Using the pedigree and biomarker data, we have estimated the broad sense heritability (H2) of each biomarker (ranging from 0.09–0.56). A genome-wide panel of 6,015 SNPs was used subsequently to map these biomarkers as quantitative traits. Four showed noteworthy evidence for linkage in multipoint analysis (LOD score ? 2.6): paraoxonase (chromosome 8p11, 21), the chemokine RANTES (22q13.33), matrix metalloproteinase 3 (MMP3, 17p13.3), and granulocyte colony stimulating factor (GCSF, 8q22.1). Identifying the causal variation underlying each linkage score will help to unravel the genetic architecture of these quantitative traits and, by extension, the genetic architecture of cardiovascular risk. PMID:23936524

  3. Large gene family expansion and variable selective pressures for cathepsin B in aphids.

    PubMed

    Rispe, Claude; Kutsukake, Mayako; Doublet, Vincent; Hudaverdian, Sylvie; Legeai, Fabrice; Simon, Jean-Christophe; Tagu, Denis; Fukatsu, Takema

    2008-01-01

    Aphids exclusively feed on plant phloem sap that contains much sugar and some nonessential amino acids but is poor in lipids and proteins. Conventionally, it has been believed that aphids substantially have no intestinal digestion of proteins. However, we here report an unexpected finding that cysteine protease genes of the family cathepsin B are massively amplified in the lineage of aphids and that many of the protease genes exhibit gut-specific overexpression. By making use of expressed sequence tag data, sequenced cDNAs, and genomic trace sequences of the pea aphid Acyrthosiphon pisum, we identified a total of 28 cathepsin B-like gene copies in the genome of A. pisum. Phylogenetic analyses of all the cathepsin B genes in aphids revealed that genic expansion has continuously proceeded with basal, intermediary, and recent duplications. Estimation of molecular evolutionary rates indicated that major alterations of the rates often occurred after duplications. For example, a gene copy ("348") was shown to be slow evolving and close to genes of other insects like Drosophila melanogaster, whereas the other gene copies appeared to have evolved faster with higher ratios of nonsynonymous to synonymous substitutions. We identified a number of gene copies (16 in A. pisum) that contained a replacement at the site required for catalytic activity of the protease. Among these, 2 copies were pseudogenes, whereas the remaining copies were structurally intact and possibly acquired new functions. For example, a cluster of such gene copies ("1674") has been subjected to positive selection. Quantitative reverse transcriptase-polymerase chain reaction analyses revealed that the more conserved gene copy ("348") showed a constitutive expression, whereas 5 other forms ("84," "16," "16D," "1874," and "2744") were preferentially expressed in the gut of A. pisum. Putative biological roles of the diversified cathepsin B-like gene copies in aphids are discussed in relation to their nutritional physiology specialized for plant sap feeding lifestyle. PMID:17934209

  4. Evolutionary expansion and divergence in a large family of primate-specific zinc finger transcription factor genes

    SciTech Connect

    Hamilton, A T; Huntley, S; Tran-Gyamfi, M; Baggott, D; Gordon, L; Stubbs, L

    2005-09-28

    Although most genes are conserved as one-to-one orthologs in different mammalian orders, certain gene families have evolved to comprise different numbers and types of protein-coding genes through independent series of gene duplications, divergence and gene loss in each evolutionary lineage. One such family encodes KRAB-zinc finger (KRAB-ZNF) genes, which are likely to function as transcriptional repressors. One KRAB-ZNF subfamily, the ZNF91 clade, has expanded specifically in primates to comprise more than 110 loci in the human genome, yielding large gene clusters in human chromosomes 19 and 7 and smaller clusters or isolated copies at other chromosomal locations. Although phylogenetic analysis indicates that many of these genes arose before the split between old world monkeys and new world monkeys, the ZNF91 subfamily has continued to expand and diversify throughout the evolution of apes and humans. The paralogous loci are distinguished by sequence divergence within their zinc finger arrays indicating a selection for proteins with different DNA binding specificities. RT-PCR and in situ hybridization data show that some of these ZNF genes can have tissue-specific expression patterns, however many KRAB-ZNFs that are near-ubiquitous could also be playing very specific roles in halting target pathways in all tissues except for a few, where the target is released by the absence of its repressor. The number of variant KRAB-ZNF proteins is increased not only because of the large number of loci, but also because many loci can produce multiple splice variants, which because of the modular structure of these genes may have separate and perhaps even conflicting regulatory roles. The lineage-specific duplication and rapid divergence of this family of transcription factor genes suggests a role in determining species-specific biological differences and the evolution of novel primate traits.

  5. MPI-PHYLIP: Parallelizing Computationally Intensive Phylogenetic Analysis Routines for the Analysis of Large Protein Families

    PubMed Central

    Ropelewski, Alexander J.; Nicholas, Hugh B.; Gonzalez Mendez, Ricardo R.

    2010-01-01

    Background Phylogenetic study of protein sequences provides unique and valuable insights into the molecular and genetic basis of important medical and epidemiological problems as well as insights about the origins and development of physiological features in present day organisms. Consensus phylogenies based on the bootstrap and other resampling methods play a crucial part in analyzing the robustness of the trees produced for these analyses. Methodology Our focus was to increase the number of bootstrap replications that can be performed on large protein datasets using the maximum parsimony, distance matrix, and maximum likelihood methods. We have modified the PHYLIP package using MPI to enable large-scale phylogenetic study of protein sequences, using a statistically robust number of bootstrapped datasets, to be performed in a moderate amount of time. This paper discusses the methodology used to parallelize the PHYLIP programs and reports the performance of the parallel PHYLIP programs that are relevant to the study of protein evolution on several protein datasets. Conclusions Calculations that currently take a few days on a state of the art desktop workstation are reduced to calculations that can be performed over lunchtime on a modern parallel computer. Of the three protein methods tested, the maximum likelihood method scales the best, followed by the distance method, and then the maximum parsimony method. However, the maximum likelihood method requires significant memory resources, which limits its application to more moderately sized protein datasets. PMID:21085574

  6. Adult-onset familial vocal fold paralysis.

    PubMed

    Amir, Ida; Crow, Yanick J; Morar, Pradeep

    2015-09-01

    We describe the cases of 2 brothers in their early 50s, born to consanguineous parents, who presented with acute stridor as a result of adult-onset bilateral abductor vocal fold paralysis. Both patients had a history of adult-onset asthma. No other associated symptoms were evident, and findings on neurologic examination and all other investigations were normal. Both patients required emergency surgical tracheostomy. Another brother with a similar history had died of an airway problem when he was 53 years of age; 2 other younger brothers and 3 younger sisters were currently unaffected. To the best of our knowledge, this is the first report of adult-onset familial bilateral vocal fold paralysis in the absence of associated features. The parents' consanguinity suggested an autosomal recessive basis to this disorder. In addition to describing the features of this case, we review the literature relating to adult-onset familial vocal fold paralysis. PMID:26401672

  7. Compound heterozygous PLEC mutations in a patient of consanguineous parentage with epidermolysis bullosa simplex with muscular dystrophy and diffuse alopecia.

    PubMed

    Yin, Jinghua; Ren, Yali; Lin, Zhimiao; Wang, Huijun; Zhou, Yun; Yang, Yong

    2015-02-01

    Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; OMIM 226670) is an autosomal recessive form of EBS, characterized by skin blistering at birth and delayed onset of muscle dystrophy. Mutations in PLEC, the gene encoding plectin, have been identified to be causal for EBS-MD. We report a case of EBS-MD with diffuse alopecia. Genetic study revealed the patient carrying compound heterozygous mutations in PLEC despite the consanguineous parentage. PMID:25209331

  8. A global assessment of a large monocot family highlights the need for group-specific analyses of invasiveness.

    PubMed

    Moodley, Desika; Procheş, Şerban; Wilson, John R U

    2016-01-01

    Significant progress has been made in understanding biological invasions recently, and one of the key findings is that the determinants of naturalization and invasion success vary from group to group. Here, we explore this variation for one of the largest plant families in the world, the Araceae. This group provides an excellent opportunity for identifying determinants of invasiveness in herbaceous plants, since it is one of the families most popular with horticulturalists, with species occupying various habitats and comprising many different life forms. We first developed a checklist of 3494 species of Araceae using online databases and literature sources. We aimed to determine whether invasiveness across the introduction-naturalization-invasion continuum is associated to particular traits within the family, and whether analyses focussed on specific life forms can reveal any mechanistic correlates. Boosted regression tree models were based on species invasion statuses as the response variables, and traits associated with human use, biological characteristics and distribution as the explanatory variables. The models indicate that biological traits such as plant life form and pollinator type are consistently strong correlates of invasiveness. Additionally, large-scale correlates such as the number of native floristic regions and number of introduced regions are also influential at particular stages in the invasion continuum. We used these traits to build a phenogram showing groups defined by the similarity of characters. We identified nine groups that have a greater tendency to invasiveness (includingAlocasia, the Lemnoideae andEpipremnum). From this, we propose a list of species that are not currently invasive for which we would recommend a precautionary approach to be taken. The successful management of plant invasions will depend on understanding such context-dependent effects across taxonomic groups, and across the different stages of the invasion process. PMID:26873404

  9. A global assessment of a large monocot family highlights the need for group-specific analyses of invasiveness

    PubMed Central

    Moodley, Desika; Procheş, Şerban; Wilson, John R. U.

    2016-01-01

    Significant progress has been made in understanding biological invasions recently, and one of the key findings is that the determinants of naturalization and invasion success vary from group to group. Here, we explore this variation for one of the largest plant families in the world, the Araceae. This group provides an excellent opportunity for identifying determinants of invasiveness in herbaceous plants, since it is one of the families most popular with horticulturalists, with species occupying various habitats and comprising many different life forms. We first developed a checklist of 3494 species of Araceae using online databases and literature sources. We aimed to determine whether invasiveness across the introduction–naturalization–invasion continuum is associated to particular traits within the family, and whether analyses focussed on specific life forms can reveal any mechanistic correlates. Boosted regression tree models were based on species invasion statuses as the response variables, and traits associated with human use, biological characteristics and distribution as the explanatory variables. The models indicate that biological traits such as plant life form and pollinator type are consistently strong correlates of invasiveness. Additionally, large-scale correlates such as the number of native floristic regions and number of introduced regions are also influential at particular stages in the invasion continuum. We used these traits to build a phenogram showing groups defined by the similarity of characters. We identified nine groups that have a greater tendency to invasiveness (including Alocasia, the Lemnoideae and Epipremnum). From this, we propose a list of species that are not currently invasive for which we would recommend a precautionary approach to be taken. The successful management of plant invasions will depend on understanding such context-dependent effects across taxonomic groups, and across the different stages of the invasion process. PMID:26873404

  10. Assessment of individuals with BRCA1 and BRCA2 large rearrangements in high-risk breast and ovarian cancer families.

    PubMed

    Arnold, Angela G; Otegbeye, Ebunoluwa; Fleischut, Megan Harlan; Glogowski, Emily A; Siegel, Beth; Boyar, Sherry R; Salo-Mullen, Erin; Amoroso, Kim; Sheehan, Margaret; Berliner, Janice L; Stadler, Zsofia K; Kauff, Noah D; Offit, Kenneth; Robson, Mark E; Zhang, Liying

    2014-06-01

    BRCA1/2 large rearrangement (LR) testing has been available to patients since 2006. Three existing models commonly used in cancer genetics clinical and research settings (BRCAPRO, Penn II and Myriad II) have not been assessed for their performance in predicting the presence of BRCA1/2 large genomic rearrangements in patients who do not have mutations detectable by the traditional Sanger sequencing approach. This study sought to determine if there is an optimal pre-test probability "cut off" value, calculated using these models, to optimize detection of large rearrangements (LRs). Our cohort consisted of 3,301 probands seen for genetic counseling and BRCA1/2 clinical testing from September 2006 to September 2011. A detailed personal and three-generation family history, including self-reported ethnicity, was taken as part of our standard clinical practice. We applied the BRCAPRO, Penn II, and Myriad II models to the probands with LRs. In our cohort of 3,301 probands, 150 carried a non-Ashkenazi mutation in BRCA1 or BRCA2. Seventeen unrelated probands carried a private BRCA1/2 LR (17/150, 11.3 % of all detectable non-AJ mutations). At a pre-test probability cutoff of 10 %, all three empiric risk models would have failed to identify almost 30 % of probands with LRs. Our study shows that BRCA1/2 LR testing should be offered to all women who meet criteria for BRCA1/2 sequence analysis. PMID:24825132

  11. A large deletion encompassing the entire alpha-like globin gene cluster in a family of northern European extraction.

    PubMed Central

    Fortina, P; Delgrosso, K; Rappaport, E; Poncz, M; Ballas, S K; Schwartz, E; Surrey, S

    1988-01-01

    We describe a new deletional form of alpha thalassemia segregating in three generations of a family of northern European origin. A full-term female girl had hypochromic, microcytic anemia since early infancy associated with delayed language development, slow growth and weight gain. Hematologic studies suggested the presence of alpha thalassemia. Gene-blotting studies showed no abnormal alpha-like globin gene fragments; however, studies of inheritance of informative polymorphic restriction fragments using zeta, alpha and 3'-alpha-hypervariable region (3'-HVR) probes showed evidence for an extensive deletion encompassing the entire alpha-like globin gene cluster. The 3' breakpoint of this deletion maps beyond the 3'-HVR, a region implicated as a hot spot for the generation of other large deletional events within the alpha-like cluster. The 5' breakpoint maps at least 10 kilobases (kb) 5' to the zeta-globin gene. The minimum size estimate for this deletion is greater than 47 kilobases. Images PMID:2905048

  12. The Crystal Structure of Bacteriophage HK97 gp6: Defining a Large Family of Head-Tail Connector Proteins

    SciTech Connect

    Cardarelli, Lia; Lam, Robert; Tuite, Ashleigh; Baker, Lindsay A; Sadowski, Paul D; Radford, Devon R; Rubinstein, John L; Battaile, Kevin P; Chirgadze, Nickolay; Maxwell, Karen L; Davidson, Alan R

    2011-11-23

    The final step in the morphogenesis of long-tailed double-stranded DNA bacteriophages is the joining of the DNA-filled head to the tail. The connector is a specialized structure of the head that serves as the interface for tail attachment and the point of egress for DNA from the head during infection. Here, we report the determination of a 2.1 Å crystal structure of gp6 of bacteriophage HK97. Through structural comparisons, functional studies, and bioinformatic analysis, gp6 has been determined to be a component of the connector of phage HK97 that is evolutionarily related to gp15, a well-characterized connector component of bacteriophage SPP1. Whereas the structure of gp15 was solved in a monomeric form, gp6 crystallized as an oligomeric ring with the dimensions expected for a connector protein. Although this ring is composed of 13 subunits, which does not match the symmetry of the connector within the phage, sequence conservation and modeling of this structure into the cryo-electron microscopy density of the SPP1 connector indicate that this oligomeric structure represents the arrangement of gp6 subunits within the mature phage particle. Through sequence searches and genomic position analysis, we determined that gp6 is a member of a large family of connector proteins that are present in long-tailed phages. We have also identified gp7 of HK97 as a homologue of gp16 of phage SPP1, which is the second component of the connector of this phage. These proteins are members of another large protein family involved in connector assembly.

  13. The Crystal Structure of Bacteriophage HK97 gp6: Defining a Large Family of Head-Tail Connector Proteins

    SciTech Connect

    Cardarelli, Lia; Lam, Robert; Tuite, Ashleigh; Baker, Lindsay A; Sadowski, Paul D; Radford, Devon R; Rubinstein, John L; Battaile, Kevin P; Chirgadze, Nickolay; Maxwell, Karen L; Davidson, Alan R

    2010-08-17

    The final step in the morphogenesis of long-tailed double-stranded DNA bacteriophages is the joining of the DNA-filled head to the tail. The connector is a specialized structure of the head that serves as the interface for tail attachment and the point of egress for DNA from the head during infection. Here, we report the determination of a 2.1 {angstrom} crystal structure of gp6 of bacteriophage HK97. Through structural comparisons, functional studies, and bioinformatic analysis, gp6 has been determined to be a component of the connector of phage HK97 that is evolutionarily related to gp15, a well-characterized connector component of bacteriophage SPP1. Whereas the structure of gp15 was solved in a monomeric form, gp6 crystallized as an oligomeric ring with the dimensions expected for a connector protein. Although this ring is composed of 13 subunits, which does not match the symmetry of the connector within the phage, sequence conservation and modeling of this structure into the cryo-electron microscopy density of the SPP1 connector indicate that this oligomeric structure represents the arrangement of gp6 subunits within the mature phage particle. Through sequence searches and genomic position analysis, we determined that gp6 is a member of a large family of connector proteins that are present in long-tailed phages. We have also identified gp7 of HK97 as a homologue of gp16 of phage SPP1, which is the second component of the connector of this phage. These proteins are members of another large protein family involved in connector assembly.

  14. New Family of Quantum Spin Hall Insulators in Two-dimensional Transition-Metal Halide with Large Nontrivial Band Gaps.

    PubMed

    Zhou, Liujiang; Kou, Liangzhi; Sun, Yan; Felser, Claudia; Hu, Feiming; Shan, Guangcun; Smith, Sean C; Yan, Binghai; Frauenheim, Thomas

    2015-12-01

    Topological insulators (TIs) are promising for achieving dissipationless transport devices due to the robust gapless states inside the insulating bulk gap. However, currently realized two-dimensional (2D) TIs, quantum spin Hall (QSH) insulators, suffer from ultrahigh vacuum and extremely low temperature. Thus, seeking for desirable QSH insulators with high feasibility of experimental preparation and large nontrivial gap is of great importance for wide applications in spintronics. On the basis of the first-principles calculations, we predict a novel family of 2D QSH insulators in transition-metal halide MX (M = Zr, Hf; X = Cl, Br, and I) monolayers, especially, which is the first case based on transition-metal halide-based QSH insulators. MX family has the large nontrivial gaps of 0.12-0.4 eV, comparable with bismuth (111) bilayer (0.2 eV), stanene (0.3 eV), and larger than ZrTe5 (0.1 eV) monolayers and graphene-based sandwiched heterstructures (30-70 meV). Their corresponding 3D bulk materials are weak topological insulators from stacking QSH layers, and some of bulk compounds have already been synthesized in experiment. The mechanism for 2D QSH effect in this system originates from a novel d-d band inversion, significantly different from conventional band inversion between s-p, p-p, or d-p orbitals. The realization of pure layered MX monolayers may be prepared by exfoliation from their 3D bulk phases, thus holding great promise for nanoscale device applications and stimulating further efforts on transition metal-based QSH materials. PMID:26524118

  15. A Novel Locus Harbouring a Functional CD164 Nonsense Mutation Identified in a Large Danish Family with Nonsyndromic Hearing Impairment

    PubMed Central

    Nielsen, Morten S.; Corydon, Thomas J.; Demontis, Ditte; Starnawska, Anna; Hedemand, Anne; Buniello, Annalisa; Niola, Francesco; Overgaard, Michael T.; Leal, Suzanne M.; Ahmad, Wasim; Wikman, Friedrik P.; Petersen, Kirsten B.; Crüger, Dorthe G.; Oostrik, Jaap; Kremer, Hannie; Tommerup, Niels; Frödin, Morten; Steel, Karen P.; Tranebjærg, Lisbeth; Børglum, Anders D.

    2015-01-01

    Nonsyndromic hearing impairment (NSHI) is a highly heterogeneous condition with more than eighty known causative genes. However, in the clinical setting, a large number of NSHI families have unexplained etiology, suggesting that there are many more genes to be identified. In this study we used SNP-based linkage analysis and follow up microsatellite markers to identify a novel locus (DFNA66) on chromosome 6q15-21 (LOD 5.1) in a large Danish family with dominantly inherited NSHI. By locus specific capture and next-generation sequencing, we identified a c.574C>T heterozygous nonsense mutation (p.R192*) in CD164. This gene encodes a 197 amino acid transmembrane sialomucin (known as endolyn, MUC-24 or CD164), which is widely expressed and involved in cell adhesion and migration. The mutation segregated with the phenotype and was absent in 1200 Danish control individuals and in databases with whole-genome and exome sequence data. The predicted effect of the mutation was a truncation of the last six C-terminal residues of the cytoplasmic tail of CD164, including a highly conserved canonical sorting motif (YXXФ). In whole blood from an affected individual, we found by RT-PCR both the wild-type and the mutated transcript suggesting that the mutant transcript escapes nonsense mediated decay. Functional studies in HEK cells demonstrated that the truncated protein was almost completely retained on the plasma cell membrane in contrast to the wild-type protein, which targeted primarily to the endo-lysosomal compartments, implicating failed endocytosis as a possible disease mechanism. In the mouse ear, we found CD164 expressed in the inner and outer hair cells of the organ of Corti, as well as in other locations in the cochlear duct. In conclusion, we have identified a new DFNA locus located on chromosome 6q15-21 and implicated CD164 as a novel gene for hearing impairment. PMID:26197441

  16. Living in a Large Family Does Something For You: Influence of Family on the Achievement of African and Caribbean Women in Science.

    ERIC Educational Resources Information Center

    Beoku-Betts, Josephine A.

    2000-01-01

    Examines the influence of the family on women's achievement in scientific careers in the sub-Saharan African and Caribbean regions. Concludes that when compared with their North American and European counterparts, there are significant differences in the family experiences of African and Caribbean women scientists. (Author/SAH)

  17. Lack of Evidence for Increased Genetic Loading for Autism among Families of Affected Females: A Replication from Family History Data in Two Large Samples

    ERIC Educational Resources Information Center

    Goin-Kochel, Robin P.; Abbacchi, Anna; Constantino, John N.

    2007-01-01

    Both the broad and narrow phenotypes of autism have been consistently observed in family members of affected individuals. Additionally, autism spectrum disorders (ASDs) present four times more often in males than in females, for reasons that are currently unknown. In this study, we examined whether there were differences in familial loading of ASD…

  18. Large Deviations for Stationary Probabilities of a Family of Continuous Time Markov Chains via Aubry-Mather Theory

    NASA Astrophysics Data System (ADS)

    Lopes, Artur O.; Neumann, Adriana

    2015-05-01

    In the present paper, we consider a family of continuous time symmetric random walks indexed by , . For each the matching random walk take values in the finite set of states ; notice that is a subset of , where is the unitary circle. The infinitesimal generator of such chain is denoted by . The stationary probability for such process converges to the uniform distribution on the circle, when . Here we want to study other natural measures, obtained via a limit on , that are concentrated on some points of . We will disturb this process by a potential and study for each the perturbed stationary measures of this new process when . We disturb the system considering a fixed potential and we will denote by the restriction of to . Then, we define a non-stochastic semigroup generated by the matrix , where is the infinifesimal generator of . From the continuous time Perron's Theorem one can normalized such semigroup, and, then we get another stochastic semigroup which generates a continuous time Markov Chain taking values on . This new chain is called the continuous time Gibbs state associated to the potential , see (Lopes et al. in J Stat Phys 152:894-933, 2013). The stationary probability vector for such Markov Chain is denoted by . We assume that the maximum of is attained in a unique point of , and from this will follow that . Thus, here, our main goal is to analyze the large deviation principle for the family , when . The deviation function , which is defined on , will be obtained from a procedure based on fixed points of the Lax-Oleinik operator and Aubry-Mather theory. In order to obtain the associated Lax-Oleinik operator we use the Varadhan's Lemma for the process . For a careful analysis of the problem we present full details of the proof of the Large Deviation Principle, in the Skorohod space, for such family of Markov Chains, when . Finally, we compute the entropy of the invariant probabilities on the Skorohod space associated to the Markov Chains we analyze.

  19. The Value of Family History in Diagnosing Primary Immunodeficiency Disorders

    PubMed Central

    Alhammadi, Ahmad; Al-Yafei, Fawzia

    2014-01-01

    Eliciting proper family medical history is critical in decreasing morbidity and mortality in patients with primary immunodeficiency disorders (PIDs). Communities with a common practice of consanguinity have a high rate of PIDs. We are presenting 2 cases where digging deeply into the family medical history resulted in the diagnosis of Omenn syndrome, a possibly fatal entity if not managed in a reasonable period. PMID:25161792

  20. Chlamydia abortus YhbZ, a truncated Obg family GTPase, associates with the Escherichia coli large ribosomal subunit.

    PubMed

    Polkinghorne, Adam; Vaughan, Lloyd

    2011-01-01

    The stringent stress response is vital for bacterial survival under adverse environmental conditions. Obligate intracellular Chlamydia lack key stringent response proteins, but nevertheless can interrupt the cell cycle and enter stasis or persistence upon amino acid starvation. A possible key protein retained is YhbZ, a homologue of the ObgE guanosine triphosphatase (GTPase) superfamily connecting the stringent stress response to ribosome maturation. Curiously, chlamydial YhbZ lacks the ObgE C-terminal domain thought to be essential for binding the large ribosomal subunit. We expressed recombinant Chlamydia abortus YhbZ and showed it to be a functional GTPase, with similar activity to other Obg GTPase family members. As Chlamydia are resistant to genetic manipulation, we performed heterologous expression and gradient centrifugation experiments in Escherichia coli and found that, despite the missing C-terminal domain, C. abortus YhbZ co-fractionates with the E. coli 50S large ribosomal subunit. In addition, overexpression of chlamydial YhbZ in E. coli leads to growth defects and elongation, as reported for other Obg members. YhbZ did not complement an E. coli obgE temperature-sensitive mutant, indicating the C-terminal acidic domain may have an additional role. This data supports a role for YhbZ linking the chlamydial stress response to ribosome function and cellular growth. PMID:21195156

  1. [Interview. Mgr. Henry Harry: "The reticence of men with regard to family planning has been based largely..."].

    PubMed

    Kpatoukpa, L

    1993-01-01

    In an interview for the newsletter of the Association for Family Promotion (ABPF) of Benin, ABPF's honorary president Henry Harry, a Christian pastor, explains why men have been silent about family planning. The president of Benin reflected the view of many people when he said to ABPF that it is tolerated but not accepted. But the fact is that family planning gives mothers excellent health; a flourishing, prosperous, and happy family; and healthy children. A family in which the father has all responsibility provides an adequate education for its children and saves money for difficult days. It is for all these reasons that government began to be interested in family planning in the framework of promotion of the family and social welfare. Women should participate in the family planning movement because family planning helps their health and family. One of the principle causes for men being reluctant about family planning is hypocrisy. Some speak about sexual abstinence with their wife but have 3-5 women who can satisfy them when they want. According to men, family planning opens the door for their wives to be unfaithful. ABPF strategies to reduce adolescent pregnancies and abortion include family life education, establishment of dialogue at the heart of the family, and communication of the dangers of too close pregnancies, of unwanted pregnancies, and of uncontrolled sexual pleasures. Family planning is an apostolic work, a work of sacrifice, and a work of self-control. Those who work for the development of family planning must sacrifice themselves and help others without waiting for material returns for the well-being and prosperity of our populations. PMID:12318555

  2. High proportion of large genomic deletions and a genotype–phenotype update in 80 unrelated families with juvenile polyposis syndrome

    PubMed Central

    Aretz, S; Stienen, D; Uhlhaas, S; Stolte, M; Entius, M M; Loff, S; Back, W; Kaufmann, A; Keller, K‐M; Blaas, S H; Siebert, R; Vogt, S; Spranger, S; Holinski‐Feder, E; Sunde, L; Propping, P; Friedl, W

    2007-01-01

    Background In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown. Methods Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS. Results By direct sequencing of the two genes, point mutations were identified in 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were found in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 mutation negative cases uncovered a point mutation in two patients (5%). SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) than did patients with BMPR1A mutations (8%) (p<0.001); all seven cases of gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation carriers with gastric polyps were significantly older at gastroscopy than those without (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, hereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The documented histologic findings encompassed a wide distribution of different polyp types, comparable with that described in hereditary mixed polyposis syndromes (HMPS). Conclusions Screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. A strong genotype‐phenotype correlation for gastric polyposis, gastric cancer, and HHT was identified, which should have implications for counselling and surveillance. Histopathological results in hamartomatous polyposis syndromes must be critically interpreted. PMID:17873119

  3. Sifting through genomes with iterative-sequence clustering produces a large, phylogenetically diverse protein-family resource

    PubMed Central

    2012-01-01

    Background New computational resources are needed to manage the increasing volume of biological data from genome sequencing projects. One fundamental challenge is the ability to maintain a complete and current catalog of protein diversity. We developed a new approach for the identification of protein families that focuses on the rapid discovery of homologous protein sequences. Results We implemented fully automated and high-throughput procedures to de novo cluster proteins into families based upon global alignment similarity. Our approach employs an iterative clustering strategy in which homologs of known families are sifted out of the search for new families. The resulting reduction in computational complexity enables us to rapidly identify novel protein families found in new genomes and to perform efficient, automated updates that keep pace with genome sequencing. We refer to protein families identified through this approach as “Sifting Families,” or SFams. Our analysis of ~10.5 million protein sequences from 2,928 genomes identified 436,360 SFams, many of which are not represented in other protein family databases. We validated the quality of SFam clustering through statistical as well as network topology–based analyses. Conclusions We describe the rapid identification of SFams and demonstrate how they can be used to annotate genomes and metagenomes. The SFam database catalogs protein-family quality metrics, multiple sequence alignments, hidden Markov models, and phylogenetic trees. Our source code and database are publicly available and will be subject to frequent updates (http://edhar.genomecenter.ucdavis.edu/sifting_families/). PMID:23061897

  4. New Family of Quantum Spin Hall Insulators in Two-dimensional Transition-Metal Halide with Large Nontrivial Band Gaps

    NASA Astrophysics Data System (ADS)

    Zhou, Liujiang; Kou, Liangzhi; Sun, Yan; Felser, Claudia; Hu, Feiming; Shan, Guangcun; Smith, Sean C.; Yan, Binghai; Frauenheim, Thomas

    2015-12-01

    Topological insulators (TIs) are promising for achieving dissipationless transport devices due to the robust gapless states inside the insulating bulk gap. However, currently realized 2D TIs, quantum spin Hall (QSH) insulators, suffer from ultra-high vacuum and extremely low temperature. Thus, seeking for desirable QSH insulators with high feasibility of experimental preparation and large nontrivial gap is of great importance for wide applications in spintronics. Based on the first-principles calculations, we predict a novel family of two-dimensional (2D) QSH insulators in transition-metal halide MX (M = Zr, Hf; X = Cl, Br, and I) monolayers with large nontrivial gaps of 0.12$-$0.4 eV, comparable with bismuth (111) bilayer (0.2 eV), stanene (0.3 eV) and larger than ZrTe$_5$ (0.1 eV) monolayers and graphene-based sandwiched heterstructures (30$-$70 meV). Their corresponding 3D bulk materials are weak topological insulators from stacking QSH layers, and some of bulk compounds have already been synthesized in experiment. The mechanism for 2D QSH effect in this system originates from a novel d$-$d band inversion, which is different from conventional band inversion between s$-$s orbitals, or p$-$p orbitals. The realization of pure layered MX monolayers may be prepared by exfoliation from their 3D bulk phases, thus holding great promise for nanoscale device applications and stimulating further efforts on transition metal-based QSH materials.

  5. A whole-genome scan in a large family with leukodystrophy and oligodontia reveals linkage to 10q22.

    PubMed

    Chouery, Eliane; Delague, Valérie; Jalkh, Nadine; Salem, Nabiha; Kfoury, Jessy; Rodriguez, Diana; Chabrol, Brigitte; Boespflug-Tanguy, Odile; Lévy, Nicolas; Serre, Jean Louis; Mégarbané, André

    2011-02-01

    Dentoleukoencephalopathies with autosomal recessive inheritance are very rare. Recently, a large inbred Syrian pedigree was reported with oligodontia in association with a degenerative neurologic condition characterized by progressive ataxia and pyramidal syndrome and abnormalities in the white matter and cortical atrophy. A whole-genome screening of this family using 382 microsatellite markers was completed, but no evidence was found of linkage to any chromosomal region. A genome-wide linkage analysis using the 260K single nucleotide polymorphism Affymetrix array was then undertaken and a maximum multipoint logarithm of the odds score of 5.66 (NPL score = 7.65) was detected on chromosome 10q22 region. This genomic interval contains 95 known genes including the Prosaposin gene (PSAP) responsible for metachromatic leukodystrophy, which was excluded. Seventeen additional candidate genes were tested and excluded. Sequencing of the whole candidate locus is in progress and should allow the identification of the causative gene in this rare disease, thereby improving the understanding of the physiopathology of this disease. PMID:20721593

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

    PubMed

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

    2015-08-01

    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 referred to the Genetic and Developmental Medicine clinic in Sultan Qaboos University in Oman for autism spectrum disorders in a highly consanguineous population. Copy number variants were seen in 27% of our studied cohort of patients and it was strongly associated with dysmorphic features and congenital anomalies. PMID:25703031

  7. 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

  8. Living in a Large Family does Something for You: Influence of Family on the Achievement of African and Caribbean Women in Science

    NASA Astrophysics Data System (ADS)

    Beoku-Betts, Josephine A.

    This article examines the influence of the family on women's achievement in scientific careers in the sub-Saharan African and Caribbean regions. It is based on semistructured interviews with 20 doctoral-level African and Caribbean women scientists working in research and academic institutions in these societies. Given the diversity of structural conditions, and economic, geopolitical, and sociocultural experiences, it is argued that the road to success in the pursuance of a scientific career are not the same, although there are areas of common ground. The study shows that when compared with their North American and European counterparts, there are significant differences in the family experiences of African and Caribbean women scientists that must be made visible and pursued more rigorously in further studies.

  9. Mapping of a possible X-linked form of familial developmental dysphasia (FDD) in a single large pedigree

    SciTech Connect

    Dunne, P.W.; Doody, R.S.; Epstein, H.F.

    1994-09-01

    Children diagnosed with developmental dysphasia develop speech very late without exhibiting sensory or motor dysfunction, and when they do begin to speak their grammar is abnormal. A large three-generation British pedigree was recently identified in which 16 out of 30 members were diagnosed as dysphasic. Assuming a dominant mode of inheritance with homogeneous phenotypic expression and complete penetrance among affected members, we showed by simulation analysis that this pedigree has the power to detect linkage to marker loci with an average maximum LOD score of 3.67 at {theta}=0.1. Given the absence of male-to-male transmission and a ratio of female to male affecteds (10/6) in this pedigree within the expected range for an X-linked dominant mode of inheritance, we decided to begin a genome-wide linkage analysis with microsatellite markers on the human X chromosome. Fifteen individuals (10 affected) from three generations were genotyped with 35 polymorphic STS`s (Research Genetics) which were approximately uniformly distributed along the X chromosome. Two-point linkage was assessed using the MLINK and ILINK programs from the LINKAGE package. Markers DXS1223, DXS987, DXS996 and DXS1060 on Xp22 showed consistent linkage to the disease locus with a maximum LOD score of 0.86 at a distance of 22 cM for DXS1060. If further analysis with additional markers and additional family members confirms X-linkage, such a localization would provide support for Lehrke`s hypothesis for X-linkage of major intellectual traits including verbal functioning.

  10. Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel

    PubMed Central

    Steiner, Hillel A.; Uradu, Andrea; Lynnes, Ty C.; Groh, William J.; Miller, John M.; Lin, Hai; Gao, Hongyu; Wang, Zhiping; Liu, Yunlong; Chen, Peng-Sheng; Vatta, Matteo

    2015-01-01

    Background The etiology of conduction disturbances necessitating permanent pacemaker (PPM) implantation is often unknown, although familial aggregation of PPM (faPPM) suggests a possible genetic basis. We developed a pan-cardiovascular next generation sequencing (NGS) panel to genetically characterize a selected cohort of faPPM. Materials and Methods We designed and validated a custom NGS panel targeting the coding and splicing regions of 246 genes with involvement in cardiac pathogenicity. We enrolled 112 PPM patients and selected nine (8%) with faPPM to be analyzed by NGS. Results Our NGS panel covers 95% of the intended target with an average of 229x read depth at a minimum of 15-fold depth, reaching a SNP true positive rate of 98%. The faPPM patients presented with isolated cardiac conduction disease (ICCD) or sick sinus syndrome (SSS) without overt structural heart disease or identifiable secondary etiology. Three patients (33.3%) had heterozygous deleterious variants previously reported in autosomal dominant cardiac diseases including CCD: LDB3 (p.D117N) and TRPM4 (p.G844D) variants in patient 4; TRPM4 (p.G844D) and ABCC9 (p.V734I) variants in patient 6; and SCN5A (p.T220I) and APOB (p.R3527Q) variants in patient 7. Conclusion FaPPM occurred in 8% of our PPM clinic population. The employment of massive parallel sequencing for a large selected panel of cardiovascular genes identified a high percentage (33.3%) of the faPPM patients with deleterious variants previously reported in autosomal dominant cardiac diseases, suggesting that genetic variants may play a role in faPPM. PMID:26636822

  11. Development and Two-Year Follow-Up Evaluation of a Training Workshop for the Large Preventive Positive Psychology Happy Family Kitchen Project in Hong Kong.

    PubMed

    Lai, Agnes Y; Mui, Moses W; Wan, Alice; Stewart, Sunita M; Yew, Carol; Lam, Tai-Hing; Chan, Sophia S

    2016-01-01

    Evidence-based practice and capacity-building approaches are essential for large-scale health promotion interventions. However, there are few models in the literature to guide and evaluate training of social service workers in community settings. This paper presents the development and evaluation of the "train-the-trainer" workshop (TTT) for the first large scale, community-based, family intervention projects, entitled "Happy Family Kitchen Project" (HFK) under the FAMILY project, a Hong Kong Jockey Club Initiative for a Harmonious Society. The workshop aimed to enhance social workers' competence and performance in applying positive psychology constructs in their family interventions under HFK to improve family well-being of the community they served. The two-day TTT was developed and implemented by a multidisciplinary team in partnership with community agencies to 50 social workers (64% women). It focused on the enhancement of knowledge, attitude, and practice of five specific positive psychology themes, which were the basis for the subsequent development of the 23 family interventions for 1419 participants. Acceptability and applicability were enhanced by completing a needs assessment prior to the training. The TTT was evaluated by trainees' reactions to the training content and design, changes in learners (trainees) and benefits to the service organizations. Focus group interviews to evaluate the workshop at three months after the training, and questionnaire survey at pre-training, immediately after, six months, one year and two years after training were conducted. There were statistically significant increases with large to moderate effect size in perceived knowledge, self-efficacy and practice after training, which sustained to 2-year follow-up. Furthermore, there were statistically significant improvements in family communication and well-being of the participants in the HFK interventions they implemented after training. This paper offers a practical example of development, implementation and model-based evaluation of training programs, which may be helpful to others seeking to develop such programs in diverse communities. PMID:26808541

  12. Development and Two-Year Follow-Up Evaluation of a Training Workshop for the Large Preventive Positive Psychology Happy Family Kitchen Project in Hong Kong

    PubMed Central

    Lai, Agnes Y.; Mui, Moses W.; Wan, Alice; Stewart, Sunita M.; Yew, Carol; Lam, Tai-hing; Chan, Sophia S.

    2016-01-01

    Evidence-based practice and capacity-building approaches are essential for large-scale health promotion interventions. However, there are few models in the literature to guide and evaluate training of social service workers in community settings. This paper presents the development and evaluation of the “train-the-trainer” workshop (TTT) for the first large scale, community-based, family intervention projects, entitled “Happy Family Kitchen Project” (HFK) under the FAMILY project, a Hong Kong Jockey Club Initiative for a Harmonious Society. The workshop aimed to enhance social workers’ competence and performance in applying positive psychology constructs in their family interventions under HFK to improve family well-being of the community they served. The two-day TTT was developed and implemented by a multidisciplinary team in partnership with community agencies to 50 social workers (64% women). It focused on the enhancement of knowledge, attitude, and practice of five specific positive psychology themes, which were the basis for the subsequent development of the 23 family interventions for 1419 participants. Acceptability and applicability were enhanced by completing a needs assessment prior to the training. The TTT was evaluated by trainees’ reactions to the training content and design, changes in learners (trainees) and benefits to the service organizations. Focus group interviews to evaluate the workshop at three months after the training, and questionnaire survey at pre-training, immediately after, six months, one year and two years after training were conducted. There were statistically significant increases with large to moderate effect size in perceived knowledge, self-efficacy and practice after training, which sustained to 2-year follow-up. Furthermore, there were statistically significant improvements in family communication and well-being of the participants in the HFK interventions they implemented after training. This paper offers a practical example of development, implementation and model-based evaluation of training programs, which may be helpful to others seeking to develop such programs in diverse communities. PMID:26808541

  13. Consanguinity and founder effect for Gaucher disease mutation G377S in a population from Tabuleiro do Norte, Northeastern Brazil.

    PubMed

    Chaves, R G; Pereira, L da Veiga; de Araújo, F T; Rozenberg, R; Carvalho, M D F; Coelho, J C; Michelin-Tirelli, K; Chaves, M de Freitas; Cavalcanti, G B

    2015-10-01

    Gaucher's disease (GD) is caused by a β-glucocerebrosidase deficiency, leading to the accumulation of glucocerebroside in the reticuloendothelial system. The prevalence of GD in Tabuleiro do Norte (TN) (1:4000) is the highest in Brazil. The purpose of this study was to present evidence of consanguinity and founder effect for the G377S mutation (c.1246G>A) among GD patients in TN based on enzyme, molecular and genealogical studies. Between March 2009 and December 2010, 131 subjects at risk for GD (GC in dried blood ≤2.19 nmol/h/ml) and 5 confirmed GD patients from the same community were submitted for molecular analysis to characterize the genetic profile of the population. Based on the enzymatic and molecular analysis, the subjects were classified into three categories: affected (n = 5), carrier (n = 20) and non-carrier (n = 111). All carriers were (G377S/wt). Affected subjects were homozygous (G377S/G377S). The identification of a single mutation in carriers and homozygotes from different generations, the history of the community and the genealogy study suggest that the high prevalence of GD in this population may be due to a combination of consanguinity and founder effect for the G377S mutation. PMID:25287185

  14. The Politics of School Choice in Two Countries with Large Private-Dependent Sectors (Spain and Chile): Family Strategies, Collective Action and Lobbying

    ERIC Educational Resources Information Center

    Rambla, Xavier; Valiente, Oscar; Frias, Carla

    2011-01-01

    In many countries choice of school is an increasing concern for families and governments. In Spain and Chile, it is also associated with a long-standing political cleavage on the regulation of large sectors of private-dependent schools. This article analyses both the micro- and the macro-politics of choice in these two countries, where low-status…

  15. A report of 8 cases with hemoglobin H disease in an Iranian family.

    PubMed

    Azarkeivan, Azita; Azita, Azarkeivan; Neishabury, Maryam; Hadavi, Valeh; Esteghamat, Fatemehsadat; Fatemehsadat, Esteghamat; Enrahimkhani, Saideh; Najmabadi, Hossein; Hossein, Najmabadi

    2010-08-01

    alpha-Thalassemia is a common genetic disorder in Iran. However, no comprehensive data on epidemiology of severe forms of alpha-thalassemia, including hemoglobin H (HbH) or hydrops fetalis, is available in this population. This is a first case report of an Iranian family with large number of HbH individuals. The proband is a 48-year-old woman, referred to our center with anemia and no history of previous blood transfusions. Similar clinical phenotype has been observed in all of her 5 siblings, 2 of her 4 children, and her granddaughter, whose parents are first cousins. A reverse hybridization assay covering 21 alpha globin mutations was performed to determine the genotype in 11 members of this family and a fetus. HbH genotype was identified in 9 individuals, representing 3 generations, including a fetus. The high prevalence of alpha-thalassemia carriers together with the high rate of consanguineous marriages could lead to a large number of individuals with HbH or even hydrops fetalis in Iranian families. Therefore, to avoid the risk of having affected offspring, carrier detection, genetic counseling, and prenatal diagnosis would be of vital importance for individuals with low red blood cell (RBC) indices, normal iron status, and normal HbA(2) level, who are suspected to be alpha-thalassemia carriers. PMID:20670167

  16. Familial Gigantiform Cementoma

    PubMed Central

    Ma, Chunyue; Wang, Hongwei; He, Guang; Qin, Xingjun

    2016-01-01

    Abstract Familial gigantiform cementoma is an exceedingly rare but distinct subtype of cemento-osseous-fibrous lesion. Undocumented radiographic changes and related bone metabolism disorder are herein hypothesized and discussed. We present an adolescent case with recurrent familial gigantiform cementoma who received surgical intervention in our hospital. Apart from typical multiquadrant and expansile abnormalies involving both jaws, he also suffered from several times of fractures in lower extremity. Furthermore, radiographic examinations of calvaria, pelvis, femoris, tibia, and fibula all revealed radiolucent areas signifying diffuse osteopenic bone losses. Some of his consanguineous relatives bore the same burden of fractures during pubertal period. Considering these polyostotic conditions, a correlation of congenital bone metabolism disorder in cases with familial gigantiform cementoma, named “calcium steal disorder,” was thus proposed. Familial gigantiform cementoma is closely associated with “calcium steal disorder.” Whole-body dual-energy absorptiometry should be considered as a routine examination for fracture-related risk prediction. PMID:26945411

  17. 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,…

  18. A Novel Syntaxin 11 Gene (STX11) Mutation c.650T>C, p.Leu217Pro, in a Korean Child With Familial Hemophagocytic Lymphohistiocytosis.

    PubMed

    Sultanova, Ardak K; Kim, Seong Koo; Lee, Jae Wook; Jang, Pil Sang; Chung, Nack Gyun; Cho, Bin; Park, Joonhong; Kim, Yonggoo; Kim, Myungshin

    2016-03-01

    We report the first Far Eastern case of a Korean child with familial hemophagocytic lymphohistiocytosis (HLH) caused by a novel syntaxin 11 (STX11) mutation. A 33-month-old boy born to non-consanguineous Korean parents was admitted for intermittent fever lasting one week, pancytopenia, hepatosplenomegaly, and HLH in the bone marrow. Under the impression of HLH, genetic study revealed a novel homozygous missense mutation of STX11: c.650T>C, p.Leu217Pro. Although no large deletion or allele drop was identified, genotype analysis demonstrated that the homozygous c.650T>C may have resulted from the duplication of a maternal (unimaternal) chromosomal region and concurrent loss of the other paternal allele, likely caused by meiotic errors such as two crossover events. A cumulative study of such novel mutations and their effects on specific protein interactions may deepen the understanding of how abnormal STX1 expression results in deficient cytotoxic function. PMID:26709266

  19. A Comparative Analysis of Training and Development and Work-Family Education Systems in a Large Corporate Organization

    ERIC Educational Resources Information Center

    Gibson, Sharon K.

    2005-01-01

    This paper reviews the findings of a comparative analysis of two education systems in one corporate organization: training and development and work-family. Key learning features across these systems were analyzed to determine similarities and differences and to identify common concerns. The findings indicated that, although this organization…

  20. The large soybean (Glycine max) WRKY TF family expanded by segmental duplication events and subsequent divergent selection among subgroups

    PubMed Central

    2013-01-01

    Background WRKY genes encode one of the most abundant groups of transcription factors in higher plants, and its members regulate important biological process such as growth, development, and responses to biotic and abiotic stresses. Although the soybean genome sequence has been published, functional studies on soybean genes still lag behind those of other species. Results We identified a total of 133 WRKY members in the soybean genome. According to structural features of their encoded proteins and to the phylogenetic tree, the soybean WRKY family could be classified into three groups (groups I, II, and III). A majority of WRKY genes (76.7%; 102 of 133) were segmentally duplicated and 13.5% (18 of 133) of the genes were tandemly duplicated. This pattern was not apparent in Arabidopsis or rice. The transcriptome atlas revealed notable differential expression in either transcript abundance or in expression patterns under normal growth conditions, which indicated wide functional divergence in this family. Furthermore, some critical amino acids were detected using DIVERGE v2.0 in specific comparisons, suggesting that these sites have contributed to functional divergence among groups or subgroups. In addition, site model and branch-site model analyses of positive Darwinian selection (PDS) showed that different selection regimes could have affected the evolution of these groups. Sites with high probabilities of having been under PDS were found in groups I, II c, II e, and III. Together, these results contribute to a detailed understanding of the molecular evolution of the WRKY gene family in soybean. Conclusions In this work, all the WRKY genes, which were generated mainly through segmental duplication, were identified in the soybean genome. Moreover, differential expression and functional divergence of the duplicated WRKY genes were two major features of this family throughout their evolutionary history. Positive selection analysis revealed that the different groups have different evolutionary rates. Together, these results contribute to a detailed understanding of the molecular evolution of the WRKY gene family in soybean. PMID:24088323

  1. 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. PMID:24345578

  2. Clinical variability of the cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy phenotype in two siblings of a large family showing the same mutation

    PubMed Central

    Vyshka, Gentian; Kruja, Jera

    2013-01-01

    A 44-year-old Albanian male was consulted and diagnosed with dementia. His magnetic resonance imaging suggested diffuse white matter changes. The suspicion of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) was raised, and a genetic analysis confirmed such a suspicion through uncovering a pathogenic mutation at the level of exon 4 (c.475C>T) of chromosome 19. The patient came from a large family of 13 children, all of whom underwent clinical, genetic, and imaging examination. The pathogenic mutation was found present only in his eldest sister (50 years old), and she presented also very suggestive signs of CADASIL in her respective imaging study, but without any clinically significant counterpart. All other siblings were free from clinical and radiological signs of the disorder. Our opinion was that we were dealing with a mutation showing a very low level of penetrance, with only two siblings affected in a large Albanian family with 13 children. PMID:24124395

  3. Hereditary motor neuron disease in a large Norwegian family with a "H46R" substitution in the superoxide dismutase 1 gene.

    PubMed

    Østern, Rune; Fagerheim, Toril; Ørstavik, Kristin; Holmøy, Trygve; Heiberg, Arvid; Lund-Petersen, Inger; Strom, Tim M; Nilssen, Øivind; Dahl, Arve

    2012-06-01

    Mutant genes associated with Charcot Marie Tooth type 2, distal hereditary motor neuropathy and familial amyotrophic lateral sclerosis may cause overlapping clinical phenotypes. We performed whole genome linkage analysis, haplotype analysis, sequencing and detailed clinical and neurophysiological investigations in a large Norwegian kindred with a condition that clinically had been classified as Charcot Marie Tooth type 2. The mutation c.140A>G, p.His47Arg (alias p.His46Arg or H46R) in the superoxide dismutase 1 gene (SOD1) segregated with the disease. The patients present a hereditary motor neuropathy-like clinical picture and long survival (mean 29years). To our knowledge, this is the first extensive report describing a large non-Japanese kindred. The prognostic implications of the condition seen in this family have little in common with what is normally associated with sporadic amyotrophic lateral sclerosis and illustrates the complexity of the genetic etiology of lower motor neuron disease. PMID:22475618

  4. Contribution of clinical screening to carrier detection in a large Chinese family with Fabry disease due to a novel alpha-galactosidase A gene deletion.

    PubMed

    Ro, L-S; Chen, C-M; Chang, H-S; Lyu, R-K; Wu, Y-R; Hsu, W-C; Lee-Chen, G-J

    2007-05-01

    Diagnosis of heterozygous Fabry patients is difficult because of its variable clinical manifestations and overlapping serum alpha-galactosidase A (AGA) activity between carriers and non-carriers. We tried to facilitate diagnosis of heterozygous Fabry patients by detailed clinical examination. We analyzed clinical presentations, biochemical, electrophysiological and genetic characteristics of 16 patients with Fabry disease in a large Chinese family. Male patients demonstrated significantly higher pain scores, poorer renal function, and higher frequency of hypohidrosis and corpora angiokeratomas than female patients. Interestingly, all the males and females had corneal verticilata by slit lamp examination. However, there was no association of serum AGA activity with renal function or pain symptom scores. The results indicated that detailed ocular and neurological examination might provide an alternative way of detecting heterozygous patients. We also report a novel large deletion spanning across the joint of Alu repetitive elements in introns 1 and 2 with resultant exon 2 deletion in a Chinese family with Fabry disease. PMID:17437606

  5. Skinfold over toenail is pathognomonic for the popliteal pterygium syndrome in a Congolese family with large intrafamilial variability

    PubMed Central

    Mubungu, Gerrye; Lumaka, Aimé; Matondo, Rosette; Mbayabo, Gloire; Tuka, Deborah; Kayembe, Claudarche; Mulowhe, Didier; Molua, Antoine; Tady, Bruno-Paul; Nkidiaka, Emmanuel; Bunga, Paulo; Lukusa Tshilobo, Prosper; Devriendt, Koenraad

    2014-01-01

    Key Clinical Message We report on three related Congolese popliteal pterygium syndrome (PPS) patients concordant only for the skinfold over the toenail. Mutation analysis revealed that the three affected individuals carried a heterozygous missense mutation in the Exon 4, NM_006147.2:c.250C>T; p.Arg84Cys. This is the first molecularly confirmed PPS family from central Africa. PMID:25548624

  6. The hemoglobins of Notothenia angustata, a temperate fish belonging to a family largely endemic to the Antarctic Ocean.

    PubMed

    Fago, A; D'Avino, R; Di Prisco, G

    1992-12-15

    The blood of the teleost Notothenia angustata contains a major hemoglobin (Hb 1, over 95% of the total), accompanied by a minor component (Hb 2). The two hemoglobins have identical beta chains and differ in their alpha chains. The primary structure of both hemoglobins has been established through the elucidation of the complete amino acid sequence of the three chains. The study of the oxygen-binding properties shows that Hb 1 displays the Bohr and Root effects and has high affinity for organic phosphates. N. angustata belongs to the family Nototheniidae, suborder Notothenioidei. Unlike the vast majority of nototheniid species, which live in isolation in the Antarctic Ocean and have developed cold adaptation, N. angustata inhabits the waters of southern New Zealand and is not cold adapted. Although some hematological parameters typically favour oxygen transport in a temperate environment, the hemoglobin multiplicity and structural and functional features closely resemble those of the Antarctic species of the same family and suborder. Thus, N. angustata may be considered as a link between temperate and Antarctic habitats. The hypothetical separation history of N. angustata from the Antarctic species of the same family is discussed in the light of the present findings. PMID:1483479

  7. Clinical and molecular characterization of a large family with an interstitial 15q11q13 duplication.

    PubMed

    Piard, Juliette; Philippe, Christophe; Marvier, Marie; Beneteau, Claire; Roth, Virginie; Valduga, Mylène; Béri, Mylène; Bonnet, Céline; Grégoire, Marie-José; Jonveaux, Philippe; Leheup, Bruno

    2010-08-01

    The clinical significance of an interstitial duplication of chromosome 15q11q13 is still not well documented. This abnormality has been associated with autistic spectrum disorders (ASD) and varying degrees of mental retardation. The clinical variability appears to be influenced by the parental origin of the duplication. We present here the clinical evaluation and psychological assessment of the largest reported family with 12 carriers on three generations. Patients exhibit mental retardation, motor and visuo-motor skills impairments and adaptive functioning deficit without formal diagnosis of autism. There appeared to be evidence in the family of reduced penetrance in duplication of paternal origin. This familial 15q11q13 duplication was precisely investigated by cytogenetic and molecular techniques including fluorescence in situ hybridization (FISH), PCR analysis of microsatellite markers, array-comparative genomic hybridization analysis (Array-CGH) and semi-quantitative methylation-sensitive PCR. Results showed an inherited 15q11q13 duplication of maternal origin in 10 patients and of paternal origin in the remaining two. The size of the duplicated area was around 6 Mb with breakpoints in accordance with those previously reported. This report extends the clinical spectrum of the 15q11q13 duplication, and we recommend the investigation of 15q11q13 duplication not only in subjects with autistic spectrum disorder but also in patients with low normal intelligence and dyspraxia. PMID:20635369

  8. A large deletion in the LDL receptor gene--the cause of familial hypercholesterolemia in three Italian families: a study that dates back to the 17th century (FH-Pavia).

    PubMed Central

    Bertolini, S; Lelli, N; Coviello, D A; Ghisellini, M; Masturzo, P; Tiozzo, R; Elicio, N; Gaddi, A; Calandra, S

    1992-01-01

    In the LDL-receptor gene, a large rearrangement causing hypercholesterolemia was detected in three apparently unrelated families living in northern Italy. In all probands, binding, internalization, and degradation of 125I-LDL measured in skin fibroblasts were found to be 40%-50% of control values, indicative of heterozygous familial hypercholesterolemia (FH). Southern blot analysis revealed that the probands were heterozygous for a large (25-kb) deletion of the LDL-receptor gene eliminating exons 2-12. The affected subjects possessed two LDL-receptor mRNA species: one of normal size (5.3 kb) and one of smaller size (3.5 kb). In the latter mRNA, the coding sequence of exon 1 is joined to the coding sequence of exon 13, causing a change in the reading frame and thereby giving rise to a premature stop codon. The receptor protein deduced from the sequence of the defective mRNA is a short polypeptide of 29 amino acids, devoid of any function. Tracing these three families back to the 17th century, we found both their common ancestor and the possible origin of the mutation, in a region which is called "Lomellina" and which is located in southwest Lombardy, near the old city of Pavia. Therefore we named the mutation "FH-Pavia." Images Figure 3 Figure 4 Figure 5 Figure 6 PMID:1609792

  9. Novel KCNQ2 and KCNQ3 mutations in a large cohort of families with benign neonatal epilepsy: first evidence for an altered channel regulation by syntaxin-1A.

    PubMed

    Soldovieri, Maria Virginia; Boutry-Kryza, Nadia; Milh, Mathieu; Doummar, Diane; Heron, Benedicte; Bourel, Emilie; Ambrosino, Paolo; Miceli, Francesco; De Maria, Michela; Dorison, Nathalie; Auvin, Stephane; Echenne, Bernard; Oertel, Julie; Riquet, Audrey; Lambert, Laetitia; Gerard, Marion; Roubergue, Anne; Calender, Alain; Mignot, Cyril; Taglialatela, Maurizio; Lesca, Gaetan

    2014-03-01

    Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression-burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy." In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies. PMID:24375629

  10. Homozygous familial hypercholesterolemia.

    PubMed

    Alicezah, M K; Razali, R; Rahman, T; Hoh, B P; Suhana, N H; Muid, S; Nawawi, H M; Koshy, M

    2014-08-01

    We report a rare case of homozygous familial hypercholesterolemia (HoFH), a 22-year-old Malay woman who presented initially with minor soft tissue injury due to a cycling accident. She was then incidentally found to have severe xanthelasma and hypercholesterolemia (serum TC 15.3 mmol/L and LDL-C 13.9 mmol/L). She was referred to the Specialized Lipid Clinic and was diagnosed with familial hypercholesterolemia (FH) based on the Simon Broome (SB) diagnostic criteria. There was a family history of premature coronary heart disease (CHD) in that three siblings had sudden cardiac death, and of consanguineous marriage in that her parents are cousins. DNA screening of LDLR and APOB genes was done by Polymerase Chain Reaction (PCR), followed by Denaturing High Performance Liquid Chromatography (DHPLC). Homozygous mutation C255S in Exon 5 of her LDLR gene was found. There was no mutation was found in Exon 26 and Exon 29 of the APOB gene. This report is to emphasize the importance of identifying patients with FH and cascade screening through established diagnostic criteria and genetic studies in order to ensure early detection and early treatment intervention to minimize the risk of developing CHD and related complications. PMID:25194536

  11. Topological properties of large-scale structural brain networks in children with familial risk for reading difficulties

    PubMed Central

    Hosseini, S.M. Hadi; Black, Jessica M.; Soriano, Teresa; Bugescu, Nicolle; Martinez, Rociel; Raman, Mira M.; Kesler, Shelli R.; Hoeft, Fumiko

    2013-01-01

    Developmental dyslexia is a neurobiological deficit characterized by persistent difficulty in learning to read in children and adults who otherwise possess normal intelligence. Functional and structural connectivity data suggest that developmental dyslexia could be a disconnection syndrome. However, whether abnormalities in connectivity exist in beginning readers at-risk for reading difficulties is unknown. Using graphtheoretical analysis, we investigated differences in global and regional topological properties of structural brain networks in 42 beginning readers with (FH+) and without (FH?) familial risk for reading difficulties. We constructed separate structural correlation networks based on measures of surface area and cortical thickness. Results revealed changes in topological properties in brain regions known to be abnormal in dyslexia (left supramarginal gyrus, left inferior frontal gyrus) in the FH+ group mainly in the network constructed from measures of cortical surface area. We also found alterations in topological properties in regions that are not often advertised as dyslexia but nonetheless play important role in reading (left posterior cingulate, hippocampus, and left precentral gyrus). To our knowledge, this is the first report of altered topological properties of structural correlation networks in children at risk for reading difficulty, and motivates future studies that examine the mechanisms underlying how these brain networks may mediate the influences of family history on reading outcome. PMID:23333415

  12. Regulatory patterns of a large family of defensin-like genes expressed in nodules of Medicago truncatula.

    PubMed

    Nallu, Sumitha; Silverstein, Kevin A T; Samac, Deborah A; Bucciarelli, Bruna; Vance, Carroll P; VandenBosch, Kathryn A

    2013-01-01

    Root nodules are the symbiotic organ of legumes that house nitrogen-fixing bacteria. Many genes are specifically induced in nodules during the interactions between the host plant and symbiotic rhizobia. Information regarding the regulation of expression for most of these genes is lacking. One of the largest gene families expressed in the nodules of the model legume Medicago truncatula is the nodule cysteine-rich (NCR) group of defensin-like (DEFL) genes. We used a custom Affymetrix microarray to catalog the expression changes of 566 NCRs at different stages of nodule development. Additionally, bacterial mutants were used to understand the importance of the rhizobial partners in induction of NCRs. Expression of early NCRs was detected during the initial infection of rhizobia in nodules and expression continued as nodules became mature. Late NCRs were induced concomitantly with bacteroid development in the nodules. The induction of early and late NCRs was correlated with the number and morphology of rhizobia in the nodule. Conserved 41 to 50 bp motifs identified in the upstream 1,000 bp promoter regions of NCRs were required for promoter activity. These cis-element motifs were found to be unique to the NCR family among all annotated genes in the M. truncatula genome, although they contain sub-regions with clear similarity to known regulatory motifs involved in nodule-specific expression and temporal gene regulation. PMID:23573247

  13. Utility of STR markers for the molecular diagnosis of a large Brazilian family with Charcot-Marie-Tooth disease.

    PubMed

    Possamai, C O; Carvalho, F M; Silva, M F C; Wolfgramm, E V; Sartori, M P N; Malta, F S V; Ribeiro, V P; Spina, V P; Gomes, K B; Ferreira, A C S; Louro, I D

    2008-01-01

    Charcot-Marie-Tooth type 1A disease (CMT1A) is most frequently caused by a tandem DNA duplication of a 1.4-Mb genomic fragment in the 17p11.2-12 chromosomal region. The disease is probably the product of a dosage effect of the peripheral myelin protein 22 gene located within the duplicated segment. We sought to study the largest reported Brazilian family with suspected diagnosis of CMT1A using eight short tandem repeat microsatellite markers. In addition, we analyzed the informativeness of these markers in the normal Brazilian population. The duplication was found in 12 members of the family. In two patients with CMT1A symptoms, the duplication was not detected, and one asymptomatic subject showed the duplication. D17S2230, D17S9B, D17S2220, D17S2227, D17S9A, and D17S4A markers showed the highest heterozygosity rates, and D17S2228 and D17S2224 markers were the least informative in our analysis. PMID:19048496

  14. Isolation of a gene (DLG3) encoding a second member of the discs-large family on chromosome 17q12-q21

    SciTech Connect

    Smith, S.A.; Holik, P.; Stevens, J.

    1996-01-15

    The discs-large family is a collection of proteins that have a common structural organization and are thought to be involved in signal transduction and mediating protein-protein interactions at the cytoplasmic surface of the cell membrane. The defining member of this group of proteins is the gene product of the Drosophila lethal (1) discs large (dlg) 1 locus, which was originally identified by the analysis of recessive lethal mutants. Germline mutations in dlg result in loss of apical-basolateral polarity, disruption of normal cell-cell adhesion, and neoplastic overgrowth of the imaginal disc epithelium. We have isolated and characterized a novel human gene, DLG3, that encodes a new member of the discs-large family of proteins. The putative DLG3 gene product has a molecular weight of 66 kDa and contains a discs-large homologous region, an src oncogene homology motif 3, and a domain with homology to guanylate kinase. The DLG3 gene is located on chromosome 17, in the same segment, 17q12-q21, as the related gene, DLG2. The products of the DLG2 and DLG3 genes show 36% identity and 58% similarity to each other, and both show nearly 60% sequence similarity to p55, an erythroid phosphoprotein that is a component of the red cell membrane. We suggest that p55, DLG2, and DLG3 are closely related members of a gene family, whose protein products have a common structural organization and probably a similar function. 25 refs., 3 figs.

  15. Immunoglobulin Heavy Chain Variable Region and Major Histocompatibility Region Genes Are Linked to Induced Graves' Disease in Females From Two Very Large Families of Recombinant Inbred Mice

    PubMed Central

    Aliesky, Holly; Banuelos, Bianca; Magana, Jessica; Williams, Robert W.; Rapoport, Basil

    2014-01-01

    Graves' hyperthyroidism is caused by antibodies to the TSH receptor (TSHR) that mimic thyroid stimulation by TSH. Stimulating TSHR antibodies and hyperthyroidism can be induced by immunizing mice with adenovirus expressing the human TSHR A-subunit. Prior analysis of induced Graves' disease in small families of recombinant inbred (RI) female mice demonstrated strong genetic control but did not resolve trait loci for TSHR antibodies or elevated serum T4. We investigated the genetic basis for induced Graves' disease in female mice of two large RI families and combined data with earlier findings to provide phenotypes for 178 genotypes. TSHR antibodies measured by inhibition of TSH binding to its receptor were highly significantly linked in the BXD set to the major histocompatibility region (chromosome 17), consistent with observations in 3 other RI families. In the LXS family, we detected linkage between T4 levels after TSHR-adenovirus immunization and the Ig heavy chain variable region (Igvh, chromosome 12). This observation is a key finding because components of the antigen binding region of Igs determine antibody specificity and have been previously linked to induced thyroid-stimulating antibodies. Data from the LXS family provide the first evidence in mice of a direct link between induced hyperthyroidism and Igvh genes. A role for major histocompatibility genes has now been established for genetic susceptibility to Graves' disease in both humans and mice. Future studies using arrays incorporating variation in the complex human Ig gene locus will be necessary to determine whether Igvh genes are also linked to Graves' disease in humans. PMID:25051451

  16. Analysis of two Arab families reveals additional support for a DFNB2 nonsyndromic phenotype of MYO7A.

    PubMed

    Ben-Salem, Salma; Rehm, Heidi L; Willems, Patrick J; Tamimi, Zakaria A; Ayadi, Hammadi; Ali, Bassam R; Al-Gazali, Lihadh

    2014-01-01

    Variants in the head and tail domains of the MYO7A gene, encoding myosin VIIA, cause Usher syndrome type 1B (USH1B) and nonsyndromic deafness (DFNB2, DFNA11). In order to identify the genetic defect(s) underling profound deafness in two consanguineous Arab families living in UAE, we have sequenced a panel of 19 genes involved in Usher syndrome and nonsyndromic deafness in the index cases of the two families. This analysis revealed a novel homozygous insertion of AG (c.1952_1953insAG/p.C652fsX11) in exon 17 of the MYO7A gene in an Iraqi family, and a homozygous point mutation (c.5660C>T/p.P1887L) in exon 41 affecting the same gene in a large Palestinian family. Moreover, some individuals from the Palestinian family also harbored a novel heterozygous truncating variant (c.1267C>T/p.R423X) in the DFNB31 gene, which is involved in autosomal recessive nonsyndromic deafness type DFNB31 and Usher syndrome type II. Assuming an autosomal recessive mode of inheritance in the two inbred families, we conclude that the homozygous variants in the MYO7A gene are the disease-causing mutations in these families. Furthermore, given the absence of retinal disease in all affected patients examined, particularly a 28 year old patient, suggests that at least one family may segregate a DFNB2 presentation rather than USH1B. This finding further supports the premise that the MYO7A gene is responsible for two distinct diseases and gives evidence that the p.P1887L mutation in a homozygous state may be responsible for nonsyndromic hearing loss. PMID:24194196

  17. Families in the Military

    MedlinePLUS

    ... AACAP Facts for Families Guide Skip breadcrumb navigation Military Families Quick Links Facts For Families Guide Facts ... have led to deployment of large numbers of military personnel (active duty, Reserves, National Guard). As a ...

  18. Xq21.31-q21.32 duplication underlies intellectual disability in a large family with five affected males.

    PubMed

    Basit, Sulman; Malibari, Omhani I; Al-Balawi, Alia M; Afzal, Sibtain; Eldardear, Amr Elsayed Mohamed; Ramzan, Khushnooda

    2016-01-01

    X-linked intellectual disability is the most common form of neurological disorder in male and accounts for 5-10% of incidence in the population. Copy number variants (CNVs) have been studied extensively to identify genomic regions responsible for neurological disorders. Array CGH and SNP genotyping have identified several CNVs on X-chromosome in patients with X-linked intellectual disability. We genotyped 2.5 million SNPs in 10 individuals of a 4 generation family segregating X-linked intellectual disability using Illumina Infinium BeadChip assay. Whole genome genotyping data analysis identified a single duplication of 3.95 Mb on X-chromosome in all five affected male individuals. This CNV is inherited from a healthy mother. All five affected individuals manifest moderate to severe intellectual disability, seizures and behavioral abnormalities. X-chromosome inactivation analysis showed that X-chromosome of the mother with duplication is completely inactivated which has also been found in daughters. © 2015 Wiley Periodicals, Inc. PMID:26358363

  19. Inheritance of skewed X chromosome inactivation in a large family with an X-linked recessive deafness syndrome

    SciTech Connect

    Orstavik, K.H.; Orstavik, R.E.; Eiklid, K.; Tranebjaerg, L.

    1996-07-12

    A new X-linked recessive deafness syndrome was recently reported and mapped to Xq22 (Mohr-Tranebjaeerg syndrome). In addition to deafness, the patients had visual impairment, dystonia, fractures, and mental deterioration. The female carriers did not have any significant manifestations of the syndrome. We examined X chromosome inactivation in 8 obligate and 12 possible carriers by using a polymerase chain reaction analysis of the methylation-dependent amplification of the polymorphic triplet repeat at the androgen receptor locus. Seven of 8 obligate carriers and 1 of 5 carriers by linkage analysis had an extremely skewed pattern in blood DNA not found in 30 normal females. The X inactivation pattern in fibroblast DNA from 2 of the carriers with the extremely skewed pattern was also skewed but to a lesser degree than in blood DNA. One obligate carrier had a random X inactivation pattern in both blood and fibroblast DNA. A selection mechanism for the skewed pattern is therefore not likely. The extremely skewed X inactivation in 8 females of 3 generations in this family may be caused by a single gene that influences skewing of X chromosome inactivation. 22 refs., 2 figs., 1 tab.

  20. A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled.

    PubMed

    Wang, Y; Macke, J P; Abella, B S; Andreasson, K; Worley, P; Gilbert, D J; Copeland, N G; Jenkins, N A; Nathans, J

    1996-02-23

    In Drosophila melanogaster, the frizzled gene plays an essential role in the development of tissue polarity as assessed by the orientation of cuticular structures. Through a combination of random cDNA sequencing, degenerate polymerase chain reaction amplification, and low stringency hybridization we have identified six novel frizzled homologues from mammals, at least 11 from zebrafish, several from chicken and sea urchin, and one from Caenorhabditis elegans. The complete deduced amino acid sequences of the mammalian and nematode homologues share with the Drosophila frizzled protein a conserved amino-terminal cysteine-rich domain and seven putative transmembrane segments. Each of the mammalian homologues is expressed in a distinctive set of tissues in the adult, and at least three are expressed during embryogenesis. As hypothesized for the Drosophila frizzled protein, the frizzled homologues are likely to act as transmembrane receptors for as yet unidentified ligands. These observations predict the existence of a family of signal transduction pathways that are homologous to the pathway that determines tissue polarity in Drosophila. PMID:8626800

  1. A clinical evaluation tool for SNP arrays, especially for autosomal recessive conditions in offspring of consanguineous parents

    PubMed Central

    Wierenga, Klaas J.; Jiang, Zhijie; Yang, Amy C.; Mulvihill, John J.; Tsinoremas, Nicholas F.

    2013-01-01

    Purpose: This report describes a fast online tool to accelerate and improve clinical interpretation of single nucleotide polymorphism array results for diagnostic purposes, when consanguinity or inbreeding is identified. Methods: We developed a web-based program that permits entry of regions of homozygosity and, using OMIM, UCSC, and NCBI databases, retrieves genes within these regions as well as their associated autosomal recessive disorders. Relevant OMIM Clinical Synopses can be searched, using key clinical terms permitting further filtering for candidate genes and disorders. Results: The tool aids the clinician by arriving at a short list of relevant candidate disorders, guiding the continued diagnostic work-up. Its efficacy is illustrated by presenting seven patients who were diagnosed using this tool. Conclusion: The online single nucleotide polymorphism array evaluation tool rapidly and systematically identifies relevant genes and associated conditions mapping to identified regions of homozygosity. The built-in OMIM clinical feature search allows the user to further filter to reach a short list of candidate conditions relevant for the diagnosis, making it possible to strategize more focused diagnostic testing. The tabulated results can be downloaded and saved to the desktop in an Excel format. Its efficacy is illustrated by providing a few clinical examples. PMID:23100014

  2. Mutations in Danish patients with long QT syndrome and the identification of a large founder family with p.F29L in KCNH2

    PubMed Central

    2014-01-01

    Background Long QT syndrome (LQTS) is a cardiac ion channelopathy which presents clinically with palpitations, syncope or sudden death. More than 700 LQTS-causing mutations have been identified in 13 genes, all of which encode proteins involved in the execution of the cardiac action potential. The most frequently affected genes, covering?>?90% of cases, are KCNQ1, KCNH2 and SCN5A. Methods We describe 64 different mutations in 70 unrelated Danish families using a routine five-gene screen, comprising KCNQ1, KCNH2 and SCN5A as well as KCNE1 and KCNE2. Results Twenty-two mutations were found in KCNQ1, 28 in KCNH2, 9 in SCN5A, 3 in KCNE1 and 2 in KCNE2. Twenty-six of these have only been described in the Danish population and 18 are novel. One double heterozygote (1.4% of families) was found. A founder mutation, p.F29L in KCNH2, was identified in 5 “unrelated” families. Disease association, in 31.2% of cases, was based on the type of mutation identified (nonsense, insertion/deletion, frameshift or splice-site). Functional data was available for 22.7% of the missense mutations. None of the mutations were found in 364 Danish alleles and only three, all functionally characterised, were recorded in the Exome Variation Server, albeit at a frequency of?large founder family with p.F29L in KCNH2 was identified. In 48.4% of the mutations disease causation was based on mutation type or functional analysis. PMID:24606995

  3. Inherited Mutations in 17 Breast Cancer Susceptibility Genes Among a Large Triple-Negative Breast Cancer Cohort Unselected for Family History of Breast Cancer

    PubMed Central

    Couch, Fergus J.; Hart, Steven N.; Sharma, Priyanka; Toland, Amanda Ewart; Wang, Xianshu; Miron, Penelope; Olson, Janet E.; Godwin, Andrew K.; Pankratz, V. Shane; Olswold, Curtis; Slettedahl, Seth; Hallberg, Emily; Guidugli, Lucia; Davila, Jaime I.; Beckmann, Matthias W.; Janni, Wolfgang; Rack, Brigitte; Ekici, Arif B.; Slamon, Dennis J.; Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Fountzilas, George; Pelttari, Liisa M.; Tapper, William J.; Durcan, Lorraine; Cross, Simon S.; Pilarski, Robert; Shapiro, Charles L.; Klemp, Jennifer; Yao, Song; Garber, Judy; Cox, Angela; Brauch, Hiltrud; Ambrosone, Christine; Nevanlinna, Heli; Yannoukakos, Drakoulis; Slager, Susan L.; Vachon, Celine M.; Eccles, Diana M.; Fasching, Peter A.

    2015-01-01

    Purpose Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC. Patients and Methods Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations. Results Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P < .001) and had higher-grade tumors (P = .01) than those without mutations. Conclusion Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives. PMID:25452441

  4. The large-conductance calcium-activated potassium channel holds the key to the conundrum of familial hypokalemic periodic paralysis

    PubMed Central

    Kim, Sung-Jo; Kang, Sun-Yang; Yi, Jin Woong; Kim, Seung-Min

    2014-01-01

    Purpose Familial hypokalemic periodic paralysis (HOKPP) is an autosomal dominant channelopathy characterized by episodic attacks of muscle weakness and hypokalemia. Mutations in the calcium channel gene, CACNA1S, or the sodium channel gene, SCN4A, have been found to be responsible for HOKPP; however, the mechanism that causes hypokalemia remains to be determined. The aim of this study was to improve the understanding of this mechanism by investigating the expression of calcium-activated potassium (KCa) channel genes in HOKPP patients. Methods We measured the intracellular calcium concentration with fura-2-acetoxymethyl ester in skeletal muscle cells of HOKPP patients and healthy individuals. We examined the mRNA and protein expression of KCa channel genes (KCNMA1, KCNN1, KCNN2, KCNN3, and KCNN4) in both cell types. Results Patient cells exhibited higher cytosolic calcium levels than normal cells. Quantitative reverse transcription polymerase chain reaction analysis showed that the mRNA levels of the KCa channel genes did not significantly differ between patient and normal cells. However, western blot analysis showed that protein levels of the KCNMA1 gene, which encodes KCa1.1 channels (also called big potassium channels), were significantly lower in the membrane fraction and higher in the cytosolic fraction of patient cells than normal cells. When patient cells were exposed to 50 mM potassium buffer, which was used to induce depolarization, the altered subcellular distribution of BK channels remained unchanged. Conclusion These findings suggest a novel mechanism for the development of hypokalemia and paralysis in HOKPP and demonstrate a connection between disease-associated mutations in calcium/sodium channels and pathogenic changes in nonmutant potassium channels. PMID:25379045

  5. A rare variant of the leptin gene has large effects on blood pressure and carotid intima-medial thickness: a study of 1428 individuals in 248 families

    PubMed Central

    Gaukrodger, N; Mayosi, B; Imrie, H; Avery, P; Baker, M; Connell, J; Watkins, H; Farrall, M; Keavney, B

    2005-01-01

    Background: Rare mutations in the leptin (LEP) gene cause severe obesity. Common polymorphisms of LEP have been associated with obesity, but their association with cardiovascular disease has been little studied. We have examined the impact of both common and rare polymorphisms of the LEP gene on blood pressure (BP), subclinical atherosclerosis as measured by carotid intima-medial thickness (CIMT), and body mass index (BMI) in a large family study. Methods: Five polymorphisms spanning LEP were typed in 1428 individuals from 248 nuclear families. BP, CIMT, BMI, and plasma leptin were measured. Results: The polymorphisms typed captured all common haplotypes present at LEP. There was strong association between a rare polymorphism in the 3' untranslated region of LEP (C538T) and both pulse pressure (p = 0.0001) and CIMT (p = 0.008). C/T heterozygotes had a 22% lower pulse pressure and a 17% lower CIMT than C/C homozygotes. The polymorphism accounted for 3–5% of the population variation in pulse pressure and CIMT. There was no association between any LEP polymorphism and either BMI or plasma leptin level. Conclusions: This large family study shows that the rare T allele at the C538T polymorphism of LEP substantially influences pulse pressure and CIMT, but does not appear to exert this effect through actions on plasma leptin level or BMI. This suggests that autocrine or paracrine effects in vascular tissue may be important physiological functions of leptin. This study also provides evidence that rare polymorphisms of particular genes may have substantial effects within the normal range of certain quantitative traits. PMID:15937081

  6. Direct repeats located within a large family of human endogenous retroviral LTRs have transcriptional suppressor activity in human cells

    SciTech Connect

    Nelson, D.T.; Mager, D.L.

    1994-09-01

    The human genome harbors thousands of sequences that resemble retroviral long terminal repeats (LTRs). These LTR-like elements are associated with full length endogenous retroviral sequences and can also be found as solitary units. Since the U3 regions of retroviral LTRs contain transcriptional regulatory sequences, we have been interested in determining how the presence of endogenous LTRs may affect adjacent gene expression. One endogenous retroviral family, termed HERV-H, has {approximately}1000 copies per haploid genome in addition to {approximately}1000 solitary LTRs. HERV-H LTRs can be grouped into 3 subtypes that vary greatly in their promoter and enhancer activity. The primary feature that distinguishes the 3 LTR subtypes is the sequence of direct repeats located in U3. The most numerous LTR subtype, type 1, has 2 copies of a 47 bp repeat while the next most abundant type, type 2, usually has 5 copies of a different 31 bp repeat. The transcriptional activity of both type 1 and 2 LTRs is limited compared to the activity of a less abundant third subtype, type 1a, which is a much stronger promoter. Type 1a LTRs appear to be a recombinant between types 1 and 2, having only a single type 1 and a single type 2 repeat. In this study, we have analyzed type 1 and 2 repeats for enhancer or suppressor function. Using transient expression of a reporter gene, we have found that a set of type 2 repeats suppresses activity of a type 1a LTR promoter and the human {beta}-globulin promoter. Two sets of the type 1 repeat also have a suppressor effect. Thus, it is possible that type 1 and 2 LTRs in the genome could suppress the expression of nearby genes. Interestingly, HERV-H elements with type 1a LTRs appeared most recently in evolution, being restricted to the great apes and humans. These results suggest that disruption of the repeat structure in type 1a LTRs may be at least partially responsible for their strong promoter activity and their resultant genomic expansion.

  7. Association of SLC6A4 variants with obsessive-compulsive disorder in a large multicenter US family study.

    PubMed

    Voyiaziakis, E; Evgrafov, O; Li, D; Yoon, H-J; Tabares, P; Samuels, J; Wang, Y; Riddle, M A; Grados, M A; Bienvenu, O J; Shugart, Y Y; Liang, K-Y; Greenberg, B D; Rasmussen, S A; Murphy, D L; Wendland, J R; McCracken, J T; Piacentini, J; Rauch, S L; Pauls, D L; Nestadt, G; Fyer, A J; Knowles, J A

    2011-01-01

    Genetic association studies of SLC6A4 (SERT) and obsessive-compulsive disorder (OCD) have been equivocal. We genotyped 1241 individuals in 278 pedigrees from the OCD Collaborative Genetics Study for 13 single-nucleotide polymorphisms, for the linked polymorphic region (LPR) indel with molecular haplotypes at rs25531, for VNTR polymorphisms in introns 2 and 7 and for a 381-bp deletion 3' to the LPR. We analyzed using the Family-Based Association Test (FBAT) under additive, dominant, recessive and genotypic models, using both OCD and sex-stratified OCD as phenotypes. Two-point FBAT analysis detected association between Int2 (P = 0.0089) and Int7 (P = 0.0187) (genotypic model). Sex-stratified two-point analysis showed strong association in females with Int2 (P<0.0002), significant after correction for linkage disequilibrium, and multiple marker and model testing (P(Adj) = 0.0069). The SLC6A4 gene is composed of two haplotype blocks (our data and the HapMap); FBAT whole-marker analysis conducted using this structure was not significant. Several noteworthy nonsignificant results have emerged. Unlike Hu et al., we found no evidence for overtransmission of the LPR L(A) allele (genotype relative risk = 1.11, 95% confidence interval: 0.77-1.60); however, rare individual haplotypes containing L(A) with P<0.05 were observed. Similarly, three individuals (two with OCD/OCPD) carried the rare I425V SLC6A4 variant, but none of them passed it on to their six OCD-affected offspring, suggesting that it is unlikely to be solely responsible for the 'OCD plus syndrome', as reported by Ozaki et al. In conclusion, we found evidence of genetic association at the SLC6A4 locus with OCD. A noteworthy lack of association at the LPR, LPR-rs25531 and rare 425V variants suggests that hypotheses about OCD risk need revision to accommodate these new findings, including a possible gender effect. PMID:19806148

  8. 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. PMID:26109232

  9. HERV-K113 is not associated with multiple sclerosis in a large family-based study.

    PubMed

    Moyes, David L; Goris, An; Ban, Maria; Compston, Alistair; Griffiths, David J; Sawcer, Stephen; Venables, Patrick J

    2008-03-01

    Numerous studies have invoked a role for retroviruses in multiple sclerosis (MS). Most have identified human endogenous retroviruses (HERVs) as possible etiological agents. The majority of HERVs originate from ancestral infection and then become progressively disabled by mutations over millions of years of primate evolution. Their presence in 100% of healthy humans, together with the paucity of functional retroviral genes, argues strongly against a causal role in disease. Recently, a new class of insertionally polymorphic HERVs has been described that is present in only a proportion of the population. One of them, HERV-K113, is notable for open reading frames for all of its genes and is found in 0-28% of humans with widespread geographic and racial variation. Thus HERV-K113 is a credible candidate for causing disease in a manner comparable to infectious retroviruses. Genomic DNA samples from 951 patients with MS were tested for the presence of the HERV-K113 allele by PCR, with their unaffected parents (n = 1902) acting as controls. HERV-K113 provirus was found in 70 out of 951 (7.36%) patients with MS and was not significantly increased compared to the combined parent group (6.52%). The results do not support an association between this endogenous retrovirus and MS. This study also emphasizes the need for large cohorts with controls for race and geographic location when examining possible links between polymorphic HERVs and disease. PMID:18327982

  10. Identification of Rare Recurrent Copy Number Variants in High-Risk Autism Families and Their Prevalence in a Large ASD Population

    PubMed Central

    Christensen, G. Bryce; Kim, Cecilia; Frackelton, Edward; Thomas, Kelly; da Silva, Renata Pellegrino; Stevens, Jeff; Baird, Lisa; Otterud, Brith; Ho, Karen; Varvil, Tena; Leppert, Tami; Lambert, Christophe G.; Leppert, Mark; Hakonarson, Hakon

    2013-01-01

    Structural variation is thought to play a major etiological role in the development of autism spectrum disorders (ASDs), and numerous studies documenting the relevance of copy number variants (CNVs) in ASD have been published since 2006. To determine if large ASD families harbor high-impact CNVs that may have broader impact in the general ASD population, we used the Affymetrix genome-wide human SNP array 6.0 to identify 153 putative autism-specific CNVs present in 55 individuals with ASD from 9 multiplex ASD pedigrees. To evaluate the actual prevalence of these CNVs as well as 185 CNVs reportedly associated with ASD from published studies many of which are insufficiently powered, we designed a custom Illumina array and used it to interrogate these CNVs in 3,000 ASD cases and 6,000 controls. Additional single nucleotide variants (SNVs) on the array identified 25 CNVs that we did not detect in our family studies at the standard SNP array resolution. After molecular validation, our results demonstrated that 15 CNVs identified in high-risk ASD families also were found in two or more ASD cases with odds ratios greater than 2.0, strengthening their support as ASD risk variants. In addition, of the 25 CNVs identified using SNV probes on our custom array, 9 also had odds ratios greater than 2.0, suggesting that these CNVs also are ASD risk variants. Eighteen of the validated CNVs have not been reported previously in individuals with ASD and three have only been observed once. Finally, we confirmed the association of 31 of 185 published ASD-associated CNVs in our dataset with odds ratios greater than 2.0, suggesting they may be of clinical relevance in the evaluation of children with ASDs. Taken together, these data provide strong support for the existence and application of high-impact CNVs in the clinical genetic evaluation of children with ASD. PMID:23341896

  11. Comparison of autoantibody specificities between traditional and bead-based assays in a large, diverse collection of SLE patients and family members

    PubMed Central

    Bruner, Benjamin F.; Guthridge, Joel M.; Lu, Rufei; Vidal, Gabriel; Kelly, Jennifer A.; Robertson, Julie M.; Kamen, Diane L.; Gilkeson, Gary S.; Neas, Barbara R.; Reichlin, Morris; Scofield, R. Hal; Harley, John B.; James, Judith A.

    2012-01-01

    Objective The replacement of standard immunofluorescence anti-nuclear antibody (ANA) methods with bead-based assays is a new clinical option. A large, multi-racial cohort of SLE patients, blood relatives and unaffected control individuals was evaluated for familial aggregation and subset clustering of autoantibodies by high-throughput serum screening technology and traditional methods. Methods Serum samples (1,540 SLE patients, 1,127 unaffected relatives, and 906 healthy, population-based controls) were analyzed for SLE autoantibodies using a bead-based assay, immunofluorescence, and immunodiffusion. Autoantibody prevalence, disease sensitivity, clustering, and association with standard immunodiffusion results were evaluated. Results ANA frequency in SLE patient sera were 89%, 73%, and 67% by BioPlex 2200 and 94%, 84%, and 86% by immunofluorescence in African-American, Hispanic, and European-American patients respectively. 60kD Ro, La, Sm, nRNP A, and ribosomal P prevalence were compared across assays, with sensitivities ranging from 0.92 to 0.83 and specificities ranging from 0.90 to 0.79. Cluster autoantibody analysis showed association of three subsets: 1) 60kD Ro, 52kD Ro and La, 2) spliceosomal proteins, and 3) dsDNA, chromatin, and ribosomal P. Familial aggregation of Sm/RNP, ribosomal P, and 60kD Ro in SLE patient sibling pairs was observed (p ? 0.004). Simplex pedigree patients had a greater prevalence for dsDNA (p=0.0003) and chromatin (p=0.005) autoantibodies than multiplex patients. Conclusion ANA frequencies detected by a bead-based assay are lower in European-American SLE patients compared to immunofluorescence. These assays have strong positive predictive values across racial groups, provide useful information for clinical care, and provide unique insights to familial aggregation and autoantibody clustering. PMID:23112091

  12. A Large Family of AvrLm6-like Genes in the Apple and Pear Scab Pathogens, Venturia inaequalis and Venturia pirina

    PubMed Central

    Shiller, Jason; Van de Wouw, Angela P.; Taranto, Adam P.; Bowen, Joanna K.; Dubois, David; Robinson, Andrew; Deng, Cecilia H.; Plummer, Kim M.

    2015-01-01

    Venturia inaequalis and V. pirina are Dothideomycete fungi that cause apple scab and pear scab disease, respectively. Whole genome sequencing of V. inaequalis and V. pirina isolates has revealed predicted proteins with sequence similarity to AvrLm6, a Leptosphaeria maculans effector that triggers a resistance response in Brassica napus and B. juncea carrying the resistance gene, Rlm6. AvrLm6-like genes are present as large families (>15 members) in all sequenced strains of V. inaequalis and V. pirina, while in L. maculans, only AvrLm6 and a single paralog have been identified. The Venturia AvrLm6-like genes are located in gene-poor regions of the genomes, and mostly in close proximity to transposable elements, which may explain the expansion of these gene families. An AvrLm6-like gene from V. inaequalis with the highest sequence identity to AvrLm6 was unable to trigger a resistance response in Rlm6-carrying B. juncea. RNA-seq and qRT-PCR gene expression analyses, of in planta- and in vitro-grown V. inaequalis, has revealed that many of the AvrLm6-like genes are expressed during infection. An AvrLm6 homolog from V. inaequalis that is up-regulated during infection was shown (using an eYFP-fusion protein construct) to be localized to the sub-cuticular stroma during biotrophic infection of apple hypocotyls. PMID:26635823

  13. Members of the glutathione and ABC-transporter families are associated with clinical outcome in patients with diffuse large B-cell lymphoma.

    PubMed

    Andreadis, Charalambos; Gimotty, Phyllis A; Wahl, Peter; Hammond, Rachel; Houldsworth, Jane; Schuster, Stephen J; Rebbeck, Timothy R

    2007-04-15

    Standard chemotherapy fails in 40% to 50% of patients with diffuse large B-cell lymphoma (DLBCL). Some of these failures can be salvaged with high-dose regimens, suggesting a role for drug resistance in this disease. We examined the expression of genes in the glutathione (GSH) and ATP-dependent transporter (ABC) families in 2 independent tissue-based expression microarray datasets obtained prior to therapy from patients with DLBCL. Among genes in the GSH family, glutathione peroxidase 1 (GPX1) had the most significant adverse effect on disease-specific overall survival (dOS) in the primary dataset (n = 130) (HR: 1.68; 95% CI: 1.26-2.22; P < .001). This effect remained statistically significant after controlling for biologic signature, LLMPP cell-of-origin signature, and IPI score, and was confirmed in the validation dataset (n = 39) (HR: 1.7; 95% CI: 1.05-2.8; P = .033). Recursive partitioning identified a group of patients with low-level expression of GPX1 and multidrug resistance 1 (MDR1; ABCB1) without early treatment failures and with superior dOS (P < .001). Overall, our findings suggest an important association of oxidative-stress defense and drug elimination with treatment failure in DLBCL and identify GPX1 and ABCB1 as potentially powerful biomarkers of early failure and disease-specific survival. PMID:17179223

  14. A novel single-base deletion in ROR2 causes atypical brachydactyly type B1 with cutaneous syndactyly in a large Chinese family.

    PubMed

    Lv, Dan; Luo, Yang; Yang, Wei; Cao, Lihua; Wen, Yaran; Zhao, Xiuli; Sun, Miao; Lo, Wilson H-Y; Zhang, Xue

    2009-07-01

    Mutations in ROR2, encoding the receptor tyrosine kinase-like orphan receptor 2, cause two distinct skeletal diseases: autosomal dominant brachydactyly type B1 (BDB1) and autosomal recessive Robinow syndrome. In a large Chinese family with a limb phenotype, consisting of atypical BDB1 and cutaneous syndactyly of varying degrees, we performed a two-point linkage analysis using microsatellite markers on 2q33-q37 and 9q22.31, and found a significant linkage to the ROR2 locus. We identified a novel single-base deletion in ROR2, c.2243delC (p.W749fsX24), and confirmed its segregation with the limb phenotype in the family. This deletion is predicted to produce a truncated ROR2 protein with an additional C-terminal polypeptide of 24 amino-acid residues. To the best of our knowledge, the deletion represents the second ROR2 mutation associated with a BDB1-syndactyly phenotype. PMID:19461659

  15. The vertebrate makorin ubiquitin ligase gene family has been shaped by large-scale duplication and retroposition from an ancestral gonad-specific, maternal-effect gene

    PubMed Central

    2010-01-01

    Background Members of the makorin (mkrn) gene family encode RING/C3H zinc finger proteins with U3 ubiquitin ligase activity. Although these proteins have been described in a variety of eukaryotes such as plants, fungi, invertebrates and vertebrates including human, almost nothing is known about their structural and functional evolution. Results Via partial sequencing of a testis cDNA library from the poeciliid fish Xiphophorus maculatus, we have identified a new member of the makorin gene family, that we called mkrn4. In addition to the already described mkrn1 and mkrn2, mkrn4 is the third example of a makorin gene present in both tetrapods and ray-finned fish. However, this gene was not detected in mouse and rat, suggesting its loss in the lineage leading to rodent murids. Mkrn2 and mkrn4 are located in large ancient duplicated regions in tetrapod and fish genomes, suggesting the possible involvement of ancestral vertebrate-specific genome duplication in the formation of these genes. Intriguingly, many mkrn1 and mkrn2 intronless retrocopies have been detected in mammals but not in other vertebrates, most of them corresponding to pseudogenes. The nature and number of zinc fingers were found to be conserved in Mkrn1 and Mkrn2 but much more variable in Mkrn4, with lineage-specific differences. RT-qPCR analysis demonstrated a highly gonad-biased expression pattern for makorin genes in medaka and zebrafish (ray-finned fishes) and amphibians, but a strong relaxation of this specificity in birds and mammals. All three mkrn genes were maternally expressed before zygotic genome activation in both medaka and zebrafish early embryos. Conclusion Our analysis demonstrates that the makorin gene family has evolved through large-scale duplication and subsequent lineage-specific retroposition-mediated duplications in vertebrates. From the three major vertebrate mkrn genes, mkrn4 shows the highest evolutionary dynamics, with lineage-specific loss of zinc fingers and even complete gene elimination from certain groups of vertebrates. Comparative expression analysis strongly suggests that the ancestral E3 ubiquitin ligase function of the single copy mkrn gene before duplication in vertebrates was gonad-specific, with maternal expression in early embryos. PMID:21172006

  16. Large linkage analysis in 100 families with autosomal recessive spinal muscular atrophy (SMA) and 11 EPH families using 15 polymorphic loci in the region 5q11. 2-q13. 3

    SciTech Connect

    Wirth, B.; Pick, E.; Leutner, A.; Dadze, A.; Voosen, B.; Piechaczek-Wappenschmidt, B.; Rudnik-Schoeneborn, S.; Schoenling, J.; Zerres, K. ); Knapp, M. )

    1994-03-01

    The autosomal recessive proximal spinal muscular atrophy (SMA) gene was mapped to the region 5q11.2-q.13.3 in 1990. Here, the authors present a large genetic linkage study of 100 SMA families and 11 CEPH families using 14 polymorphic simple sequence repeats (SSRs) and one RFLP in the region 5q11.2-q.13.3. The genetic interval between the closest SMA flanking loci D5S435 and D5S557 comprises 1 cM at z[sub max] = 27.94. Two recombinants were identified between the SMA gene and the closest telomeric marker D5S557. The first places the SMA gene centromeric to this marker; the second suggests a double recombinant at D5S557, which is very unlikely. More likely explanations are discussed in the paper. No recombinant was found between D5S435 and the SMA gene. They localized a recently described polymorphic marker, D5S351, close to the SMA. Due to its high PIC value of 0.70, it represents a very useful marker for prenatal diagnosis. In addition, they developed a new reverse primer for the nearest centromeric locus D5S435, a useful marker for prenatal diagnosis, which has been very difficult to amplify in the past. Three of the markers presented here are newly developed polymorphic SSRs (one tetranucleotide repeat, D5s507/W15CATT, and two dinucleotide repeats, D5S544/C88.2GT and D5S682/C88.3GT). These markers are too far from the SMA gene to be relevant for cloning; nevertheless, as part of the human genome project, they are contributing to the fine genetic mapping of the region 5q11.2-q.13.3. The most likely order of the loci based on two-point and multipoint linkage analyses as well as on specific recombination events and physical mapping studies is D5S76-D5S507-D5S6-D5S125-D5S680-D5S435-SMA-D5S557-D5S35 -15[prime]MAP1B-3[prime]MAP1B-JK53CA1/2-(D5S127-D5S39)-(D5S544-D5S682). In general, the genetic distances obtained from the SMA and CEPH families are comparable. 25 refs., 4 figs., 5 tabs.

  17. A Homozygous CARD9 Mutation in a Family with Susceptibility to Fungal Infections

    PubMed Central

    Glocker, Erik-Oliver; Hennigs, Andre; Nabavi, Mohammad; Schäffer, Alejandro A.; Woellner, Cristina; Salzer, Ulrich; Pfeifer, Dietmar; Veelken, Hendrik; Warnatz, Klaus; Tahami, Fariba; Jamal, Sarah; Manguiat, Annabelle; Rezaei, Nima; Amirzargar, Ali Akbar; Plebani, Alessandro; Hannesschläger, Nicole; Gross, Olaf; Ruland, Jürgen; Grimbacher, Bodo

    2009-01-01

    BACKGROUND Chronic mucocutaneous candidiasis may be manifested as a primary immunodeficiency characterized by persistent or recurrent infections of the mucosa or the skin with candida species. Most cases are sporadic, but both autosomal dominant inheritance and autosomal recessive inheritance have been described. METHODS We performed genetic studies in 36 members of a large, consanguineous five-generation family, in which 4 members had recurrent fungal infections and an additional 3 members died during adolescence, 2 after invasive infection of the brain with candida species. All 36 family members were enrolled in the study, and 22 had blood samples taken for DNA analysis. Homozygosity mapping was used to locate the mutated gene. In the 4 affected family members (patients) and the 18 unaffected members we sequenced CARD9, the gene encoding the caspase recruitment domain-containing protein 9, carried out T-cell phenotyping, and performed functional studies, with the use of either leukocytes from the patients or a reconstituted murine model of the genetic defect. RESULTS We found linkage (lod score, 3.6) to a genomic interval on chromosome 9q, including CARD9. All four patients had a homozygous point mutation in CARD9, resulting in a premature termination codon (Q295X). Healthy family members had wild-type expression of the CARD9 protein; the four patients lacked wild-type expression, which was associated with low numbers of Th17 cells (helper T cells producing interleukin-17). Functional studies based on genetic reconstitution of myeloid cells from Card9?/? mice showed that the Q295X mutation impairs innate signaling from the antifungal pattern-recognition receptor dectin-1. CONCLUSIONS An autosomal recessive form of susceptibility to chronic mucocutaneous candidiasis is associated with homozygous mutations in CARD9. PMID:19864672

  18. Low prevalence of Connexin 26 (GJB2) variants in Pakistani families with autosomal recessive non-syndromic hearing impairment

    PubMed Central

    Santos, RLP; Wajid, M; Pham, TL; Hussan, J; Ali, G; Ahmad, W; Leal, SM

    2010-01-01

    The Pakistani population has become an important resource for research on autosomal recessive non-syndromic hearing impairment (ARNSHI) due to the availability of large extended and highly consanguineous pedigrees. Here is presented the first report on the prevalence of gap junction beta-2 (GJB2) variants in Pakistan. One hundred and ninety-six unrelated Pakistani families with ARNSHI were recruited for a study on the genetics of NSHI. DNA sequencing of the GJB2 coding region was done on two affected individuals per family. Evolutionary conservation and predicted effect on the protein product were studied in order to hypothesize whether or not a variant was potentially deleterious. Homozygous putatively functional GJB2 variants were identified in 6.1% of families. None of the putatively functional GJB2 variants were observed in the compound heterozygous state. The six putatively causative variants noted were 231G > A(W77X), 71G > A(W24X), 167delT, 95G > A(R32H), 358–360delGAG(delE120), and 269T > C(L90P), with 231G > A(W77X) and 71G > A(W24X) being the most common. In addition, five benign polymorphisms, 380G > A(R127H), 457G > A(V153I), 493C > T(R165W), 79G > A(V27I), and 341A > G(E114G), were identified within this population. In a few individuals, benign polymorphisms were observed to occur on the same haplotype, namely [457G > A(V153I); 493C > T(R165W)] and [79G > A(V27I); 341A > G(E114G)]. The spectrum of GJB2 sequence variants in Pakistan may reflect shared origins of hearing impairment alleles within the Indian subcontinent. The high degree of consanguinity within Pakistan may have maintained the GJB2 prevalence at a much lower rate than within India and other populations. PMID:15617550

  19. Identification of mutation c.632G>A (p.G211D) in the ATP2A2 gene and genotype-phenotype correlation in a large Chinese family with Darier's disease.

    PubMed

    Lu, Feng-Yan; Xu, Ling; Yin, Xun-Guo; Wan, Ping; Zhang, Xiao-De; Chen, Wei-Wen; Ding, Shao-Ping; Yao, Yong-Gang

    2011-11-01

    Darier's disease (DD, MIM 124200) is an autosomal dominant inherited skin disease. Mutations in the ATP2A2 gene, which encoded the sarcoplasmic/endoplasmic reticulum Ca(2+) -ATPase isoform 2 (SERCA2), are responsible for this skin disorder. Here we report the clinical, genetic, and molecular characterization of a large Chinese family with DD. We identified mutation c.632G>A (p.G211D) in the ATP2A2 gene in this family. Genotype-phenotype correlation in available family members provided helpful genetic counseling information for mutation carriers. PMID:22004489

  20. Comparative Analysis of P450 Signature Motifs EXXR and CXG in the Large and Diverse Kingdom of Fungi: Identification of Evolutionarily Conserved Amino Acid Patterns Characteristic of P450 Family

    PubMed Central

    Syed, Khajamohiddin; Mashele, Samson Sitheni

    2014-01-01

    Cytochrome P450 monooxygenases (P450s) are heme-thiolate proteins distributed across the biological kingdoms. P450s are catalytically versatile and play key roles in organisms primary and secondary metabolism. Identification of P450s across the biological kingdoms depends largely on the identification of two P450 signature motifs, EXXR and CXG, in the protein sequence. Once a putative protein has been identified as P450, it will be assigned to a family and subfamily based on the criteria that P450s within a family share more than 40% homology and members of subfamilies share more than 55% homology. However, to date, no evidence has been presented that can distinguish members of a P450 family. Here, for the first time we report the identification of EXXR- and CXG-motifs-based amino acid patterns that are characteristic of the P450 family. Analysis of P450 signature motifs in the under-explored fungal P450s from four different phyla, ascomycota, basidiomycota, zygomycota and chytridiomycota, indicated that the EXXR motif is highly variable and the CXG motif is somewhat variable. The amino acids threonine and leucine are preferred as second and third amino acids in the EXXR motif and proline and glycine are preferred as second and third amino acids in the CXG motif in fungal P450s. Analysis of 67 P450 families from biological kingdoms such as plants, animals, bacteria and fungi showed conservation of a set of amino acid patterns characteristic of a particular P450 family in EXXR and CXG motifs. This suggests that during the divergence of P450 families from a common ancestor these amino acids patterns evolve and are retained in each P450 family as a signature of that family. The role of amino acid patterns characteristic of a P450 family in the structural and/or functional aspects of members of the P450 family is a topic for future research. PMID:24743800

  1. The fucoxanthin-chlorophyll proteins from a chromophyte alga are part of a large multigene family: structural and evolutionary relationships to other light harvesting antennae.

    PubMed

    Durnford, D G; Aebersold, R; Green, B R

    1996-12-13

    A fucoxanthin-chlorophyll protein (FCP) cDNA from the raphidophyte Heterosigma carterae encodes a 210-amino acid polypeptide that has similarity to other FCPs and to the chlorophyll a/b-binding proteins (CABs) of terrestrial plants and green algae. The putative transit sequence has characteristics that resemble a signal sequence. The Heterosigma fcp genes are part of a large multigene family which includes members encoding at least two significantly different polypeptides (Fcp1, Fcp2). Comparison of the FCP sequences to the recently determined three-dimensional structure of the pea LHC II complex indicates that many of the key amino acids thought to participate in the binding of chlorophyll and the formation of complex-stabilizing ionic interactions are well conserved. Phylogenetic analyses of sequences of light-harvesting proteins shows that the FCPs of several chromophyte phyla form a natural group separate from the intrinisic peridinin-chlorophyll proteins (iPCPs) of the dinoflagellates: Although the FCP and CAB genes shared a common ancestor, these lineages diverged from each other prior to the separation of the CAB LHC I and LHC II sequences in the green algae and terrestrial plants. PMID:9003325

  2. Inherited multicentric osteolysis with arthritis: a variant resembling Torg syndrome in a Saudi family.

    PubMed

    Al Aqeel, A; Al Sewairi, W; Edress, B; Gorlin, R J; Desnick, R J; Martignetti, J A

    2000-07-01

    The autosomal recessive multicentric osteolytic disorders of childhood-Torg, Winchester, and François syndromes-predominantly affect the carpal, tarsal, and interphalangeal joints, and their progressive bone loss and crippling arthritic deformities mimic severe juvenile rheumatoid arthritis. In a consanguineous Saudi Arabian family two affected sibs with facial anomalies and short stature displayed a distal arthropathy of the metacarpal, metatarsal, and interphalangeal joints starting in the first few months of life that eventually progressed to the proximal joints and resulted in crippling ankylosis and severe generalized osteopenia. Facial changes included proptosis, a narrow nasal bridge, bulbous nose, and micrognathia. In addition, they had large, painful fibrocollagenous palmar and plantar pads and mild body hirsutism. Affected individuals were of normal intelligence and had normal renal function. Routine hematologic, chemistry, and rheumatoid studies were within normal limits. Histologic examination of bone marrow and an interphalangeal joint biopsy were not informative. The autosomal recessive inheritance, clinical, and radiologic characteristics of the affected sibs suggested that they had a form of multicentric osteolysis most closely resembling the Torg syndrome, but with a unique facial appearance, fibrocollagenous pads, and body hirsutism not noted in the original description of the syndrome. PMID:10861676

  3. Human KZNF Gene Catalog - A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors

    DOE Data Explorer

    Huntley, S; Baggott, D. M.; Hamilton, A. T.; Tran-Gyamfi, M.; Yang, S.; Kim, J.; Gordon, L.; Branscomb, E.; Stubbs, L.

    Kruppel-type zinc finger (ZNF) motifs are prevalent components of transcription factor proteins in all eukaryotes. KRAB-ZNF proteins, in which a potent repressor domain is attached to a tandem array of DNA-binding zinc-finger motifs, are specific to tetrapod vertebrates and represent the largest class of ZNF proteins in mammals. To define the full repertoire of human KRAB-ZNF proteins, we searched the genome sequence for key motifs and then constructed and manually curated gene models incorporating those sequences. The resulting gene catalog contains 423 KRAB-ZNF protein-coding loci, yielding alternative transcripts that altogether predict at least 742 structurally distinct proteins. Active rounds of segmental duplication, involving single genes or larger regions and including both tandem and distributed duplication events, have driven the expansion of this mammalian gene family. Comparisons between the human genes and ZNF loci mined from the draft mouse, dog, and chimpanzee genomes not only identified 103 KRAB-ZNF genes that are conserved in mammals but also highlighted a substantial level of lineage-specific change; at least 136 KRAB-ZNF coding genes are primate specific, including many recent duplicates. KRAB-ZNF genes are widely expressed and clustered genes are typically not coregulated, indicating that paralogs have evolved to fill roles in many different biological processes. To facilitate further study, we have developed a Web-based public resource with access to gene models, sequences, and other data, including visualization tools to provide genomic context and interaction with other public data sets. [This abstract was copied from: S Huntley, DM Baggott, AT Hamilton, M Tran-Gyamfi, S Yang, J Kim, L Gordon, E Branscomb, and L Stubbs. 2006. A comprehensive catalog of human KRAB-associated zinc finger genes: insights into the evolutionary history of a large family of transcriptional repressors, Genome Research 16(5):669 - 677] The website provides the ability to search the online catalog by genomic coordinates, name, locus type, and motifs, to utilize a graphical browser and to download data files.

  4. A Novel Mutation of LAMB2 in a Multi-Generational Mennonite Family Reveals a New Phenotypic Variant of Pierson Syndrome

    PubMed Central

    Mohney, Brian G.; Pulido, Jose S.; Lindor, Noralane M.; Hogan, Marie C.; Consugar, Mark B.; Peters, Justin; Pankratz, V. Shane; Nasr, Samih H.; Smith, Stephen J.; Gloor, James; Kubly, Vickie; Spencer, Dorothy; Nielson, Rebecca; Puffenberger, Erik G.; Strauss, Kevin A.; Morton, D. Holmes; Eldahdah, Lama; Harris, Peter C.

    2011-01-01

    Purpose To describe a novel laminin beta-2 (LAMB2) mutation associated with nephritic syndrome and severe retinal disease without microcoria in a large, multi-generational family with Pierson syndrome. Design Retrospective chart review and prospective family examination. Participants An extended consanguineous family of 52 members. Methods The eyes, urine, and serum DNA were evaluated in all family members after discovering 2 patients, both less than 10 years of age, with bilateral retinal detachments and concurrent renal dysfunction. Linkage analysis was performed in the 9 living affected individuals, 7 using the Illumina Human Hap370 Duo Bead Array and 2 using GeneChip 10K mapping arrays. Main Outcome Measures The prevalence and severity of ocular and kidney involvement and genetic findings. Results Eleven affected family members were identified (9 living), all manifesting chronic kidney disease and bilateral chrioretinal pigmentary changes, with or without retinal detachments, but without microcoria or neurodevelopmental deficits, segregating in an autosomal recessive pattern. The causative gene was localized to a 9Mb region on chromosome 3. Comprehensive gene sequencing revealed a novel LAMB2 variant (c. 440A>G; His147R) that was homozygous in the 9 living, affected family members, observed at a frequency of 2.1% in the Old Order Mennonite population, and absent in 91 non-Mennonite controls. The mutation is located in a highly conserved site in the N-terminal domain VI of LAMB2. Conclusions This study describes a novel mutation of LAMB2 and further expands the spectrum of eye and renal manifestations associated with defects in the laminin beta-2 chain. PMID:21236492

  5. Medical History, Lifestyle, Family History, and Occupational Risk Factors for Diffuse Large B-Cell Lymphoma: The InterLymph Non-Hodgkin Lymphoma Subtypes Project

    PubMed Central

    Kricker, Anne; Paltiel, Ora; Flowers, Christopher R.; Wang, Sophia S.; Monnereau, Alain; Blair, Aaron; Maso, Luigino Dal; Kane, Eleanor V.; Nieters, Alexandra; Foran, James M.; Miligi, Lucia; Clavel, Jacqueline; Bernstein, Leslie; Rothman, Nathaniel; Slager, Susan L.; Sampson, Joshua N.; Morton, Lindsay M.; Skibola, Christine F.

    2014-01-01

    Background Although risk factors for diffuse large B-cell lymphoma (DLBCL) have been suggested, their independent effects, modification by sex, and association with anatomical sites are largely unknown. Methods In a pooled analysis of 4667 cases and 22639 controls from 19 studies, we used stepwise logistic regression to identify the most parsimonious multivariate models for DLBCL overall, by sex, and for selected anatomical sites. Results DLBCL was associated with B-cell activating autoimmune diseases (odds ratio [OR] = 2.36, 95% confidence interval [CI] = 1.80 to 3.09), hepatitis C virus seropositivity (OR = 2.02, 95% CI = 1.47 to 2.76), family history of non-Hodgkin lymphoma (OR = 1.95, 95% CI = 1.54 to 2.47), higher young adult body mass index (OR = 1.58, 95% CI = 1.12 to 2.23, for 35+ vs 18.5 to 22.4 kg/m2), higher recreational sun exposure (OR = 0.78, 95% CI = 0.69 to 0.89), any atopic disorder (OR = 0.82, 95% CI = 0.76 to 0.89), and higher socioeconomic status (OR = 0.86, 95% CI = 0.79 to 0.94). Additional risk factors for women were occupation as field crop/vegetable farm worker (OR = 1.78, 95% CI = 1.22 to 2.60), hairdresser (OR = 1.65, 95% CI = 1.12 to 2.41), and seamstress/embroider (OR = 1.49, 95% CI = 1.13 to 1.97), low adult body mass index (OR = 0.46, 95% CI = 0.29 to 0.74, for <18.5 vs 18.5 to 22.4 kg/m2), hormone replacement therapy started age at least 50 years (OR = 0.68, 95% CI = 0.52 to 0.88), and oral contraceptive use before 1970 (OR = 0.78, 95% CI = 0.62 to 1.00); and for men were occupation as material handling equipment operator (OR = 1.58, 95% CI = 1.02 to 2.44), lifetime alcohol consumption (OR = 0.57, 95% CI = 0.44 to 0.75, for >400kg vs nondrinker), and previous blood transfusion (OR = 0.69, 95% CI = 0.57 to 0.83). Autoimmune disease, atopy, and family history of non-Hodgkin lymphoma showed similar associations across selected anatomical sites, whereas smoking was associated with central nervous system, testicular and cutaneous DLBCLs; inflammatory bowel disease was associated with gastrointestinal DLBCL; and farming and hair dye use were associated with mediastinal DLBCL. Conclusion Our results support a complex and multifactorial etiology for DLBCL with some variation in risk observed by sex and anatomical site. PMID:25174023

  6. Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing

    PubMed Central

    Chang, Mun Young; Kim, Ah Reum; Kim, Nayoung K.D.; Lee, Chung; Lee, Kyoung Yeul; Jeon, Woo-Sung; Koo, Ja-Won; Oh, Seung Ha; Park, Woong-Yang; Kim, Dongsup; Choi, Byung Yoon

    2015-01-01

    Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development. PMID:26242193

  7. The Clinical Spectrum of Missense Mutations of the First Aspartic Acid of cbEGF-like Domains in Fibrillin-1 Including a Recessive Family

    PubMed Central

    Hilhorst-Hofstee, Yvonne; Rijlaarsdam, Marry EB; Scholte, Arthur JHA; Swart-van den Berg, Marietta; Versteegh, Michel IM; van der Schoot-van Velzen, Iris; Schäbitz, Hans-Joachim; Bijlsma, Emilia K; Baars, Marieke J; Kerstjens-Frederikse, Wilhelmina S; Giltay, Jacques C; Hamel, Ben C; Breuning, Martijn H; Pals, Gerard

    2010-01-01

    Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation. © 2010 Wiley-Liss, Inc. PMID:20886638

  8. The clinical spectrum of missense mutations of the first aspartic acid of cbEGF-like domains in fibrillin-1 including a recessive family.

    PubMed

    Hilhorst-Hofstee, Yvonne; Rijlaarsdam, Marry E B; Scholte, Arthur J H A; Swart-van den Berg, Marietta; Versteegh, Michel I M; van der Schoot-van Velzen, Iris; Schäbitz, Hans-Joachim; Bijlsma, Emilia K; Baars, Marieke J; Kerstjens-Frederikse, Wilhelmina S; Giltay, Jacques C; Hamel, Ben C; Breuning, Martijn H; Pals, Gerard

    2010-12-01

    Marfan syndrome (MFS) is a dominant disorder with a recognizable phenotype. In most patients with the classical phenotype mutations are found in the fibrillin-1 gene (FBN1) on chromosome 15q21. It is thought that most mutations act in a dominant negative way or through haploinsufficiency. In 9 index cases referred for MFS we detected heterozygous missense mutations in FBN1 predicted to substitute the first aspartic acid of different calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. A similar mutation was found in homozygous state in 3 cases in a large consanguineous family. Heterozygous carriers of this mutation had no major skeletal, cardiovascular or ophthalmological features of MFS. In the literature 14 other heterozygous missense mutations are described leading to the substitution of the first aspartic acid of a cbEGF domain and resulting in a Marfan phenotype. Our data show that the phenotypic effect of aspartic acid substitutions in the first position of a cbEGF domain can range from asymptomatic to a severe neonatal phenotype. The recessive nature with reduced expression of FBN1 in one of the families suggests a threshold model combined with a mild functional defect of this specific mutation. PMID:20886638

  9. Role of family susceptibility, occupational and family histories and individuals' blood groups in the development of silicosis.

    PubMed Central

    Noweir, M H; Moselhi, M; Amine, E K

    1980-01-01

    A previous investigation has shown that family susceptibility and occupational and family histories have a decisive role in the development of byssinosis among workers exposed to flax dust. Results of investigation of silicosis in 814 male workers exposed to silica-bearing dust showed that family susceptibility has an important role in the development of silicosis among examined workers, and workers whose fathers had an occupational history of exposure to silica-bearing dust were more resistant to the development of the disease than those with non-exposed fathers. The degree of consanguinity of parents and individuals' blood groups, also, have a role. Workers with cousin parents were relatively highly susceptible to the development of silicosis as well as workers with blood groups "O" or "AB". It has been concluded that the investigated factors might have a role in the development of other occupational diseases and further investigations are indicated. PMID:6255981

  10. Inbreeding coefficients for X-linked and autosomal genes in consanguineous marriages in Spanish populations: the case of Guipúzcoa (Basque Country).

    PubMed

    Calderón, R; Aresti, U; Ambrosio, B; González-Martín, A

    2009-03-01

    Inbreeding patterns over the past two centuries have been studied more extensively in Spain and Italy than anywhere else in Europe. Consanguinity studies in mainland Spain have shown that populations settled along the Cantabrian cornice share inbreeding patterns that distinguish them from other populations further south. A visual representation of spatial variations of two key inbreeding variables is presented here for the first time via contour maps. This paper also analyzes time trends of mean inbreeding coefficients for X-linked (F(x)) and autosomal genes (F) (1862-1995) together with variations in F(x)/F ratios in Guipúzcoa, the most autochthonous Spanish Basque province. Because close cousin marriages are a mark of identity of the study population, we evaluated the contribution of uncle-niece/aunt-nephew (M12) and first cousin (M22) marriages to F(x) and F values and compared the frequencies of M12 and M22 pedigree subtypes and their corresponding F(x)/F ratios to those found in other Spanish populations. The mean Fx and F inbreeding levels in Guipúzcoa for the 134-year period analyzed were 1.51 x 10(-3) and 1.04 x 10(-3), respectively, and the F(x)/F ratio was seen to be very stable over time. Our findings show that major similarities exist for close consanguineous marriage subtypes between Basque and non-Basque Spanish populations, despite significant geographic variability in terms of first cousin pedigrees. The distortion seems to be caused by Guipúzcoa. The F(x)/F ratios for first cousins in Spanish populations were higher than expected (1.25), with values ranging from 1.34 to 1.48. The findings of the present study may be useful for advancing knowledge on the effects of the interaction between biology and culture and for exploring associations between mating patterns and the prevalence of certain diseases. PMID:19133940

  11. Autosomal dominant Kufs` disease: Clinical heterogeneity in nine families, and exclusion of linkage to CLN1 and CLN3 markers in a large American kindred

    SciTech Connect

    Andermann, F.; Andermann, E.; Carpenter, S.

    1994-09-01

    Most forms of neuronal ceroid lipofuscinosis (NCL) are autosomal recessive, and three genes have already been mapped: the infantile form (CLN 1); the juvenile form (CLN 3); and the early juvenile variant (CLN 5) on chromosomes 1, 16 and 13, respectively. Kufs` disease or adolescent-adult onset NCL is usually inherited as an autosomal recessive trait, and presents as three distinct clinical syndromes: progressive myoclonus epilepsy (PME) with onset in the early teens or around age 30; and onset of dementia with motor disability in the 30s. We have studied three families originating from different parts of the USA manifesting dominantly inherited Kufs` disease. Granular osmophilic deposits (GROD) were found in brain, but storage in skin was not an obligatory feature. Six dominantly inherited PME families have been ascertained from three different regions of Spain. No storage was found in skin or muscle in any of these families. The mean age of onset in the American families is earlier, the clinical manifestations more severe, and the progression much more rapid that in the Spanish families. These findings would suggest the possibility of genetic heterogeneity involving two or more loci, or different mutations at the same gene locus. Genetic linkage studies have been carried out in a six-generation New Jersey family in an attempt to characterize the gene(s) responsible for this disorder. The infantile NCL locus on chromosome 1p (CLN1) and the juvenile NCL locus on chromosome 16p (CLN 3) have been excluded in this family. Further clinical, pathological and molecular genetic studies should lead to the clarification of the diagnostic approaches in this disorder.

  12. Prevalence and Healthcare Actions of Women in a Large Health System with a Family History Meeting the 2005 USPSTF Recommendation for BRCA Genetic Counseling Referral

    PubMed Central

    Bellcross, Cecelia A.; Leadbetter, Steven; Alford, Sharon Hensley; Peipins, Lucy A.

    2016-01-01

    Background In 2005, the United States Preventive Services Task Force (USPSTF) released guidelines which outlined specific family history patterns associated with an increased risk for BRCA1/2 mutations, and recommended at-risk individuals be referred for genetic counseling and evaluation for BRCA testing. The purpose of this study was to assess the prevalence of individuals with a USPSTF increased-risk family history pattern, the frequency with which specific patterns were met, and resulting healthcare actions among women from the Henry Ford Health System. Methods As part of a study evaluating ovarian cancer risk perception and screening, 2,524 randomly selected participants completed a detailed interview (response rate 76%) from an initial eligible cohort of 16,720 women. Results Approximately 6% of participants had a family history fulfilling one or more of the USPSTF patterns. Although 90% of these women had shared their family history with their provider, less than 20% had been referred for genetic counseling and only 8% had undergone genetic testing. Caucasian women with higher income and education levels were more likely to receive referrals. Among the 95 participants in the total study cohort who reported BRCA testing, 78% did not have a family history that met one of the USPSTF patterns. Conclusions These results suggest a higher prevalence of women with an increased-risk family history than originally predicted by the USPSTF, and lack of provider recognition and referral for genetic services. Impact Improvements in healthcare infrastructure and clinician education will be required to realize population level benefits from BRCA genetic counseling and testing. PMID:23371291

  13. Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q

    SciTech Connect

    Fink, J.K.; Wu, C.T.B.; Jones, S.M.

    1994-09-01

    Familial spastic paraplegia (FSP) (MIM No.18260) constitutes a clinically and genetically diverse group of disorders that share the primary feature of progressive, severe, lower extremity spasticity. FSP is classified according to the mode of inheritance and whether progressive spasticity occurs in isolation ({open_quotes}uncomplicated FSP{close_quotes}) or with other neurologic abnormalities ({open_quotes}complicated FSP{close_quotes}), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, or deafness. Recently, autosomal dominant, uncomplicated FSP was shown to be genetically heterogeneous and tightly linked to a group of microsatellite markers on chromosome 14q in one large kindred. We examined 126 members of a non-consanguineous North American kindred of Irish descent. FSP was diagnosed in 31 living subjects who developed insidiously progressive gait disturbance between ages 12 and 35 years. Using genetic linkage analysis to microsatellite DNA polymorphisms, we showed that the FSP locus on chromosome 14q was exluded from linkage with the disorder in our family. Subsequently, we searched for genetic linkage between the disorder and microsatellite DNA polymorphisms spanning approximately 50% of the genome. We observed significantly positive, two-point maximum lod scores (Z) for markers on chromosome 15q: D15S128 (Z=9.70, {theta}=0.05), D15S165 (Z=3.30, {theta}=0.10), and UT511 (Z=3.86, {theta}=0.10). Our data clearly establishes that one locus for autosomal dominant, uncomplicated FSP is mapped to the pericentric region of chromosome 15q. Identifying genes responsible for chromosome 15q-linked and chromosome 14q-linked FSP will greatly advance our understanding of this condition and hopefully other inherited and degenerative brain and spinal cord disorders that are also characterized by axonal degeneration.

  14. Familiality of Tourette Syndrome, Obsessive-Compulsive Disorder, and Attention-Deficit/Hyperactivity Disorder: Heritability Analysis in a Large Sib-Pair Sample

    ERIC Educational Resources Information Center

    Mathews, Carol A.; Grados, Marco A.

    2011-01-01

    Objective: Tourette syndrome (TS) is a neuropsychiatric disorder with a genetic component that is highly comorbid with obsessive-compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD). However, the genetic relations between these disorders have not been clearly elucidated. This study examined the familial relations among TS,…

  15. Structure-activity relationships of a novel group of large-conductance Ca(2+)-activated K(+) (BK) channel modulators: the GoSlo-SR family.

    PubMed

    Roy, Subhrangsu; Morayo Akande, Adebola; Large, Roddy J; Webb, Tim I; Camarasu, Costin; Sergeant, Gerard P; McHale, Noel G; Thornbury, Keith D; Hollywood, Mark A

    2012-10-01

    Opening up ion channels: We synthesised a series of anthraquinone analogues, called the GoSlo-SR family. Their effects on bladder smooth muscle BK channels were examined and, as shown, shifted voltage dependent activation >-100 mV (at 10 ?M). They were more efficacious than NS11021 and could provide a new scaffold for the design of efficacious BK openers. PMID:22930560

  16. Familiality of Tourette Syndrome, Obsessive-Compulsive Disorder, and Attention-Deficit/Hyperactivity Disorder: Heritability Analysis in a Large Sib-Pair Sample

    ERIC Educational Resources Information Center

    Mathews, Carol A.; Grados, Marco A.

    2011-01-01

    Objective: Tourette syndrome (TS) is a neuropsychiatric disorder with a genetic component that is highly comorbid with obsessive-compulsive disorder (OCD) and attention deficit/hyperactivity disorder (ADHD). However, the genetic relations between these disorders have not been clearly elucidated. This study examined the familial relations among TS,…

  17. Sfr13, a member of a large family of asymmetrically localized Sfi1-repeat proteins, is important for basal body separation and stability in Tetrahymena thermophila

    PubMed Central

    Stemm-Wolf, Alexander J.; Meehl, Janet B.; Winey, Mark

    2013-01-01

    Summary Directed fluid flow, which is achieved by the coordinated beating of motile cilia, is required for processes as diverse as cellular swimming, developmental patterning and mucus clearance. Cilia are nucleated, anchored and aligned at the plasma membrane by basal bodies, which are cylindrical microtubule-based structures with ninefold radial symmetry. In the unicellular ciliate Tetrahymena thermophila, two centrin family members associated with the basal body are important for both basal body organization and stabilization. We have identified a family of 13 proteins in Tetrahymena that contain centrin-binding repeats related to those identified in the Saccharomyces cerevisiae Sfi1 protein. We have named these proteins Sfr1–Sfr13 (for Sfi1-repeat). Nine of the Sfr proteins localize in unique polarized patterns surrounding the basal body, suggesting non-identical roles in basal body organization and association with basal body accessory structures. Furthermore, the Sfr proteins are found in distinct basal body populations in Tetrahymena cells, indicating that they are responsive to particular developmental programs. A complete genetic deletion of one of the family members, Sfr13, causes unstable basal bodies and defects in daughter basal body separation from the mother, phenotypes also observed with centrin disruption. It is likely that the other Sfr family members are involved in distinct centrin functions, providing specificity to the tasks that centrins perform at basal bodies. PMID:23426847

  18. The Quality of Teachers' Interactive Conversations with Preschool Children from Low-Income Families during Small-Group and Large-Group Activities

    ERIC Educational Resources Information Center

    Chen, Jennifer J.; de Groot Kim, Sonja

    2014-01-01

    This study examined the quality of preschool teachers' interactive conversations with three- and four-year-olds in two Head Start classrooms serving children from low-income families in the United States. Over a period of 20?weeks, 10 bi-weekly observations of conversations (totaling 15?h per classroom) were conducted in one small-group (Play…

  19. Attitudes towards people with mental illness among psychiatrists, psychiatric nurses, involved family members and the general population in a large city in Guangzhou, China

    PubMed Central

    2014-01-01

    Purpose Stigma towards people with mental illness is believed to be widespread in low and middle income countries. Methods This study assessed the attitudes towards people with mental illness among psychiatrists, psychiatric nurses, involved family members of patients in a psychiatric facility and the general public using a standard 43-item survey (N?=?535). Exploratory factor analysis identified four distinctive attitudes which were then compared using Analysis of Covariance (ANCOVA) among the four groups, all with ties to the largest psychiatric facility in Guangzhou, China, adjusting for sociodemographic differences. Results Four uncorrelated factors expressed preferences for 1) community-based treatment, social integration and a biopsychosocial model of causation, 2) direct personal relationships with people with mental illness, 3) a lack of fear and positive views of personal interactions with people with mental illness, 4) disbelief in superstitious explanations of mental illness. Statistically significant differences favored community-based treatment and biopsychosocial causation (factor 1) among professional groups (psychiatrists and nurses) as compared with family members and the general public (p?family members, unexpectedly, showed far weaker personal preferences for direct personal relationships with people with mental illness than all three other groups (p?family members showed the least positive attitudes towards direct personal relationships with people with mental illness. These findings suggest support for a more extensive, formal system of care that gives family members some distance from the problems of their relatives and support in their care. PMID:25053975

  20. A Case of Nasu-Hakola Disease without Fractures or Consanguinity Diagnosed Using Exome Sequencing and Treated with Sodium Valproate.

    PubMed

    Yamazaki, Kiyohiro; Yoshino, Yuta; Mori, Yoko; Ochi, Shinichiro; Yoshida, Taku; Ishimaru, Takashi; Ueno, Shu-Ichi

    2015-12-31

    Nasu-Hakola disease (NHD) is a rare autosomal recessive neuropsychiatric disorder characterized by bone cysts, fractures, and cognitive impairment. Two genes are responsible for the development of NHD; TYROBPand TREM2. Although it presents with typical signs and symptoms, diagnosing this disease remains difficult. This case report describes a male with NHD with no family or past history of bone fractures who was diagnosed using exome sequencing. His frontal lobe psychiatric symptoms recovered partially following treatment with sodium valproate, but not with an antipsychotic. PMID:26598595

  1. A Case of Nasu-Hakola Disease without Fractures or Consanguinity Diagnosed Using Exome Sequencing and Treated with Sodium Valproate

    PubMed Central

    Yamazaki, Kiyohiro; Yoshino, Yuta; Mori, Yoko; Ochi, Shinichiro; Yoshida, Taku; Ishimaru, Takashi; Ueno, Shu-ichi

    2015-01-01

    Nasu-Hakola disease (NHD) is a rare autosomal recessive neuropsychiatric disorder characterized by bone cysts, fractures, and cognitive impairment. Two genes are responsible for the development of NHD; TYROBP and TREM2. Although it presents with typical signs and symptoms, diagnosing this disease remains difficult. This case report describes a male with NHD with no family or past history of bone fractures who was diagnosed using exome sequencing. His frontal lobe psychiatric symptoms recovered partially following treatment with sodium valproate, but not with an antipsychotic. PMID:26598595

  2. Linkage mapping and whole exome sequencing identify a shared variant in CX3CR1 in a large multi-generation family.

    PubMed

    Feldman, George J; Parvizi, Javad; Sawan, Hind; Erickson, Jill A; Peters, Christopher L

    2014-09-01

    Developmental dysplasia of the hip (DDH) is a crippling condition that affects children and adults, with an average incidence of 1-1.5 cases per 1000 live births. It results in disabling arthritis of the hip in up to 60% patients in the 20-40 year age group. There is no accurate diagnostic test available for newborns. The purpose of our study is to develop a sensitive and specific genetic test for DDH by identifying causative mutations. Linkage analysis and whole exome sequencing of 4 severely affected individuals of a 4 generation 71 member family was performed. The damaging rs3732378 variant in the CX3CR1 chemokine receptor was shared by all affected family members and by 15% of 28 sporadic dysplastics. PMID:24998320

  3. A Novel GCAP1 Missense Mutation (L151F) in a Large Family with Autosomal Dominant Cone-Rod Dystrophy (adCORD)

    PubMed Central

    Sokal, Izabela; Dupps, William J.; Grassi, Michael A.; Brown, Jeremiah; Affatigato, Louisa M.; Roychowdhury, Nirmalya; Yang, Lili; Filipek, Slawomir; Palczewski, Krzysztof; Stone, Edwin M.; Baehr, Wolfgang

    2005-01-01

    Purpose To elucidate the phenotypic and biochemical characteristics of a novel mutation associated with autosomal dominant cone–rod dystrophy (adCORD). Methods Twenty-three family members of a CORD pedigree underwent clinical examinations, including visual acuity tests, standardized full-field ERG, and fundus photography. Genomic DNA was screened for mutations in GCAP1 exons using DNA sequencing and single-strand conformational polymorphism (SSCP) analysis. Function and stability of recombinant GCAP1-L151F were tested as a function of [Ca2+], and its structure was probed by molecular dynamics. Results Affected family members experienced dyschromatopsia, hemeralopia, and reduced visual acuity by the second to third decade of life. Electrophysiology revealed a nonrecordable photopic response with later attenuation of the scotopic response. Affected family members harbored a C→T transition in exon 4 of the GCAP1 gene, resulting in an L151F missense mutation affecting the EF hand motif 4 (EF4). This change was absent in 11 unaffected family members and in 100 unrelated normal subjects. GCAP1-L151F stimulation of photoreceptor guanylate cyclase was not completely inhibited at high physiological [Ca2+], consistent with a lowered affinity for Ca2+-binding to EF4. Conclusions A novel L151F mutation in the EF4 hand domain of GCAP1 is associated with adCORD. The clinical phenotype is characterized by early cone dysfunction and a progressive loss of rod function. The biochemical phenotype is best described as persistent stimulation of photoreceptor guanylate cyclase, representing a gain of function of mutant GCAP1. Although a conservative substitution, molecular dynamics suggests a significant change in Ca2+-binding to EF4 and EF2 and changes in the shape of L151F-GCAP1. PMID:15790869

  4. Challenges and solutions for gene identification in the presence of familial locus heterogeneity.

    PubMed

    Rehman, Atteeq U; Santos-Cortez, Regie Lyn P; Drummond, Meghan C; Shahzad, Mohsin; Lee, Kwanghyuk; Morell, Robert J; Ansar, Muhammad; Jan, Abid; Wang, Xin; Aziz, Abdul; Riazuddin, Saima; Smith, Joshua D; Wang, Gao T; Ahmed, Zubair M; Gul, Khitab; Shearer, A Eliot; Smith, Richard J H; Shendure, Jay; Bamshad, Michael J; Nickerson, Deborah A; Hinnant, John; Khan, Shaheen N; Fisher, Rachel A; Ahmad, Wasim; Friderici, Karen H; Riazuddin, Sheikh; Friedman, Thomas B; Wilch, Ellen S; Leal, Suzanne M

    2015-09-01

    Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification. PMID:25491636

  5. A new locus for autosomal recessive congenital cataract identified in a Pakistani family

    PubMed Central

    Kaul, Haiba; Riazuddin, S. Amer; Yasmeen, Afshan; Mohsin, Sadia; Khan, Mohsin; Nasir, Idrees A.; Khan, Shaheen N.; Husnain, Tayyab; Akram, Javed; Hejtmancik, J. Fielding

    2010-01-01

    Purpose To identify the disease locus for autosomal recessive congenital cataract in a consanguineous Pakistani family. Methods All affected individuals underwent detailed ophthalmologic and medical examination. Blood samples were collected and DNA was extracted. A genome-wide scan was performed with polymorphic microsatellite markers on genomic DNA from affected and unaffected family members, and logarithm of odds (LOD) scores were calculated. Results The clinical records and ophthalmological examinations suggested that all affected individuals have nuclear cataracts. Maximum LOD scores of 5.01, 4.38, and 4.17 at ?=0 were obtained with markers D7630, D7S657, and D7S515, respectively. Fine mapping refined the critical interval and suggested that markers in a 27.78 cM (27.96 Mb) interval are flanked by markers D7S660 and D7S799, which co-segregate with the disease phenotype in family PKCC108. Conclusions We have identified a new locus for autosomal recessive congenital cataract, localized to chromosome 7q21.11-q31.1 in a consanguineous Pakistani family. PMID:20161816

  6. Challenges and solutions for gene identification in the presence of familial locus heterogeneity

    PubMed Central

    Rehman, Atteeq U; Santos-Cortez, Regie Lyn P; Drummond, Meghan C; Shahzad, Mohsin; Lee, Kwanghyuk; Morell, Robert J; Ansar, Muhammad; Jan, Abid; Wang, Xin; Aziz, Abdul; Riazuddin, Saima; Smith, Joshua D; Wang, Gao T; Ahmed, Zubair M; Gul, Khitab; Shearer, A Eliot; Smith, Richard J H; Shendure, Jay; Bamshad, Michael J; Nickerson, Deborah A; Hinnant, John; Khan, Shaheen N; Fisher, Rachel A; Ahmad, Wasim; Friderici, Karen H; Riazuddin, Sheikh; Friedman, Thomas B; Wilch, Ellen S; Leal, Suzanne M

    2015-01-01

    Next-generation sequencing (NGS) of exomes and genomes has accelerated the identification of genes involved in Mendelian phenotypes. However, many NGS studies fall short of identifying causal variants, with estimates for success rates as low as 25% for uncovering the pathological variant underlying disease etiology. An important reason for such failures is familial locus heterogeneity, where within a single pedigree causal variants in two or more genes underlie Mendelian trait etiology. As examples of intra- and inter-sibship familial locus heterogeneity, we present 10 consanguineous Pakistani families segregating hearing impairment due to homozygous variants in two different hearing impairment genes and a European-American pedigree in which hearing impairment is caused by four variants in three different genes. We have identified 41 additional pedigrees with syndromic and nonsyndromic hearing impairment for which a single previously reported hearing impairment gene has been identified but only segregates with the phenotype in a subset of affected pedigree members. We estimate that locus heterogeneity occurs in 15.3% (95% confidence interval: 11.9%, 19.9%) of the families in our collection. We demonstrate novel approaches to apply linkage analysis and homozygosity mapping (for autosomal recessive consanguineous pedigrees), which can be used to detect locus heterogeneity using either NGS or SNP array data. Results from linkage analysis and homozygosity mapping can also be used to group sibships or individuals most likely to be segregating the same causal variants and thereby increase the success rate of gene identification. PMID:25491636

  7. Truncation of the E3 ubiquitin ligase component FBXO31 causes non-syndromic autosomal recessive intellectual disability in a Pakistani family.

    PubMed

    Mir, Asif; Sritharan, Kumudesh; Mittal, Kirti; Vasli, Nasim; Araujo, Carolina; Jamil, Talal; Rafiq, Muhammad Arshad; Anwar, Zubair; Mikhailov, Anna; Rauf, Sobiah; Mahmood, Huda; Shakoor, Abdul; Ali, Sabir; So, Joyce; Naeem, Farooq; Ayub, Muhammad; Vincent, John B

    2014-08-01

    In this study, we have performed autozygosity mapping on a large consanguineous Pakistani family segregating with intellectual disability. We identified two large regions of homozygosity-by-descent (HBD) on 16q12.2-q21 and 16q24.1-q24.3. Whole exome sequencing (WES) was performed on an affected individual from the family, but initially, no obvious mutation was detected. However, three genes within the HBD regions that were not fully captured during the WES were Sanger sequenced and we identified a five base pair deletion (actually six base pairs deleted plus one base pair inserted) in exon 7 of the gene FBXO31. The variant segregated completely in the family, in recessive fashion giving a LOD score of 3.95. This variant leads to a frameshift and a premature stop codon and truncation of the FBXO31 protein, p.(Cys283Asnfs*81). Quantification of mRNA and protein expression suggests that nonsense-mediated mRNA decay also contributes to the loss of FBXO31 protein in affected individuals. FBXO31 functions as a centrosomal E3 ubiquitin ligase, in association with SKP1 and Cullin-1, involved in ubiquitination of proteins targeted for degradation. The FBXO31/SKP1/Cullin1 complex is important for neuronal morphogenesis and axonal identity. FBXO31 also plays a role in dendrite growth and neuronal migration in developing cerebellar cortex. Our finding adds further evidence of the involvement of disruption of the protein ubiquitination pathway in intellectual disability. PMID:24623383

  8. Family size effects: a review.

    PubMed

    Wagner, M E; Schubert, H J; Schubert, D S

    1985-03-01

    Larger families are more frequent with early marriage and rapid birth of the first child. In larger families, child rearing becomes more rule ridden, less individualized, with corporal punishment and less investment of resources. Smaller families tend to result in higher IQ, academic achievement, and occupational performance. Large families produce more delinquents and alcoholics. Perinatal morbidity and mortality rates are higher in large families as birth weights decrease. Mothers of large families are at higher risk of several physical diseases. Common methodological errors are indicated and exemplary studies are described. PMID:3900289

  9. 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

  10. 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. PMID:26147992

  11. The HAK1 gene of barley is a member of a large gene family and encodes a high-affinity potassium transporter.

    PubMed

    Santa-María, G E; Rubio, F; Dubcovsky, J; Rodríguez-Navarro, A

    1997-12-01

    The high-affinity K+ uptake system of plants plays a crucial role in nutrition and has been the subject of extensive kinetic studies. However, major components of this system remain to be identified. We isolated a cDNA from barley roots, HvHAK1, whose translated sequence shows homology to the Escherichia coli Kup and Schwanniomyces occidentalis HAK1 K+ transporters. HvHAK1 conferred high-affinity K+ uptake to a K(+)-uptake-deficient yeast mutant exhibiting the hallmark characteristics of the high-affinity K+ uptake described for barley roots. HvHAK1 also mediated low-affinity Na+ uptake. Another cDNA (HvHAK2) encoding a polypeptide 42% identical to HvHAK1 was also isolated. Analysis of several genomes of Triticeae indicates that HvHAK1 belongs to a multigene family. Translated sequences from bacterial DNAs and Arabidopsis, rice, and possibly human cDNAs show homology to the Kup-HAK1-HvHAK1 family of K+ transporters. PMID:9437867

  12. A Novel von Hippel Lindau Gene Intronic Variant and Its Reclassification from VUS to Pathogenic: the Impact on a Large Family.

    PubMed

    Sexton, A; Rawlings, L; McKavanagh, G; Simons, K; Winship, I

    2015-12-01

    We present a case where a variant of uncertain significance in the von Hippel Lindau syndrome gene (VHL) was identified in a proband with haemangioblastoma, and in a second degree relative with phaeochromocytoma. Initial uncertainty due to the unclear nature of the variant created psychosocial challenges for this family, in which four other genetic conditions were also present. Subsequent RNA studies confirmed this as a novel pathogenic mutation affecting splicing of exon 2. A third relative has since been diagnosed with haemangioblastoma. We suggest that this mutation possibly has reduced penetrance as there was no history of haemangioblastoma, renal tumours (apart from small cysts) or other VHL tumours among five mutation positive and seven untested adult relatives at 50 % risk of the VHL mutation (average age 46 years, range 18-70 years). This case presents a novel VHL splicing mutation and highlights the psychosocial and medical value of additional laboratory studies on uncertain variants for individuals, their families and for the health professionals providing advice and counseling. PMID:26323595

  13. A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis.

    PubMed

    Yotsumoto, S; Setoyama, M; Hozumi, H; Mizoguchi, S; Fukumaru, S; Kobayashi, K; Saheki, T; Kanzaki, T

    1999-05-01

    A nerve growth factor receptor encoded by the TRKA gene plays an important part in the formation of autonomic neurons and small sensory neurons in dorsal root ganglia and in signal transduction through its intracytoplasmic tyrosine kinase domain. Recently, three mutations in the tyrosine kinase domain of TRKA have been reported in patients with congenital insensitivity to pain with anhidrosis, which is an autosomal recessive disorder characterized by recurrent fever due to absence of sweating, no reaction to noxious stimuli, self-mutilating behavior, and mental retardation. We examined the TRKA gene in five generations of a large Japanese family with many consanguineous marriages who live in a small remote island of the southern part of Japan. We found a novel point mutation at nucleotide 1825 (A-->G transition) resulting in Met-581-Val in the tyrosine kinase domain. Two of the three affected patients were homozygous for this mutation; however, the third affected patient was heterozygous. Further analysis revealed that the third patient was a compound heterozygote with the Met-581-Val mutation in one allele and with a single base C deletion mutation at nucleotide 1726 in exon 14 in the other allele, resulting in a frameshift and premature termination codon. PMID:10233776

  14. Family History

    MedlinePLUS

    Your family history includes health information about you and your close relatives. Families have many factors in common, including their genes, ... as heart disease, stroke, and cancer. Having a family member with a disease raises your risk, but ...

  15. Familial hypercholesterolemia

    MedlinePLUS

    Familial hypercholesterolemia is a disorder that is passed down through families. It causes LDL ("bad") cholesterol level to ... Familial hypercholesterolemia is a genetic disorder. It is caused by a defect on chromosome 19. The defect makes ...

  16. Whole-genome sequencing identifies a novel ABCB7 gene mutation for X-linked congenital cerebellar ataxia in a large family of Mongolian ancestry.

    PubMed

    Protasova, Maria S; Grigorenko, Anastasia P; Tyazhelova, Tatiana V; Andreeva, Tatiana V; Reshetov, Denis A; Gusev, Fedor E; Laptenko, Alexander E; Kuznetsova, Irina L; Goltsov, Andrey Y; Klyushnikov, Sergey A; Illarioshkin, Sergey N; Rogaev, Evgeny I

    2016-04-01

    X-linked congenital cerebellar ataxia is a heterogeneous nonprogressive neurodevelopmental disorder with onset in early childhood. We searched for a genetic cause of this condition, previously reported in a Buryat pedigree of Mongolian ancestry from southeastern Russia. Using whole-genome sequencing on Illumina HiSeq 2000 platform, we found a missense mutation in the ABCB7 (ABC-binding cassette transporter B7) gene, encoding a mitochondrial transporter, involved in heme synthesis and previously associated with sideroblastic anemia and ataxia. The mutation resulting in a substitution of a highly conserved glycine to serine in position 682 is apparently a major causative factor of the cerebellar hypoplasia/atrophy found in affected individuals of a Buryat family who had no evidence of sideroblastic anemia. Moreover, in these affected men we also found the genetic defects in two other genes closely linked to ABCB7 on chromosome X: a deletion of a genomic region harboring the second exon of copper-transporter gene (ATP7A) and a complete deletion of PGAM4 (phosphoglycerate mutase family member 4) retrogene located in the intronic region of the ATP7A gene. Despite the deletion, eliminating the first of six metal-binding domains in ATP7A, no signs for Menkes disease or occipital horn syndrome associated with ATP7A mutations were found in male carriers. The role of the PGAM4 gene has been previously implicated in human reproduction, but our data indicate that its complete loss does not disrupt male fertility. Our finding links cerebellar pathology to the genetic defect in ABCB7 and ATP7A structural variant inherited as X-linked trait, and further reveals the genetic heterogeneity of X-linked cerebellar disorders. PMID:26242992

  17. Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3.

    PubMed

    Budde, Birgit S; Mizumoto, Shuji; Kogawa, Ryo; Becker, Christian; Altmüller, Janine; Thiele, Holger; Rüschendorf, Franz; Toliat, Mohammad R; Kaleschke, Gerrit; Hämmerle, Johannes M; Höhne, Wolfgang; Sugahara, Kazuyuki; Nürnberg, Peter; Kennerknecht, Ingo

    2015-07-01

    We describe a large family with disproportionate short stature and bone dysplasia from Nias in which we observed differences in severity when comparing the phenotypes of affected individuals from two remote branches. We conducted a linkage scan in the more severely affected family branch and determined a critical interval of 4.7 cM on chromosome 11. Sequencing of the primary candidate gene TBX10 did not reveal a disease-causing variant. When performing whole exome sequencing we noticed a homozygous missense variant in B3GAT3, c.419C>T [p.(Pro140Leu)]. B3GAT3 encodes ?-1,3-glucuronyltransferase-I (GlcAT-I). GlcAT-I catalyzes an initial step of proteoglycan synthesis and the mutation p. (Pro140Leu) lies within the donor substrate-binding subdomain of the catalytic domain. In contrast to the previously published mutation in B3GAT3, c.830G>A [p.(Arg277Gln)], no heart phenotype could be detected in our family. Functional studies revealed a markedly reduced GlcAT-I activity in lymphoblastoid cells from patients when compared to matched controls. Moreover, relative numbers of glycosaminoglycan (GAG) side chains were decreased in patient cells. We found that Pro140Leu-mutant GlcAT-I cannot efficiently transfer GlcA to the linker region trisaccharide. This failure results in a partial deficiency of both chondroitin sulfate and heparan sulfate chains. Since the phenotype of the Nias patients differs from the Larsen-like syndrome described for patients with mutation p.(Arg277Gln), we suggest mutation B3GAT3:p.(Pro140Leu) to cause a different type of GAG linkeropathy showing no involvement of the heart. PMID:25893793

  18. Exome sequencing identifies ATP4A gene as responsible of an atypical familial type I gastric neuroendocrine tumour.

    PubMed

    Calvete, Oriol; Reyes, Jose; Zuñiga, Sheila; Paumard-Hernández, Beatriz; Fernández, Victoria; Bujanda, Luís; Rodriguez-Pinilla, María S; Palacios, Jose; Heine-Suñer, Damian; Banka, Siddharth; Newman, William G; Cañamero, Marta; Pritchard, D Mark; Benítez, Javier

    2015-05-15

    Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C>T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases. PMID:25678551

  19. Identification of an extensive gene cluster among a family of PPOs in Trifolium pratense L. (red clover) using a large insert BAC library

    PubMed Central

    2009-01-01

    Background Polyphenol oxidase (PPO) activity in plants is a trait with potential economic, agricultural and environmental impact. In relation to the food industry, PPO-induced browning causes unacceptable discolouration in fruit and vegetables: from an agriculture perspective, PPO can protect plants against pathogens and environmental stress, improve ruminant growth by increasing nitrogen absorption and decreasing nitrogen loss to the environment through the animal's urine. The high PPO legume, red clover, has a significant economic and environmental role in sustaining low-input organic and conventional farms. Molecular markers for a range of important agricultural traits are being developed for red clover and improved knowledge of PPO genes and their structure will facilitate molecular breeding. Results A bacterial artificial chromosome (BAC) library comprising 26,016 BAC clones with an average 135 Kb insert size, was constructed from Trifolium pratense L. (red clover), a diploid legume with a haploid genome size of 440–637 Mb. Library coverage of 6–8 genome equivalents ensured good representation of genes: the library was screened for polyphenol oxidase (PPO) genes. Two single copy PPO genes, PPO4 and PPO5, were identified to add to a family of three, previously reported, paralogous genes (PPO1–PPO3). Multiple PPO1 copies were identified and characterised revealing a subfamily comprising three variants PPO1/2, PPO1/4 and PPO1/5. Six PPO genes clustered within the genome: four separate BAC clones could be assembled onto a predicted 190–510 Kb single BAC contig. Conclusion A PPO gene family in red clover resides as a cluster of at least 6 genes. Three of these genes have high homology, suggesting a more recent evolutionary event. This PPO cluster covers a longer region of the genome than clusters detected in rice or previously reported in tomato. Full-length coding sequences from PPO4, PPO5, PPO1/5 and PPO1/4 will facilitate functional studies and provide genetic markers for plant breeding. PMID:19619287

  20. Large, larger, largest--a family of cluster-based tantalum copper aluminides with giant unit cells. I. Structure solution and refinement.

    PubMed

    Weber, Thomas; Dshemuchadse, Julia; Kobas, Miroslav; Conrad, Matthias; Harbrecht, Bernd; Steurer, Walter

    2009-06-01

    This is the first of two parts, where we report the structure determination of a novel family of cluster-based intermetallic phases of unprecedented complexity: cF444-Al(63.6)Ta(36.4) (AT-19), a = 19.1663 (1) A, V = 7040 A3, cF(5928-x)-Al(56.6)Cu(3.9)Ta(39.5), x = 20 (ACT-45), a = 45.376 (1) A, V = 93,428 A(3) and cF(23,256-x)-Al(55.4)Cu(5.4)Ta(39.1), x = 122 (ACT-71), a = 71.490 (4) A, V = 365,372 A3. The space group is F43m in all three cases. These cluster-based structures are closely related to the class of Frank-Kasper phases. It is remarkable that all three structures show the same average structure that resembles the cubic Laves phase. PMID:19461140

  1. Muslim families and family therapy.

    PubMed

    Daneshpour, M

    1998-07-01

    Muslim immigrant families living in the United States may well come to the attention of mental health professionals. This article examines the applicability of the Anglo-American models of family therapy to Muslim immigrant families. The most significant differences in value systems between the Muslim and Anglo-American cultures is Muslim families' preference for greater connectedness, a less flexible and more hierarchical family structure, and an implicit communication style. Systemic thinking, which deals with the pattern of relationships, is valid for all families regardless of cultural differences. However, the preferred directions of change for Muslim families need to be integrated into the assessment and goals for family therapy. PMID:9677541

  2. Family Privilege

    ERIC Educational Resources Information Center

    Seita, John R.

    2014-01-01

    Family privilege is defined as "strengths and supports gained through primary caring relationships." A generation ago, the typical family included two parents and a bevy of kids living under one roof. Now, every variation of blended caregiving qualifies as family. But over the long arc of human history, a real family was a…

  3. Family Privilege

    ERIC Educational Resources Information Center

    Seita, John R.

    2014-01-01

    Family privilege is defined as "strengths and supports gained through primary caring relationships." A generation ago, the typical family included two parents and a bevy of kids living under one roof. Now, every variation of blended caregiving qualifies as family. But over the long arc of human history, a real family was a…

  4. Two Novel Mutations in Myosin Binding Protein C Slow Causing Distal Arthrogryposis Type 2 in Two Large Han Chinese Families May Suggest Important Functional Role of Immunoglobulin Domain C2

    PubMed Central

    Li, Xuefu; Zhong, Bomeng; Han, Weitian; Zhao, Ning; Liu, Wei; Sui, Yu; Wang, Yawen; Lu, Yongping; Wang, Hong; Li, Jianxin; Jiang, Miao

    2015-01-01

    Distal arthrogryposes (DAs) are a group of disorders that mainly involve the distal parts of the limbs and at least ten different DAs have been described to date. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, but recently autosomal recessive pattern was reported in distal arthrogryposis type 5D. Mutations in the contractile genes are found in about 50% of all DA patients. Of these genes, mutations in the gene encoding myosin binding protein C slow MYBPC1 were recently identified in two families with distal arthrogryposis type 1B. Here, we described two large Chinese families with autosomal dominant distal arthrogryposis type 2(DA2) with incomplete penetrance and variable expressivity. Some unique overextension contractures of the lower limbs and some distinctive facial features were present in our DA2 pedigrees. We performed follow-up DNA sequencing after linkage mapping and first identified two novel MYBPC1 mutations (c.1075G>A [p.E359K] and c.956C>T [p.P319L]) responsible for these Chinese DA2 families of which one introduced by germline mosacism. Each mutation was found to cosegregate with the DA2 phenotype in each family but not in population controls. Both substitutions occur within C2 immunoglobulin domain, which together with C1 and the M motif constitute the binding site for the S2 subfragment of myosin. Our results expand the phenotypic spectrum of MYBPC1-related arthrogryposis multiplex congenita (AMC). We also proposed the possible molecular mechanisms that may underlie the pathogenesis of DA2 myopathy associated with these two substitutions in MYBPC1. PMID:25679999

  5. A novel type of class I gene organization in vertebrates: a large family of non-MHC-linked class I genes is expressed at the RNA level in the amphibian Xenopus.

    PubMed Central

    Flajnik, M F; Kasahara, M; Shum, B P; Salter-Cid, L; Taylor, E; Du Pasquier, L

    1993-01-01

    A Xenopus class I cDNA clone, isolated from a cDNA expression library using antisera, is a member of a large family of non-classical class I genes (class Ib) composed of at least nine subfamilies, all of which are expressed at the RNA level. The subfamilies are well conserved in their immunoglobulin-like alpha 3 domains, but their peptide-binding regions (PBRs) and cytoplasmic domains are very divergent. In contrast to the great allelic diversity found in the PBR of classical class I genes, the alleles of one of the Xenopus non-classical subfamilies are extremely well conserved in all regions. Several of the invariant amino acids essential for the anchoring of peptides in the classical class I groove are not conserved in some subfamilies, but the class Ib genes are nevertheless more closely related in the PBR to classical and non-classical genes linked to the MHC in mammals and birds than to any other described class I genes like CD1 and the neonatal rat intestinal Fc receptor. Comparison with the Xenopus MHC-linked class Ia protein indicate that amino acids presumed to interact with beta 2-microglobulin are identical or conservatively changed in the two major class I families. Genomic analyses of Xenopus species suggest that the classical and non-classical families diverged from a common ancestor before the emergence of the genus Xenopus over 100 million years ago; all of the non-classical genes appear to be linked on a chromosome distinct from the one harboring the MHC. We hypothesize that this class Ib gene family is under very different selection pressures from the classical MHC genes, and that each subfamily may have evolved for a particular function. Images PMID:8223448

  6. Two novel mutations in myosin binding protein C slow causing distal arthrogryposis type 2 in two large Han Chinese families may suggest important functional role of immunoglobulin domain C2.

    PubMed

    Li, Xuefu; Zhong, Bomeng; Han, Weitian; Zhao, Ning; Liu, Wei; Sui, Yu; Wang, Yawen; Lu, Yongping; Wang, Hong; Li, Jianxin; Jiang, Miao

    2015-01-01

    Distal arthrogryposes (DAs) are a group of disorders that mainly involve the distal parts of the limbs and at least ten different DAs have been described to date. DAs are mostly described as autosomal dominant disorders with variable expressivity and incomplete penetrance, but recently autosomal recessive pattern was reported in distal arthrogryposis type 5D. Mutations in the contractile genes are found in about 50% of all DA patients. Of these genes, mutations in the gene encoding myosin binding protein C slow MYBPC1 were recently identified in two families with distal arthrogryposis type 1B. Here, we described two large Chinese families with autosomal dominant distal arthrogryposis type 2(DA2) with incomplete penetrance and variable expressivity. Some unique overextension contractures of the lower limbs and some distinctive facial features were present in our DA2 pedigrees. We performed follow-up DNA sequencing after linkage mapping and first identified two novel MYBPC1 mutations (c.1075G>A [p.E359K] and c.956C>T [p.P319L]) responsible for these Chinese DA2 families of which one introduced by germline mosacism. Each mutation was found to cosegregate with the DA2 phenotype in each family but not in population controls. Both substitutions occur within C2 immunoglobulin domain, which together with C1 and the M motif constitute the binding site for the S2 subfragment of myosin. Our results expand the phenotypic spectrum of MYBPC1-related arthrogryposis multiplex congenita (AMC). We also proposed the possible molecular mechanisms that may underlie the pathogenesis of DA2 myopathy associated with these two substitutions in MYBPC1. PMID:25679999

  7. Deep RNA-Seq profile reveals biodiversity, plant-microbe interactions and a large family of NBS-LRR resistance genes in walnut (Juglans regia) tissues.

    PubMed

    Chakraborty, Sandeep; Britton, Monica; Martínez-García, P J; Dandekar, Abhaya M

    2016-12-01

    Deep RNA-Seq profiling, a revolutionary method used for quantifying transcriptional levels, often includes non-specific transcripts from other co-existing organisms in spite of stringent protocols. Using the recently published walnut genome sequence as a filter, we present a broad analysis of the RNA-Seq derived transcriptome profiles obtained from twenty different tissues to extract the biodiversity and possible plant-microbe interactions in the walnut ecosystem in California. Since the residual nature of the transcripts being analyzed does not provide sufficient information to identify the exact strain, inferences made are constrained to the genus level. The presence of the pathogenic oomycete Phytophthora was detected in the root through the presence of a glyceraldehyde-3-phosphate dehydrogenase. Cryptococcus, the causal agent of cryptococcosis, was found in the catkins and vegetative buds, corroborating previous work indicating that the plant surface supported the sexual cycle of this human pathogen. The RNA-Seq profile revealed several species of the endophytic nitrogen fixing Actinobacteria. Another bacterial species implicated in aerobic biodegradation of methyl tert-butyl ether (Methylibium petroleiphilum) is also found in the root. RNA encoding proteins from the pea aphid were found in the leaves and vegetative buds, while a serine protease from mosquito with significant homology to a female reproductive tract protease from Drosophila mojavensis in the vegetative bud suggests egg-laying activities. The comprehensive analysis of RNA-seq data present also unraveled detailed, tissue-specific information of ~400 transcripts encoded by the largest family of resistance (R) genes (NBS-LRR), which possibly rationalizes the resistance of the specific walnut plant to the pathogens detected. Thus, we elucidate the biodiversity and possible plant-microbe interactions in several walnut (Juglans regia) tissues in California using deep RNA-Seq profiling. PMID:26883051

  8. Sugar beet contains a large CONSTANS-LIKE gene family including a CO homologue that is independent of the early-bolting (B) gene locus

    PubMed Central

    Chia, T. Y. P.; Müller, A.; Jung, C.; Mutasa-Göttgens, E. S.

    2008-01-01

    Floral transition in the obligate long-day (LD) plant sugar beet (Beta vulgaris ssp. vulgaris) is tightly linked to the B gene, a dominant early-bolting quantitative trait locus, the expression of which is positively regulated by LD photoperiod. Thus, photoperiod regulators like CONSTANS (CO) and CONSTANS-LIKE (COL) genes identified in many LD and short-day (SD)-responsive plants have long been considered constituents and/or candidates for the B gene. Until now, the photoperiod response pathway of sugar beet (a Caryophyllid), diverged from the Rosids and Asterids has not been identified. Here, evidence supporting the existence of a COL gene family is provided and the presence of Group I, II, and III COL genes in sugar beet, as characterized by different zinc-finger (B-box) and CCT (CO, CO-like, TOC) domains is demonstrated. BvCOL1 is identified as a close-homologue of Group 1a (AtCO, AtCOL1, AtCOL2) COL genes, hence a good candidate for flowering time control and it is shown that it maps to chromosome II but distant from the B gene locus. The late-flowering phenotype of A. thaliana co-2 mutants was rescued by over-expression of BvCOL1 thereby suggesting functional equivalence with AtCO, and it is shown that BvCOL1 interacts appropriately with the endogenous downstream genes, AtFT and AtSOC1 in the transgenic plants. Curiously, BvCOL1 has a dawn-phased diurnal pattern of transcription, mimicking that of AtCOL1 and AtCOL2 while contrasting with AtCO. Taken together, these data suggest that BvCOL1 plays an important role in the photoperiod response of sugar beet. PMID:18495636

  9. Obsessive-compulsive symptoms in a large population-based twin-family sample are predicted by clinically based polygenic scores and by genome-wide SNPs.

    PubMed

    den Braber, A; Zilhão, N R; Fedko, I O; Hottenga, J-J; Pool, R; Smit, D J A; Cath, D C; Boomsma, D I

    2016-01-01

    Variation in obsessive-compulsive symptoms (OCS) has a heritable basis, with genetic association studies starting to yield the first suggestive findings. We contribute to insights into the genetic basis of OCS by performing an extensive series of genetic analyses in a homogeneous, population-based sample from the Netherlands. First, phenotypic and genetic longitudinal correlations over a 6-year period were estimated by modeling OCS data from twins and siblings. Second, polygenic risk scores (PRS) for 6931 subjects with genotype and OCS data were calculated based on meta-analysis results from IOCDF-GC, to investigate their predictive value. Third, the contribution of measured single nucleotide polymorphisms (SNPs) to the heritability was estimated using random-effects modeling. Last, we performed an exploratory genome-wide association study (GWAS) of OCS, testing for SNP- and for gene-based associations. Stability in OCS (test-retest correlation 0.63) was mainly explained by genetic stability. The PRS based on clinical samples predicted OCS in our population-based twin-family sample. SNP-based heritability was estimated at 14%. GWAS revealed one SNP (rs8100480), located within the MEF2BNB gene, associated with OCS (P=2.56 × 10(-8)). Additional gene-based testing resulted in four significantly associated genes, which are located in the same chromosomal region on chromosome 19p13.11: MEF2BNB, RFXANK, MEF2BNB-MEF2B and MEF2B. Thus, common genetic variants explained a significant proportion of OCS trait variation. Genes significantly associated with OCS are expressed in the brain and involved in development and control of immune system functions (RFXANK) and regulation of gene expression of muscle-specific genes (MEF2BNB). MEF2BNB also showed a suggestive association with OCD in an independent case-control study, suggesting a role for this gene in the development of OCS. PMID:26859814

  10. Reading Comprehension in a Large Cohort of French First Graders from Low Socio-Economic Status Families: A 7-Month Longitudinal Study

    PubMed Central

    Gentaz, Edouard; Sprenger-Charolles, Liliane; Theurel, Anne; Colé, Pascale

    2013-01-01

    Background The literature suggests that a complex relationship exists between the three main skills involved in reading comprehension (decoding, listening comprehension and vocabulary) and that this relationship depends on at least three other factors orthographic transparency, children’s grade level and socioeconomic status (SES). This study investigated the relative contribution of the predictors of reading comprehension in a longitudinal design (from beginning to end of the first grade) in 394 French children from low SES families. Methodology/Principal findings Reading comprehension was measured at the end of the first grade using two tasks one with short utterances and one with a medium length narrative text. Accuracy in listening comprehension and vocabulary, and fluency of decoding skills, were measured at the beginning and end of the first grade. Accuracy in decoding skills was measured only at the beginning. Regression analyses showed that listening comprehension and decoding skills (accuracy and fluency) always significantly predicted reading comprehension. The contribution of decoding was greater when reading comprehension was assessed via the task using short utterances. Between the two assessments, the contribution of vocabulary, and of decoding skills especially, increased, while that of listening comprehension remained unchanged. Conclusion/Significance These results challenge the ‘simple view of reading’. They also have educational implications, since they show that it is possible to assess decoding and reading comprehension very early on in an orthography (i.e., French), which is less deep than the English one even in low SES children. These assessments, associated with those of listening comprehension and vocabulary, may allow early identification of children at risk for reading difficulty, and to set up early remedial training, which is the most effective, for them. PMID:24250802

  11. Family size and delinquency.

    PubMed

    Fischer, D G

    1984-04-01

    A review of the literature shows that large family size is related to greater delinquency. The relationship remains when a number of variables, i.e., income, socioeconomic status, parental criminality, and family composition, have been controlled. The higher birth rate for lower classes does not appear to be an adequate explanation for this relationship, nor does less close parent-child affectional ties or less parental supervision although all of these may have some influence. The presence of an "infectious example" may partly account for the relationship, as does overcrowding. Large family size is typically associated with the constellation of undesirable family conditions involving poor role models (e.g., poor parental behaviour, parental criminality, sibling delinquency), poor child-rearing practices (e.g., inadequate parental supervision and discipline), and competition for physical (e.g., overcrowding, low income) and psychological (e.g., lack of attention, affection, family interaction) resources. An immediate solution is to reduce the size of families by helping prospective parents plan their families, and for those who wish it, making medical abortions more readily available. The long-range solution is through research to identify variables which significantly influence the relationship between family size and delinquency. Such studies must control for birth order, sibling spacing, siblings' sex, and sex of the delinquents in these families. PMID:6377225

  12. A family with complement factor D deficiency

    PubMed Central

    Biesma, Douwe H.; Hannema, André J.; van Velzen-Blad, Heleen; Mulder, Leontine; van Zwieten, Rob; Kluijt, Irma; Roos, Dirk

    2001-01-01

    A complement factor D deficiency was found in a young woman who had experienced a serious Neisseria meningitidis infection, in a deceased family member with a history of meningitis, and in three relatives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils. The alternative pathway-dependent hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified factor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D. The gene encoding factor D was found to contain a point mutation that changed the TCG codon for serine 42 into a TAG stop codon. This mutation was found in both alleles of the five completely factor D–deficient family members and in one allele of 21 other members of the same family who had decreased or low-normal factor D levels in their serum. The gene sequence of the signal peptide of human factor D was also identified. Our report is the first, to our knowledge, to document a Factor D gene mutation. The mode of inheritance of factor D deficiency is autosomal recessive, in accordance with the localization of the Factor D gene on chromosome 19. Increased susceptibility for infections in individuals with a partial factor D deficiency is unlikely. PMID:11457876

  13. Late Embryogenesis Abundant (LEA) Constitutes a Large and Diverse Family of Proteins Involved in Development and Abiotic Stress Responses in Sweet Orange (Citrus sinensis L. Osb.)

    PubMed Central

    Pedrosa, Andresa Muniz; Martins, Cristina de Paula Santos; Gonçalves, Luana Pereira; Costa, Marcio Gilberto Cardoso

    2015-01-01

    Late Embryogenesis Abundant (LEA) proteins are an ubiquitous group of polypeptides that were first described to accumulate during plant seed dehydration, at the later stages of embryogenesis. Since then they have also been recorded in vegetative plant tissues experiencing water limitation and in anhydrobiotic bacteria and invertebrates and, thereby, correlated with the acquisition of desiccation tolerance. This study provides the first comprehensive study about the LEA gene family in sweet orange (Citrus sinensis L. Osb.), the most important and widely grown fruit crop around the world. A surprisingly high number (72) of genes encoding C. sinensis LEAs (CsLEAs) were identified and classified into seven groups (LEA_1, LEA_2, LEA_3 and LEA_4, LEA_5, DEHYDRIN and SMP) based on their predicted amino acid sequences and also on their phylogenetic relationships with the complete set of Arabidopsis thaliana LEA proteins (AtLEAs). Approximately 60% of the CsLEAs identified in this study belongs to the unusual LEA_2 group of more hydrophobic LEA proteins, while the other LEA groups contained a relatively small number of members typically hydrophilic. A correlation between gene structure and motif composition was observed within each LEA group. Investigation of their chromosomal localizations revealed that the CsLEAs were non-randomly distributed across all nine chromosomes and that 33% of all CsLEAs are segmentally or tandemly duplicated genes. Analysis of the upstream sequences required for transcription revealed the presence of various stress-responsive cis-acting regulatory elements in the promoter regions of CsLEAs, including ABRE, DRE/CRT, MYBS and LTRE. Expression analysis using both RNA-seq data and quantitative real-time RT-PCR (qPCR) revealed that the CsLEA genes are widely expressed in various tissues, and that many genes containing the ABRE promoter sequence are induced by drought, salt and PEG. These results provide a useful reference for further exploration of the CsLEAs functions and applications on crop improvement. PMID:26700652

  14. Cancer, Families, and Family Counselors.

    ERIC Educational Resources Information Center

    Duffy, Maureen; Gillig, Scott

    2003-01-01

    Examines the role of the family counselor in working with cancer patients and their families. Suggests ways in which the family counselor can work proactively with families in the area of cancer prevention and helping them cope more effectively with its impact on their lives. Uses a clinical case example to illustrate intervention with cancer…

  15. Cancer, Families, and Family Counselors.

    ERIC Educational Resources Information Center

    Duffy, Maureen; Gillig, Scott

    2003-01-01

    Examines the role of the family counselor in working with cancer patients and their families. Suggests ways in which the family counselor can work proactively with families in the area of cancer prevention and helping them cope more effectively with its impact on their lives. Uses a clinical case example to illustrate intervention with cancer…

  16. Familial Amyloidosis Cutis Dyschromica in Three Siblings: Report from Indonesia

    PubMed Central

    Hermawan, Melyawati; Rihatmadja, Rahadi; Sirait, Sondang Pandjaitan

    2014-01-01

    Amyloidosis cutis dyschromica (ACD) is an extremely rare type of primary cutaneous amyloidosis. To date there are fewer than 40 published cases worldwide; some were reported affecting several family members. Its resemblance to other common pigmentation disorders makes it rarely recognized at first sight. Our patient, the 12-year-old firstborn son of non-consanguineous parents presented with generalized mottled pigmentation starting from lower extremities. His siblings suffered from similar condition. The clue for diagnosis is the amyloid deposition in the papillary dermis. The etiology of ACD is still unknown, but genetic factors and ultraviolet radiation are implicated. It is proposed that disturbance of keratinocyte repair following ultraviolet radiation results in amyloid deposition. The treatment remains a challenge. Oral acitretin treatment, thought to repair keratinization defect, gave a slight improvement in our case. Our is the first case of ACD reported in Indonesia. PMID:25386328

  17. Family Violence and Family Physicians

    PubMed Central

    Herbert, Carol P.

    1991-01-01

    The acronym IDEALS summarizes family physicians' obligations when violence is suspected: to identify family violence; document injuries; educate families and ensure safety for victims; access resources and coordinate care; co-operate in the legal process; and provide support for families. Failure to respond reflects personal and professional experience and attitudes, fear of legal involvement, and lack of knowledge. Risks of intervention include physician burnout, physician overfunctioning, escalation of violence, and family disruption. PMID:21228987

  18. Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency

    SciTech Connect

    Cogan, J.D.; Phillips, J.A. III; Sakati, N.; Frisch, H.; Schober, E.; Milner, R.D.G. )

    1993-05-01

    The GH1 genes of probands of two families with familial isolated GH deficiency (IGHD) were sequenced. Double stranded sequencing of the polymerase chain reaction (PCR) amplification products from genomic DNA of two affected cousins in a consanguineous Turkish family revealed a G[yields]A transition in the 20th codon of the GH1 signal peptide. This substitution converts a TGG (Trp) to a TAG (stop) codon and generates a new AluI recognition site. PCR amplification of the GH1 alleles of family members, followed by AluI digestion, revealed that the G[yields]A transition segregated with the IGHD phenotype. In a Saudi Arabian family, a G[yields]C transversion was found that alters the first base of the donor splice site of intron IV. This substitution should perturb mRNA splicing, resulting in an altered protein product which should be unstable or bioinactive. This transversion also destroys an HphI site, which was used to assay samples from relatives. Digestion of PCR amplification products with HphI demonstrated cosegregation of the G[yields]C transversion with IGHD. These results demonstrate that in the expression of the GH1 gene. 24 refs., 5 figs., 1 tab.

  19. Homozygosity mapping reveals novel and known mutations in Pakistani families with inherited retinal dystrophies

    PubMed Central

    Saqib, Muhammad Arif Nadeem; Nikopoulos, Konstantinos; Ullah, Ehsan; Sher Khan, Falak; Iqbal, Jamila; Bibi, Rabia; Jarral, Afeefa; Sajid, Sundus; Nishiguchi, Koji M.; Venturini, Giulia; Ansar, Muhammad; Rivolta, Carlo

    2015-01-01

    Inherited retinal dystrophies are phenotypically and genetically heterogeneous. This extensive heterogeneity poses a challenge when performing molecular diagnosis of patients, especially in developing countries. In this study, we applied homozygosity mapping as a tool to reduce the complexity given by genetic heterogeneity and identify disease-causing variants in consanguineous Pakistani pedigrees. DNA samples from eight families with autosomal recessive retinal dystrophies were subjected to genome wide homozygosity mapping (seven by SNP arrays and one by STR markers) and genes comprised within the detected homozygous regions were analyzed by Sanger sequencing. All families displayed consistent autozygous genomic regions. Sequence analysis of candidate genes identified four previously-reported mutations in CNGB3, CNGA3, RHO, and PDE6A, as well as three novel mutations: c.2656C?>?T (p.L886F) in RPGRIP1, c.991G?>?C (p.G331R) in CNGA3, and c.413-1G?>?A (IVS6-1G?>?A) in CNGB1. This latter mutation impacted pre-mRNA splicing of CNGB1 by creating a -1 frameshift leading to a premature termination codon. In addition to better delineating the genetic landscape of inherited retinal dystrophies in Pakistan, our data confirm that combining homozygosity mapping and candidate gene sequencing is a powerful approach for mutation identification in populations where consanguineous unions are common. PMID:25943428

  20. Familial Gigantiform Cementoma: Case Report of an Unusual Clinical Manifestation and Possible Mechanism Related To "Calcium Steal Disorder".

    PubMed

    Ma, Chunyue; Wang, Hongwei; He, Guang; Qin, Xingjun

    2016-03-01

    Familial gigantiform cementoma is an exceedingly rare but distinct subtype of cemento-osseous-fibrous lesion. Undocumented radiographic changes and related bone metabolism disorder are herein hypothesized and discussed.We present an adolescent case with recurrent familial gigantiform cementoma who received surgical intervention in our hospital. Apart from typical multiquadrant and expansile abnormalies involving both jaws, he also suffered from several times of fractures in lower extremity. Furthermore, radiographic examinations of calvaria, pelvis, femoris, tibia, and fibula all revealed radiolucent areas signifying diffuse osteopenic bone losses. Some of his consanguineous relatives bore the same burden of fractures during pubertal period.Considering these polyostotic conditions, a correlation of congenital bone metabolism disorder in cases with familial gigantiform cementoma, named "calcium steal disorder," was thus proposed.Familial gigantiform cementoma is closely associated with "calcium steal disorder." Whole-body dual-energy absorptiometry should be considered as a routine examination for fracture-related risk prediction. PMID:26945411

  1. Rural Families.

    ERIC Educational Resources Information Center

    Goetz, Kathy, Ed.

    1992-01-01

    This "special focus" journal issue consists of 13 individual articles on the theme of rural family programs relating to school, health services, church, and other institutions. It includes: (1) "Towards a Rural Family Policy" (Judith K. Chynoweth and Michael D. Campbell); (2) "Montana: Council for Families Collaborates for Prevention (Jean…

  2. Family Involvement.

    ERIC Educational Resources Information Center

    Liontos, Lynn Balster

    1992-01-01

    Family involvement in schools will work only when perceived as an enlarged concept focusing on all children, including those from at-risk families. Each publication reviewed here is specifically concerned with family involvement strategies concerned with all children or targeted at primarily high risk students. Susan McAllister Swap looks at three…

  3. Family Support.

    ERIC Educational Resources Information Center

    Wieck, Colleen, Ed.; McBride, Marijo, Ed.

    1990-01-01

    This "Feature Issue" of the quarterly journal "Impact" presents 19 brief articles on family support systems in the United States for persons with developmental disabilities and their families. Emphasis is on provisions of Public Law 99-457. Articles include: "Family Support in the United States: Setting a Course for the 1990s" (James Knoll);…

  4. The mouse DNA binding protein Rc for the kappa B motif of transcription and for the V(D)J recombination signal sequences contains composite DNA-protein interaction domains and belongs to a new family of large transcriptional proteins

    SciTech Connect

    Wu, Lai-Chu; Liu, Yiling; Li, Zhiling

    1996-08-01

    Rc is a DNA binding protein with dual specificities for the V(D)J recombination signal sequences and for the B motif of the immunoglobulin kappa chain gene enhancer. The largest Rc transcript present in lymphoid cells/tissues is {approximately} 9 kb. Molecular cloning and sequence determination for 8822 bp of mouse Rc cDNA revealed an open reading frame of 2282 amino acids and long 5{prime}- and 3{prime}- untranslated regions. The derived amino acid sequence contains multiple DNA and protein interaction domains. Composite ZAS structures with tandem zinc fingers, and acidic motif, and a Ser/Thr-rich segment are located near the N-terminal and the C-terminal regions. The middle region of Rc contains a lone zinc finger, an acidic motif, a Ser-rich region, a nucleus localization signal, and GTPase motifs. Cloning and characterization of a mouse Rc gene show that the Rc cDNA corresponds to seven exons located in a genomic region spanning 70 kb. Exon 2 is exceptionally large, with 5487 bp. cDNA cloning and Northern blot analyses revealed multiple Rc transcripts, probably generated by alternative splicings. Sequence comparisons show that Rc belongs to a ZAS protein family that is involved in gene transcription and/or DNA recombination. The major histocompatibility complex class I gene enhancer binding proteins MBP1 and MBP2 are other representatives of this ZAS protein family. 43 refs., 6 figs., 2 tabs.

  5. Synthesis, structure, and magnetism of a family of heterometallic {Cu2Ln7} and {Cu4Ln12} (Ln = Gd, Tb, and Dy) complexes: the Gd analogues exhibiting a large magnetocaloric effect.

    PubMed

    Langley, Stuart K; Moubaraki, Boujemaa; Tomasi, Corrado; Evangelisti, Marco; Brechin, Euan K; Murray, Keith S

    2014-12-15

    The syntheses, structures, and magnetic properties of two heterometallic Cu(II)-Ln(III) (Ln(III) = Gd, Tb, and Dy) families, utilizing triethanolamine and carboxylate ligands, are reported. The first structural motif displays a nonanuclear {Cu(II)2Ln(III)7} metallic core, while the second reveals a hexadecanuclear {Cu(II)4Ln(III)12} core. The differing nuclearities of the two families stem from the choice of carboxylic acid used in the synthesis. Magnetic studies show that the most impressive features are displayed by the {Cu(II)2Gd(III)7} and {Cu(II)4Gd(III)12} complexes, which display a large magnetocaloric effect, with entropy changes -?Sm = 34.6 and 33.0 J kg(-1) K(-1) at T = 2.7 and 2.9 K, respectively, for a 9 T applied field change. It is also found that the {Cu(II)4Dy(III)12} complex displays single-molecule magnet behavior, with an anisotropy barrier to magnetization reversal of 10.1 K. PMID:25494949

  6. What makes a family reliable?

    NASA Technical Reports Server (NTRS)

    Williams, James G.

    1992-01-01

    Asteroid families are clusters of asteroids in proper element space which are thought to be fragments from former collisions. Studies of families promise to improve understanding of large collision events and a large event can open up the interior of a former parent body to view. While a variety of searches for families have found the same heavily populated families, and some searches have found the same families of lower population, there is much apparent disagreement between proposed families of lower population of different investigations. Indicators of reliability, factors compromising reliability, an illustration of the influence of different data samples, and a discussion of how several investigations perceived families in the same region of proper element space are given.

  7. Molecular analysis reveals a high mutation frequency in the first untranslated exon of the PPOX gene and largely excludes variegate porphyria in a subset of clinically affected Afrikaner families.

    PubMed

    Kotze, M J; De Villiers, J N; Groenewald, J Z; Rooney, R N; Loubser, O; Thiart, R; Oosthuizen, C J; van Niekerk, M M; Groenewald, I M; Retief, A E; Warnich, L

    1998-10-01

    A subset of probands from 11 South African families with clinical and/or biochemical features of variegate porphyria (VP), but without the known protoporphyrinogen oxidase (PPOX) gene defects identified previously in the South African population, were subjected to mutation analysis. Disease-related mutation(s) could not be identified after screening virtually the entire PPOX gene by heteroduplex single-strand conformation polymorphism analysis (HEX-SSCP), although three new sequence variants were detected in exon 1 of the gene in three normal controls. The presence of these single base changes at nucleotide positions 22 (C/G), 27 (C/A) and 127 (C/A), in addition to the known exon 1 polymorphisms I-26 and I-150, indicates that this untranslated region of the PPOX gene is particularly mutation-prone. Furthermore, microsatellite markers flanking the PPOX and alpha-1 antitrypsin (PI) gene, on chromosomes 1 and 14, respectively, were used to assess the probability of involvement of these loci in disease presentation. Common alleles transmitted from affected parent to affected child were determined where possible in the mutation-negative index cases. Allelic frequencies of these alleles were compared to findings in the normal population, but no predominant disease-associated allele could be identified. Co-segregation of a specific haplotype with the disease phenotype could also not be demonstrated in a large Afrikaner family. It is concluded that further studies are warranted to determine the genetic factor(s) underlying the autosomal dominant pattern of inheritance in molecularly uncharacterized cases showing clinical symptoms of an acute porphyria. PMID:9778454

  8. 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. PMID:25936346

  9. Ethnic family structure.

    PubMed

    Mcdonald, P

    1989-04-01

    Using information from large-scale statistical collections and elaborations from ethnographic studies, this paper examines the underlying social processes and structures of migrant families in Australia. Migrants in Australia are often confronted by family values and behavior which run counter to their own. For some migrants, particularly those from the United Kingdom and Western European countries, there is little conflict as Australian family values and behavior approximate their own; the feminine conception of the family is not foreign to them. On the other hand, migrants from Mediterranean countries and from Asia are likely to face a clash between the masculine conception of the family and the dominant feminine conception they find in Australia. Economic structure also often forces an accommodation to the feminine conception of the family. For example, migrant women in Australia are heavily involved in the work force outside the family circle, and, in the main, have relatively low fertility. Age at marriage is increasing and many single women of migrant origin are being educated at the tertiary level and are working before marriage. These changes necessarily expose women and youths to the dominant social values and increase their economic independence, thus disrupting the conventional male family authority. There is evidence of a degree of accommodation to Australian patterns of behavior in migrant groups more inclined to a masculine conception of the family. In other areas, however, which are less directly related to economic pressure, migrant values have been far less accommodating. There is still a high level of endogamy, the 1st birth occurs soon after marriage, divorce rates are low, and the aged are very likely to live with their children. Large migrant groups have been able to maintain these patterns of behavior through the formation of ethnic substructures that form their principal social environment. In the longer term, however, their children are deeply exposed to the dominant Australian social environment. PMID:12282096

  10. Family Potyviridae

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The International Committee on the Taxonomy of Viruses potyvirus study group has revised the description of the family Potyviridae for inclusion in the ICTV 9th report. Characteristic features of each genus within the family is presented. Revised criteria for demarcation and nomenclature of viral sp...

  11. Family Life.

    ERIC Educational Resources Information Center

    Naturescope, 1986

    1986-01-01

    Focuses on various aspects of mammal family life ranging from ways different species are born to how different mammals are raised. Learning activities include making butter from cream, creating birth announcements for mammals, and playing a password game on family life. (ML)

  12. Family, Extended

    ERIC Educational Resources Information Center

    Patton, Jessica Rae

    2006-01-01

    Parents are a child's first and most influential teacher. People hear this truism often, yet nowhere has the author seen it more taken to heart than at Tower Street Elementary School. The school's efforts to form a true partnership with students' families--from involving families in the first day of school, to the principal making home visits, to…

  13. FAMILY POTYVIRIDAE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The International Committee on the Taxonomy of Viruses potyvirus study group has revised the description of the family Geminiviridae for inclusion in the ICTV 8th report. Characteristic features of each genus within the family is presented. Revised criteria for demarcation and nomenclature of vira...

  14. Family Workshops

    ERIC Educational Resources Information Center

    Bennett, Dave; Rees-Jones, Tanny

    1978-01-01

    A Family Workshop is an informal, multidisciplined educational program for adults and children, organized by a team of teachers. This article discusses the Lavender Hill Family Workshop, one of many, which attempts to provide education in various subject areas for adults and for children while also integrating both objectives in order to educate…

  15. Family Empowerment.

    ERIC Educational Resources Information Center

    Sinclair, Mary F., Ed.; And Others

    1992-01-01

    This feature issue of IMPACT focuses on the empowerment of families with a member who has a developmental disability. It presents strategies and models for a collaborative, respectful approach to service provision, and presents the experiences of families in seeking support and assistance. Feature articles include "Two Generations of Disability: A…

  16. FAMILY GEMINIVIRIDAE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The International Committee on the Taxonomy of Viruses geminivirus study group has revised the description of the family Geminiviridae for inclusion in the ICTV 8th report. Characteristic features of each genus within the family is presented. Revised criteria for demarcation and nomenclature of vi...

  17. Family Theory and Family Health Research

    PubMed Central

    Doherty, William J.

    1991-01-01

    Different family theories can be applied to different aspects of how families experience health and illness. The family health and illness cycle describes the phases of a family's experience, beginning with health promotion and risk reduction, then family vulnerability and disease onset or relapse, family illness appraisal, family acute response, and finally family adaptation to illness and recovery. For each phase, specific family theories that are most appropriate for guiding family and health research are discussed. PMID:21229056

  18. The sodium-phosphate co-transporter SLC34A2, and pulmonary alveolar microlithiasis: Presentation of an inbred family and a novel truncating mutation in exon 3

    PubMed Central

    Vismara, Marco Favio Michele; Colao, Emma; Fabiani, Fernanda; Bombardiere, Francesco; Tamburrini, Oscar; Alessio, Caterina; Manti, Francesco; Pelaia, Gerolamo; Romeo, Pasquale; Iuliano, Rodolfo; Perrotti, Nicola

    2015-01-01

    Pulmonary alveolar microlithiasis is a disorder in which many tiny fragments (microliths) of calcium phosphate gradually accumulate in alveoli. Loss of function mutations in the gene SLC34A2 coding for the sodium phosphate co-transporter (NaPi-IIb) are responsible for genetic forms of alveolar microlithiasis. We now report a consanguineous Italian family from Calabria with two affected members segregating alveolar microlithiasis in a recessive fashion. We describe, for the first time, a novel loss of function mutation in the gene coding for NaPi-IIb. A careful description of the clinical phenotype is provided together with technical details for direct sequencing of the gene. PMID:26744662

  19. Family Health and Family Planning.

    ERIC Educational Resources Information Center

    World Health Organization, Copenhagen (Denmark). Regional Office for Europe.

    This document is made up of a selection of some of the papers distributed to participants in courses on "Family Health and Family Planning" which have been organized each year since 1973 by the International Children's Center and the World Health Organization Regional Office for Europe. Six courses, held between 1973 and 1978, brought together a…

  20. Family Health and Family Planning.

    ERIC Educational Resources Information Center

    World Health Organization, Copenhagen (Denmark). Regional Office for Europe.

    This document is made up of a selection of some of the papers distributed to participants in courses on "Family Health and Family Planning" which have been organized each year since 1973 by the International Children's Center and the World Health Organization Regional Office for Europe. Six courses, held between 1973 and 1978, brought together a…

  1. Development and characterisation of 20 microsatellite loci isolated from the large bent-wing bat, Miniopterus schreibersii (Chiroptera: Miniopteridae) and their cross-taxa utility in the family Miniopteridae.

    PubMed

    Wood, Rebecca; Weyeneth, Nicole; Appleton, Belinda

    2011-07-01

    The large bent-wing bat, Miniopterus schreibersii (Kuhl 1819), has a long history of taxonomic uncertainty and many populations are known to be in a state of decline. Microsatellite loci were developed for the taxonomic and population genetic assessment of the Australian complex of this species. Of the 33 primer sets designed for this research, seven (21%) were deemed suitably polymorphic for population-level analyses of the Australian taxa, with five (71%) of these loci revealing moderate to high levels of polymorphism (PIC = 0.56 to 0.91). The cross-taxa utility of the M. schreibersii microsatellite markers was assessed in the microbat (Chiroptera) family Miniopteridae. Sub-species and species covering the Miniopteridae's global distribution (with the exception of the Middle East) were selected, numbering 25 taxa in total. Amplification was successful for 26 loci, of which 20 (77%) were polymorphic. High cross-taxa utility of markers was observed with amplification achieved for all taxa for between four (20%) and 20 (100%) loci, and polymorphism was considered moderate to high (PIC = 0.47-0.91) for 12 (60%) of these loci. The high cross-taxa utility of the microsatellites reported herein reveal versatile and cost-effective molecular markers, contributing an important genetic resource for the research and conservation of Miniopteridae species worldwide. PMID:21676197

  2. Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664----leu mutation in the LDL receptor gene.

    PubMed Central

    Soutar, A K; McCarthy, S N; Seed, M; Knight, B L

    1991-01-01

    In a large kindred of 66 individuals, 22 were identified as heterozygous and 3 as homozygous for a mutation (pro664----leu) in the LDL-receptor gene that gives rise to familial hypercholesterolaemia (FH). All the heterozygotes had a raised level of plasma total cholesterol and low density lipoprotein cholesterol, but were remarkably free from premature coronary disease. Determination of apolipoprotein(a) (apo(a)) phenotype and lipoprotein(a) (Lp(a)) concentration in plasma revealed that in many instances, involving individuals with various apo(a) phenotypes, there was no difference in plasma Lp(a) concentration between an FH heterozygote and an unaffected sibling with the same apo(a) phenotype. No significant difference in Lp(a) concentration was observed between groups of FH and non-FH of the same apo(a) phenotype, although in each case the mean value for the FH group was greater than that for the non-FH group. There was also evidence for an inherited trait that markedly increased Lp(a) concentration, which did not segregate with apo(a) phenotype or the defective LDL-receptor allele. The data provide no evidence for a strong multiplicative interaction between the gene loci for apo(a) and the LDL receptor. Images PMID:1830890

  3. Family acholeplasmataceae (including phytoplasmas)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The family Acholeplasmataceae was originally established to accommodate the genus Acholeplasma, comprising the mollicutes that could be cultivated without the supplement of cholesterol and that use UGA as a stop codon instead of coding for tryptophan. It was later shown that the phytoplasmas, a larg...

  4. Family Meals

    MedlinePLUS

    ... keep tension and discipline at a minimum during mealtime. The focus should remain on making your kids feel loved, connected, and part of the family. Keep the interactions positive and let the conversation ...

  5. Family History

    MedlinePLUS

    ... Sign-Up Contact Us Understanding Brain Aneurysm Basics Warning Signs/Symptoms Brain Aneurysm Statistics and Facts Seeking Medical Attention Pediatric Aneurysms Brain Aneurysm Causes and Risk Factors Family History Early Detection and Screening Unruptured Brain Aneurysms Subarachnoid Hemorrhage ...

  6. 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. PMID:26308914

  7. 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

  8. Population Landscape of Familial Cancer

    PubMed Central

    Frank, C.; Fallah, M.; Sundquist, J.; Hemminki, A.; Hemminki, K.

    2015-01-01

    Public perception and anxiety of familial cancer have increased demands for clinical counseling, which may be well equipped for gene testing but less prepared for counseling of the large domain of familial cancer with unknown genetic background. The aim of the present study was to highlight the full scope of familial cancer and the variable levels of risk that need to be considered. Data on the 25 most common cancers were obtained from the Swedish Family Cancer Database and a Poisson regression model was applied to estimate relative risks (RR) distinguishing between family histories of single or multiple affected first-degree relatives and their diagnostic ages. For all cancers, individual risks were significantly increased if a parent or a sibling had a concordant cancer. While the RRs were around 2.00 for most cancers, risks were up to 10-fold increased for some cancers. Familial risks were even higher when multiple relatives were affected. Although familial risks were highest at ages below 60 years, most familial cases were diagnosed at older ages. The results emphasized the value of a detailed family history as a readily available tool for individualized counseling and its preventive potential for a large domain of non-syndromatic familial cancers. PMID:26256549

  9. A novel family of insect-selective peptide neurotoxins targeting insect large-conductance calcium-activated K+ channels isolated from the venom of the theraphosid spider Eucratoscelus constrictus.

    PubMed

    Windley, Monique J; Escoubas, Pierre; Valenzuela, Stella M; Nicholson, Graham M

    2011-07-01

    Spider venoms are actively being investigated as sources of novel insecticidal agents for biopesticide engineering. After screening 37 theraphosid spider venoms, a family of three new "short-loop" inhibitory cystine knot insecticidal toxins (?-TRTX-Ec2a, ?-TRTX-Ec2b, and ?-TRTX-Ec2c) were isolated and characterized from the venom of the African tarantula Eucratoscelus constrictus. Whole-cell patch-clamp recordings from cockroach dorsal unpaired median neurons revealed that, despite significant sequence homology with other theraphosid toxins, these 29-residue peptides lacked activity on insect voltage-activated sodium and calcium channels. It is noteworthy that ?-TRTX-Ec2 toxins were all found to be high-affinity blockers of insect large-conductance calcium-activated K(+) (BK(Ca)) channel currents with IC(50) values of 3 to 25 nM. In addition, ?-TRTX-Ec2a caused the inhibition of insect delayed-rectifier K(+) currents, but only at significantly higher concentrations. ?-TRTX-Ec2a and ?-TRTX-Ec2b demonstrated insect-selective effects, whereas the homologous ?-TRTX-Ec2c also resulted in neurotoxic signs in mice when injected intracerebroventricularly. Unlike other theraphosid toxins, ?-TRTX-Ec2 toxins induce a voltage-independent channel block, and therefore, we propose that these toxins interact with the turret and/or loop region of the external entrance to the channel and do not project deeply into the pore of the channel. Furthermore, ?-TRTX-Ec2a and ?-TRTX-Ec2b differ from other theraphotoxins at the C terminus and positions 5 to 6, suggesting that these regions of the peptide contribute to the phyla selectivity and are involved in targeting BK(Ca) channels. This study therefore establishes these toxins as tools for studying the role of BK(Ca) channels in insects and lead compounds for the development of novel insecticides. PMID:21447641

  10. Unusual evolutionary conservation and further species-specific adaptations of a large family of Nonclassical MHC class Ib genes across different degrees of genome ploidy in the amphibian subfamily Xenopodinae

    PubMed Central

    Edholm, Eva-Stina; Goyos, Ana; Taran, Joseph; De Jesús Andino, Francisco; Ohta, Yuko; Robert, Jacques

    2014-01-01

    Nonclassical MHC class Ib (class Ib) genes are a family of highly diverse and rapidly evolving genes wherein gene numbers, organization and expression markedly differ even among closely related species rendering class Ib phylogeny difficult to establish. Whereas among mammals there are few unambiguous class Ib gene orthologs, different amphibian species belonging to the anuran subfamily Xenopodinae exhibit an unusually high degree of conservation among multiple class Ib gene lineages. Comparative genomic analysis of class Ib gene loci of two divergent (~65 million years) Xenopodinae subfamily members X. laevis (allotetraploid) and X. tropicalis (diploid) shows that both species possess a large cluster of class Ib genes denoted as Xenopus/Silurana nonclassical (XNC/SNC). Our study reveals two distinct phylogenetic patterns among these genes: some gene lineages display a high degree of flexibility, as demonstrated by species-specific expansion and contractions, whereas other class Ib gene lineages have been maintained as monogenic subfamilies with very few changes in their nucleotide sequence across divergent species. In this second category, we further investigated the XNC/SNC10 gene lineage that in X. laevis is required for the development of a distinct semi-invariant T cell population. We report compelling evidence of the remarkable high degree of conservation of this gene lineage that is present in all 12 species of the Xenopodinae examined, including species with different degrees of ploidy ranging from 2, 4, 8 to 12N. This suggests that the critical role of XNC10 during early T cell development is conserved in amphibians. PMID:24771209

  11. Homozygosity mapping in autosomal recessive retinitis pigmentosa families detects novel mutations

    PubMed Central

    Marzouka, Nour al Dain; Hebrard, Maxime; Manes, Gaël; Sénéchal, Audrey; Meunier, Isabelle; Hamel, Christian P.

    2013-01-01

    Purpose Autosomal recessive retinitis pigmentosa (arRP) is a genetically heterogeneous disease resulting in progressive loss of photoreceptors that leads to blindness. To date, 36 genes are known to cause arRP, rendering the molecular diagnosis a challenge. The aim of this study was to use homozygosity mapping to identify the causative mutation in a series of inbred families with arRP. Methods arRP patients underwent standard ophthalmic examination, Goldman perimetry, fundus examination, retinal OCT, autofluorescence measurement, and full-field electroretinogram. Fifteen consanguineous families with arRP excluded for USH2A and EYS were genotyped on 250 K SNP arrays. Homozygous regions were listed, and known genes within these regions were PCR sequenced. Familial segregation and mutation analyzes were performed. Results We found ten mutations, seven of which were novel mutations in eight known genes, including RP1, IMPG2, NR2E3, PDE6A, PDE6B, RLBP1, CNGB1, and C2ORF71, in ten out of 15 families. The patients carrying RP1, C2ORF71, and IMPG2 mutations presented with severe RP, while those with PDE6A, PDE6B, and CNGB1 mutations were less severely affected. The five families without mutations in known genes could be a source of identification of novel genes. Conclusions Homozygosity mapping combined with systematic screening of known genes results in a positive molecular diagnosis in 66.7% of families. PMID:24339724

  12. Family violence.

    PubMed

    Emery, R E

    1989-02-01

    Researchers and policymakers have begun to recognize the extent and severity of family violence in recent years, particularly its effects on children. Despite a flurry of research, however, there is much disagreement about the definition of violence, its development, the consequences for victims, and the most effective avenues for intervention. Similar conceptual, methodological, and practical problems are faced by those working in the areas of physical child abuse, child sex abuse, and child witnesses to spouse abuse. In further research on these complex problems, researchers are encouraged to use operational definitions that avoid terms like abuse and violence, to focus new efforts on emotional mediators of violent actions, to evaluate the effects of violence on the entire family system, and to redouble efforts to conduct systematic outcome research. Those professionals who are currently responsible for intervention are encouraged to use definitions of and responses to family violence that match those used for assaults between strangers. PMID:2653142

  13. Familial hypercholesterolemia.

    PubMed

    Bouhairie, Victoria Enchia; Goldberg, Anne Carol

    2015-05-01

    Familial hypercholesterolemia is a common, inherited disorder of cholesterol metabolism that leads to early cardiovascular morbidity and mortality. It is underdiagnosed and undertreated. Statins, ezetimibe, bile acid sequestrants, niacin, lomitapide, mipomersen, and low-density lipoprotein (LDL) apheresis are treatments that can lower LDL cholesterol levels. Early treatment can lead to substantial reduction of cardiovascular events and death in patients with familial hypercholesterolemia. It is important to increase awareness of this disorder in physicians and patients to reduce the burden of this disorder. PMID:25939291

  14. Familial Hypercholesterolemia.

    PubMed

    Bouhairie, Victoria Enchia; Goldberg, Anne Carol

    2016-03-01

    Familial hypercholesterolemia is a common, inherited disorder of cholesterol metabolism that leads to early cardiovascular morbidity and mortality. It is underdiagnosed and undertreated. Statins, ezetimibe, bile acid sequestrants, niacin, lomitapide, mipomersen, and low-density lipoprotein (LDL) apheresis are treatments that can lower LDL cholesterol levels. Early treatment can lead to substantial reduction of cardiovascular events and death in patients with familial hypercholesterolemia. It is important to increase awareness of this disorder in physicians and patients to reduce the burden of this disorder. PMID:26892994

  15. Homozygosity Mapping and Targeted Sanger Sequencing Reveal Genetic Defects Underlying Inherited Retinal Disease in Families from Pakistan

    PubMed Central

    Waheed, Nadia Khalida; Siddiqui, Sorath Noorani; Mustafa, Bilal; Ayub, Humaira; Ali, Liaqat; Ahmad, Shakeel; Micheal, Shazia; Hussain, Alamdar; Shah, Syed Tahir Abbas; Ali, Syeda Hafiza Benish; Ahmed, Waqas; Khan, Yar Muhammad; den Hollander, Anneke I.; Haer-Wigman, Lonneke; Collin, Rob W. J.; Khan, Muhammad Imran; Qamar, Raheel; Cremers, Frans P. M.

    2015-01-01

    Background Homozygosity mapping has facilitated the identification of the genetic causes underlying inherited diseases, particularly in consanguineous families with multiple affected individuals. This knowledge has also resulted in a mutation dataset that can be used in a cost and time effective manner to screen frequent population-specific genetic variations associated with diseases such as inherited retinal disease (IRD). Methods We genetically screened 13 families from a cohort of 81 Pakistani IRD families diagnosed with Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), congenital stationary night blindness (CSNB), or cone dystrophy (CD). We employed genome-wide single nucleotide polymorphism (SNP) array analysis to identify homozygous regions shared by affected individuals and performed Sanger sequencing of IRD-associated genes located in the sizeable homozygous regions. In addition, based on population specific mutation data we performed targeted Sanger sequencing (TSS) of frequent variants in AIPL1, CEP290, CRB1, GUCY2D, LCA5, RPGRIP1 and TULP1, in probands from 28 LCA families. Results Homozygosity mapping and Sanger sequencing of IRD-associated genes revealed the underlying mutations in 10 families. TSS revealed causative variants in three families. In these 13 families four novel mutations were identified in CNGA1, CNGB1, GUCY2D, and RPGRIP1. Conclusions Homozygosity mapping and TSS revealed the underlying genetic cause in 13 IRD families, which is useful for genetic counseling as well as therapeutic interventions that are likely to become available in the near future. PMID:25775262

  16. Spectrum of Perforin Gene Mutations in Familial Hemophagocytic Lymphohistiocytosis

    PubMed Central

    Göransdotter Ericson, Kim; Fadeel, Bengt; Nilsson-Ardnor, Sofie; Söderhäll, Cilla; Samuelsson, AnnaCarin; Janka, Gritta; Schneider, Marion; Gürgey, Aytemiz; Yalman, Nevin; Révész, Tom; Egeler, R. Maarten; Jahnukainen, Kirsi; Storm-Mathiesen, Ingebjörg; Haraldsson, Ásgeir; Poole, Janet; de Saint Basile, Geneviève; Nordenskjöld, Magnus; Henter, Jan-Inge

    2001-01-01

    Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, ?30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%–40% of the FHL cases and the FHL 1 locus on chromosome 9 for ?10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes. PMID:11179007

  17. Family Hypnotherapy.

    ERIC Educational Resources Information Center

    Araoz, Daniel L.; Negley-Parker, Esther

    1985-01-01

    A therapeutic model to help families activate experiential and right hemispheric functioning through hypnosis is presented in detail, together with a clinical illustration. Different situations in which this model is effective are mentioned and one such set of circumstances is described. (Author)

  18. Family Violence.

    ERIC Educational Resources Information Center

    Sorgen, Carol, Ed.

    1979-01-01

    This quarterly publication, issued by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), contains articles dealing with family violence and alcohol abuse, children of alcoholic parents, training programs for counselors, and confidentiality of client records. The three articles on alcohol abuse suggest that: (1) there is a clear…

  19. FAMILY TYMOVIRIDAE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This article provides a brief review of the taxonomic structure, virion properties, genome organization and replication strategy, antigenic properties, and biological properties of viruses in the family Tymoviridae. Criteria for demarcation of genus and species are provided. A brief review of each...

  20. Family Disruptions

    MedlinePLUS

    ... and Returns Do you or your spouse frequently travel on business? These can be disruptive times for your child and for the family as ... these out-of-town trips. Spend as much time as it takes to explain where you are ... before and during your travels. You need to acknowledge and accept her feelings: " ...

  1. Serving Families.

    ERIC Educational Resources Information Center

    Link, Geoffrey; Beggs, Marjorie; Seiderman, Ethel

    Parent Services Project (PSP), the first comprehensive program of resources and mental health activities for parents offered at child care centers in the San Francisco Bay Area (California), has expanded to centers in six states, serving over 19,000 families. This report describes the program's history, aims, and achievements, along with specific…

  2. Family Involvement.

    ERIC Educational Resources Information Center

    Nathanson, Jeanne H., Ed.

    1992-01-01

    This periodical issue focuses on the theme of involvement of families in the education of their children with disabilities. It includes papers with the following titles and authors: "A Message from the Assistant Secretary: Developing Successful Partnerships between Parents and Service Providers" (Robert R. Davila); "Parent Advocacy and Children…

  3. Homolog of the polymorphic 4q35 FSHD locus (p13E-11; D4F104S1) maps to 10qter; exclusion as a second FSHD locus in a large Danish family

    SciTech Connect

    Frants, R.R.; Bakker, E.; Vossen, R.H.A.M.

    1994-09-01

    Facioscapulohumeral muscular dystrophy (FSHD) has been mapped to 4q35 and shown to be associated with deletions that are detectable using probe p13E-11 (D4104S1). These deletions reside within highly polymorphic restriction fragments (20-300 kb) which can normally only be resolved completely using pulsed-field gel electrophoresis (PFGE). Family studies showed that p13E-11 detects two non-allelic loci, only one of which originates from 4q35 origin. In 20 CEPH families, 8 individuals were identified showing a `small` EcoRI fragment detectable by conventional Southern blotting. Linkage analysis allowed assignment of these fragments to 10qter (D10S212 and D10S180) in all families tested. Since FSHD shows genetic heterogeneity, this second p13E-11 locus on 10qter became an interesting candidate as a second FSHD family did not provide evidence for linkage on chromosome 10qter.

  4. Resolving the Debate over Birth Order, Family Size, and Intelligence.

    ERIC Educational Resources Information Center

    Rodgers, Joseph Lee; Cleveland, H. Harrington; van den Oord, Edwin; Rowe, David C.

    2000-01-01

    Investigated the relationship between birth order, family size, and intelligence quotient (IQ), evaluating sibling data from the National Longitudinal Survey of Youth and comparing results with those from other studies using within-family data. Results indicated that although low IQ parents were making large families, large families were not…

  5. Rapid multipoint linkage analysis of recessive traits in nuclear families, including homozygosity mapping

    SciTech Connect

    Kruglyak, L.; Daly, M.J.; Lander, E.S. |

    1995-02-01

    Homozygosity mapping is a powerful strategy for mapping rare recessive traits in children of consanguineous marriages. Practical applications of this strategy are currently limited by the inability of conventional linkage analysis software to compute, in reasonable time, multipoint LOD scores for pedigrees with inbreeding loops. We have developed a new algorithm for rapid multipoint likelihood calculations in small pedigrees, including those with inbreeding loops. The running time of the algorithm grows, at most, linearly with the number of loci considered simultaneously. The running time is not sensitive to the presence of inbreeding loops, missing genotype information, and highly polymorphic loci. We have incorporated this algorithm into a software package, MAPMAKER/HOMOZ, that allows very rapid multipoint mapping of disease genes in nuclear families, including homozygosity mapping. Multipoint analysis with dozens of markers can be carried out in minutes on a personal workstation. 23 refs., 4 figs., 1 tab.

  6. Family structure and family processes in Mexican-American families.

    PubMed

    Zeiders, Katharine H; Roosa, Mark W; Tein, Jenn-Yun

    2011-03-01

    Despite increases in single-parent families among Mexican Americans, few studies have examined the association of family structure and family adjustment. Utilizing a diverse sample of 738 Mexican-American families (21.7% single parent), the current study examined differences across family structure on early adolescent outcomes, family functioning, and parent-child relationship variables. Results revealed that early adolescents in single-parent families reported greater school misconduct, conduct disorder/oppositional deviant disorder, and major depressive disorder symptoms, and greater parent-child conflict than their counterparts in 2-parent families. Single-parent mothers reported greater economic hardship, depression, and family stress. Family stress and parent-child conflict emerged as significant mediators of the association between family structure and early adolescent outcomes, suggesting important processes linking Mexican-American single-parent families and adolescent adjustment. PMID:21361925

  7. Familial Hypercholesterolemia

    PubMed Central

    Pejic, Rade N.

    2014-01-01

    Background Familial hypercholesterolemia (FH) is an autosomal dominant-inherited genetic disorder that leads to elevated blood cholesterol levels. FH may present as severely elevated total cholesterol and low density lipoprotein (LDL) cholesterol levels or as premature coronary heart disease (CHD). Methods This review presents information on the disease and on the effects of drug treatment and lifestyle changes. Results Routine lipid testing should identify most patients with FH. Once an index case is identified, testing should be offered to family members. Early diagnosis and aggressive treatment with therapeutic lifestyle changes and statins can prevent premature CHD and other atherosclerotic sequelae in patients with FH. Conclusion Emerging therapies such as LDL apheresis and novel therapeutic agents may be useful in patients with homozygous FH or treatment-resistant FH. Liver transplantation is the only effective therapy for severe cases of homozygous FH. PMID:25598733

  8. Family Child Care Licensing Study, 2001.

    ERIC Educational Resources Information Center

    Children's Foundation, Washington, DC.

    This report presents the findings of the 2001 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 2000 study. Data on small family child care homes and group or large family child care homes are organized into the following 23 categories: (1) number of regulated…

  9. The Family Child Care Licensing Study, 1999.

    ERIC Educational Resources Information Center

    Children's Foundation, Washington, DC.

    This report presents the findings of the 1999 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 1998 study. Data on small family child care homes and group or large family child care homes are organized in 22 categories: (1) number of regulated homes; (2)…

  10. Family Child Care Licensing Study, 2000.

    ERIC Educational Resources Information Center

    Kelly, Nia, Comp.

    This report presents the findings of the 2000 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 1999 study. Data on small family child care homes and group or large family child care homes are organized in 23 categories: (1) number of regulated homes; (2)…

  11. Filling the Glass: Gender Perspectives on Families

    ERIC Educational Resources Information Center

    Ferree, Myra Marx

    2010-01-01

    The challenge feminist scholarship posed to family studies has been largely met through the incorporation of research on gender dynamics within families and intersectional differences among them. Despite growing attention to gender as performance and power in more diverse families, the more difficult work of understanding the dynamics of change…

  12. Family Child Care Licensing Study, 2003.

    ERIC Educational Resources Information Center

    Hollestelle, Kay; Koch, Pauline D.

    This report presents the findings of the 2003 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 2002 study. Data on small family child care homes and group or large family child care homes are organized into the following 23 categories: (1) number of regulated…

  13. Family Child Care Licensing Study, 2003.

    ERIC Educational Resources Information Center

    Hollestelle, Kay; Koch, Pauline D.

    This report presents the findings of the 2003 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 2002 study. Data on small family child care homes and group or large family child care homes are organized into the following 23 categories: (1) number of regulated…

  14. Family Child Care Licensing Study, 2002.

    ERIC Educational Resources Information Center

    Children's Foundation, Washington, DC.

    This report presents the findings of the 2002 national survey of state child care regulatory agencies to update and expand family child care regulatory information published in the 2001 study. Data on small family child care homes and group or large family child care homes are organized into the following 23 categories: (1) number of regulated…

  15. Familial hypercholesterolemia

    PubMed Central

    Turgeon, Ricky D.; Barry, Arden R.; Pearson, Glen J.

    2016-01-01

    Objective To summarize the pathophysiology, epidemiology, screening, diagnosis, and treatment of familial hypercholesterolemia (FH). Quality of evidence A PubMed search was conducted (inception to July 2014) for articles on pathophysiology, screening, diagnosis, and management of FH, supplemented with hand searches of bibliographies of guidelines and reviews. A supporting level of evidence for each recommendation was categorized as level I (randomized controlled trial or systematic review of randomized controlled trials), level II (observational study), or level III (expert opinion). The best available evidence is mostly level II or III. Main message Familial hypercholesterolemia affects 1 in 500 Canadians. Risk of a coronary event is high in these patients and is underestimated by risk calculators (eg, Framingham). Clinicians should screen patients according to guidelines and suspect FH in any patient with a premature cardiovascular event, physical stigmata of hypercholesterolemia, or an elevated plasma lipid level. Physicians should diagnose FH using either the Simon Broome or Dutch Lipid Network criteria. Management of heterozygous FH includes reducing low-density lipoprotein levels by 50% or more from baseline with high-dose statins and other lipid-lowering agents. Clinicians should refer any patient with homozygous FH to a specialized centre. Conclusion Familial hypercholesterolemia represents an important cause of premature cardiovascular disease in Canadians. Early identification and aggressive treatment of individuals with FH reduces cardiovascular morbidity and mortality. PMID:26796832

  16. Genetic analysis of Chinese families reveals a novel truncation allele of the retinitis pigmentosa GTPase regulator gene

    PubMed Central

    Hu, Fang; Zeng, Xiang-Yun; Liu, Lin-Lin; Luo, Yao-Ling; Jiang, Yi-Ping; Wang, Hui; Xie, Jing; Hu, Cheng-Quan; Gan, Lin; Huang, Liang

    2014-01-01

    AIM To make comprehensive molecular diagnosis for retinitis pigmentosa (RP) patients in a consanguineous Han Chinese family using next generation sequencing based Capture-NGS screen technology. METHODS A five-generation Han Chinese family diagnosed as non-syndromic X-linked recessive RP (XLRP) was recruited, including four affected males, four obligate female carriers and eleven unaffected family members. Capture-NGS was performed using a custom designed capture panel covers 163 known retinal disease genes including 47 RP genes, followed by the validation of detected mutation using Sanger sequencing in all recruited family members. RESULTS Capture-NGS in one affected 47-year-old male reveals a novel mutation, c.2417_2418insG:p.E806fs, in exon ORF15 of RP GTPase regulator (RPGR) gene results in a frameshift change that results in a premature stop codon and a truncated protein product. The mutation was further validated in three of four affected males and two of four female carriers but not in the other unaffected family members. CONCLUSION We have identified a novel mutation, c.2417_2418insG:p.E806fs, in a Han Chinese family with XLRP. Our findings expand the mutation spectrum of RPGR and the phenotypic spectrum of XLRP in Han Chinese families, and confirms Capture-NGS could be an effective and economic approach for the comprehensive molecular diagnosis of RP. PMID:25349787

  17. Family planning for travellers.

    PubMed

    Rustom, A

    1990-11-01

    A public health nurse from London describes the customs of nomadic people in the British Isles, known as "travellers," as they affect provision of family planning services. Most are of British or Irish stock, some migrate and others live in caravan sites all year. Their traditions dictate that men work and women are housewives. Early, often arranged, marriage, early childbearing and large families are the norm. Sex and contraception are not considered appropriate for discussion between the sexes, or in the presence of children. Large families and financial hardship force many women to space pregnancies. Women often have to hide contraceptives from their husbands, difficult in conditions without privacy. Therefore they prefer IUDs, but some use oral contraceptives, although sometimes erratically because most are illiterate. Traveller women are usually unwilling to do self-examination, as needed with IUDs. They often have difficulty attending regular Pap smear clinics. Cervical cancer rates are high. They experience discrimination in clinics, and need extra care about modesty. It is worth while to take time to develop trust in the clinical relationship, to deal with the traveller woman's uneasy among outsiders. PMID:2286082

  18. Homozygous 16p13.11 duplication associated with mild intellectual disability and urinary tract malformations in two siblings born from consanguineous parents.

    PubMed

    Houcinat, N; Llanas, B; Moutton, S; Toutain, J; Cailley, D; Arveiler, B; Combe, C; Lacombe, D; Rooryck, C

    2015-11-01

    The use of array-comparative genomic hybridization (array-CGH) in routine clinical work has allowed the identification of many new copy number variations (CNV). The 16p13.11 duplication has been implicated in various congenital anomalies and neurodevelopmental disorders, but it has also been identified in healthy individuals. We report a clinical observation of two brothers from related parents each carrying a homozygous 16p13.11 duplication. The propositus had mild intellectual disability and posterior urethral valves with chronic renal disease. His brother was considered a healthy child with only learning disabilities and poor academic performances. However, a routine medical examination at 25-years-old revealed a mild chronic renal disease and ureteropelvic junction obstruction. Furthermore, the father presented with a unilateral renal agenesis, thus it seemed that a "congenital anomalies of kidney and urinary tract" (CAKUT) phenotype segregated in this family. This may be related to the duplication, but we cannot exclude the involvement of additional genetic or non-genetic factors in the urological phenotype. Several cohort studies showed association between this chromosomal imbalance and different clinical manifestations, but rarely with CAKUT. The duplication reported here was similar to the larger one of 3.4?Mb previously described versus the more common of 1.6?Mb. It encompassed at least 11 known genes, including the five ohnologs previously identified. Our observation, in addition to expanding the clinical spectrum of the duplication provides further support to understanding the underlying pathogenic mechanism. PMID:26114937

  19. Identification of a novel LCA5 mutation in a Pakistani family with Leber congenital amaurosis and cataracts

    PubMed Central

    Ahmad, Adeel; Daud, Shakeela; Kakar, Naseebullah; Nürnberg, Gudrun; Nürnberg, Peter; Babar, Masroor Ellahi; Thoenes, Michaela; Kubisch, Christian; Ahmad, Jamil

    2011-01-01

    Purpose To determine the cause of Leber congenital amaurosis (LCA) and developmental cataracts in a consanguineous Pakistani family. Methods The diagnosis was established in all affected individuals of a Pakistani LCA family by medical history, funduscopy, and standard ERG. We performed genome-wide linkage analysis for mapping the disease locus in this family. Results Congenitally severely reduced visual acuity and nystagmus were reported for all patients who, in the later phase of the disease, also developed cataracts. LCA in the family cosegregated with homozygosity for a single nucleotide polymorphism (SNP) haplotype on chromosome 6p14.1. The respective candidate region contained Leber congenital amaurosis 5 (LCA5), a gene previously reported to underlie LCA. We subsequently identified a novel truncating mutation in exon 4 of LCA5, c.642delC, in homozygous state in all affected persons of the family. Conclusions We report a novel LCA5 mutation causing LCA in a Pakistani family. Developmental cataracts were present in two of the four patients, raising the possibility that LCA5 mutations may predispose to this additional ocular pathology. PMID:21850168

  20. Familial FSGS

    PubMed Central

    Pollak, Martin R.

    2014-01-01

    FSGS and nephrotic syndrome can be caused by rare highly penetrant mutations in number of genes. FSGS can follow both recessive and dominant inheritance patterns. In general, recessive forms present early, while the autosomal dominant forms present in adolescence or adulthood. Many of the genes found to be mutated in FSGS and nephrotic syndrome patients encode proteins essential for normal podocyte structure and or function. An exception appears to be APOL1, which harbors common variants responsible for the high rate of FSGS and other nephropathies in people of recent African ancestry. Familial FSGS should be regarded as part of a spectrum of inherited glomerulopathies where the precise histologic presentation may depend on age of onset, function of the responsible gene and gene products, as well as other factors. PMID:25168831

  1. Genetics of familial hypercholesterolemia.

    PubMed

    Brautbar, Ariel; Leary, Emili; Rasmussen, Kristen; Wilson, Don P; Steiner, Robert D; Virani, Salim

    2015-04-01

    Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low-density lipoprotein (LDL) cholesterol and premature cardiovascular disease, with a prevalence of approximately 1 in 200-500 for heterozygotes in North America and Europe. Monogenic FH is largely attributed to mutations in the LDLR, APOB, and PCSK9 genes. Differential diagnosis is critical to distinguish FH from conditions with phenotypically similar presentations to ensure appropriate therapeutic management and genetic counseling. Accurate diagnosis requires careful phenotyping based on clinical and biochemical presentation, validated by genetic testing. Recent investigations to discover additional genetic loci associated with extreme hypercholesterolemia using known FH families and population studies have met with limited success. Here, we provide a brief overview of the genetic determinants, differential diagnosis, genetic testing, and counseling of FH genetics. PMID:25712136

  2. Family transitions and juvenile delinquency.

    PubMed

    Schroeder, Ryan D; Osgood, Aurea K; Oghia, Michael J

    2010-01-01

    There is a large body of research that shows children from non-intact homes show higher rates of juvenile delinquency than children from intact homes, partially due to weaker parental control and supervision in non-intact homes. What has not been adequately addressed in the research is the influence of changes in family structure among individual adolescents over time on delinquent offending. Using the first and third waves of the National Youth Study, we assess the effect of family structure changes on changes in delinquent offending between waves through the intermediate process of changes in family time and parental attachment. Although prior research has documented adolescents in broken homes are more delinquent than youth in intact homes, the process of family dissolution is not associated with concurrent increases in offending. In contrast, family formation through marriage or cohabitation is associated with simultaneous increases in offending. Changes in family time and parental attachment account for a portion of the family formation effect on delinquency, and prior parental attachment and juvenile offending significantly condition the effect of family formation on offending. PMID:20879178

  3. Family: Involving Families in Student Achievement.

    ERIC Educational Resources Information Center

    Tracy, Jaclynn Rogers

    1995-01-01

    Discusses the importance of family and community involvement to student achievement. Schools can establish an effective partnership among schools, families, and the community by providing support for families, creating family-community learning centers, supporting the community, providing opportunities for shared responsibility, facilitating the…

  4. Integrating Family Resilience and Family Stress Theory.

    ERIC Educational Resources Information Center

    Patterson, Joan M.

    2002-01-01

    The construct, family resilience, is defined differently by practitioners and researchers. This study tries to clarify the concept of family resilience. The foundation is family stress and coping theory, particularly the stress models that emphasize adaptation processes in families exposed to major adversities. (JDM)

  5. Positive Family Functioning.

    ERIC Educational Resources Information Center

    Sussman, Marvin B.

    The persistence of the nuclear family as the primary social unit in the United States and most all other societies, especially complex ones, is a fact. Values shape the definition of family, especially the "good family," and the "great debate" of this period on family failure, family corruption and the family's near demise originates in…

  6. Reclaiming Family Privilege

    ERIC Educational Resources Information Center

    Seita, John

    2012-01-01

    The pull for family is strong, almost primeval, most likely it is evolutionary, and for those lacking the benefit of family or Family Privilege, the loss of family is painful and profoundly sad. Young people who struggle to cope without stable family connections are profoundly aware of their lack of "Family Privilege." In this article, the author…

  7. Homozygosity and severity of phenotypic presentation in a CADASIL family.

    PubMed

    Vinciguerra, Claudia; Rufa, Alessandra; Bianchi, Silvia; Sperduto, Antonio; De Santis, Monica; Malandrini, Alessandro; Dotti, Maria Teresa; Federico, Antonio

    2014-01-01

    Most of causative mutations of the cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) are missense point mutations either creating or deleting one cysteine residue, inherited in a heterozygous state. Only few homozygous patients are reported to date and some of them showed phenotypic peculiarities. We here describe a CADASIL family in which a member showed homozygous mutation and compare its clinical profile with five subjects throughout three generation of the pedigree, carrying the same mutation in heterozygosity. The index patient was a 44-year-old Italian man, born from consanguineous parents (first cousins). Symptoms started at 23 years and progressing with recurrent ischemic stroke episode. Diffuse leukoencephalopathy and a severe cognitive impairment were evident, GOMs were detected in skin specimens and a homozygous p.Cys183Ser mutation of the NOTCH3 gene was found. Among the other five heterozygous relatives for the same mutation, both parents developed stroke in advanced age and all the others were clinically asymptomatic. We discuss these findings in relationship to previous data from the literature in CADASIL and in other dominant neurological disorders. PMID:24277202

  8. Familial Hypercholesterolaemia

    PubMed Central

    Marais, A David

    2004-01-01

    Familial hypercholesterolaemia (FH), defined as the heritable occurrence of severe hypercholesterolaemia with cholesterol deposits in tendons and premature heart disease, is caused by at least four genes in sterol and lipoprotein pathways and displays varying gene-dose effects. The genes are the low-density lipoprotein (LDL) receptor, apolipoprotein (apo) B, proprotein convertase subtilisin/kexin 9, and the autosomal recessive hypercholesterolaemia (ARH) adaptor protein. All of these disorders have in common defective clearance of LDL within a complex system of lipid and lipoprotein metabolism and regulation. Normal cellular cholesterol and lipoprotein metabolism is reviewed before describing the disorders, their metabolic derangements and their clinical effects. FH is classified as two simplified phenotypes of disease according to the severity of the metabolic derangement. The dominantly inherited heterozygous phenotype comprises defects in the LDL receptor, apoB100, and neural apoptosis regulatory cleavage protein. The homozygous phenotype is co-dominant in defects of the LDL receptor, and occurs also as the ARH of adapter protein mutations. Defective binding of apoB100 does not result in a significant gene dose effect, but enhances the severity of heterozygotes for LDL receptor mutations. The genetic diagnosis of FH has provided greater accuracy in definition and detection of disease and exposes information about migration of populations. All of these disorders pose a high risk of atherosclerosis, especially in the homozygous phenotype. Studies of influences on the phenotype and responses to treatment are also discussed in the context of the metabolic derangements. PMID:18516203

  9. Familial hyperargininaemia.

    PubMed Central

    Terheggen, H G; Lowenthal, A; Lavinha, F; Colombo, J P

    1975-01-01

    A third case of hyperargininaemia occurring in one family was studied from birth. In cord blood serum arginine concentration was only slightly raised, but arginase activity in red blood cell haemolysates was very low. In the urine on day 2 a typical cystinuria pattern was present. Arginine concentration in serum increased to 158 mumol/100 ml on the 41st day of life. Later determinations of the arginase activity in peripheral blood showed values below the sensitivity of the method. Blood ammonia was consistently high, and cystinuria was present. The enzymatic defect was further displayed by intravenous loading tests with arginine. Serum urea values were predominantly normal or near the lower limit of normal, suggesting the presence of other metabolic pathways of urea synthesis. In urine there was no excretion of guanidinosuccinic acid, while the excretion of other monosubstituted guanidine derivatives was increased, pointing to a connexion with hyperargininaemia. Owing to parental attitude, a low protein diet (1-5 g/kg) was introduced only late. The infant developed severe mental retardation, athetosis, and spasticity. PMID:1124944

  10. The Hansa Family: A New High-Inclination Asteroid Family

    NASA Astrophysics Data System (ADS)

    Hergenrother, C. W.; Larson, S. M.; Spahr, T. B.

    1996-09-01

    At present, there are only two widely recognized high-inclination (> 20 degrees) asteroid families. The (2) Pallas family was one of the seven original Hirayama families (Hirayama. 1928; Japan J. of Astron. Geophys. 5,137-162) and a second family associated with (434) Hungaria has also been noted (Williams. 1992; Icarus 96,251-280). We present a third high-inclination family which includes as its highest numbered member (480) Hansa. Using a semi-analytical method for the determination of proper elements (Lemaitre and Morbidelli. 1994; Celest. Mech. and Dyn. Astr. 60,29-56) and the D-criterion for the identification of asteroid families (Lindblad. 1994; Seventy-Five Years of Hirayama Asteroid Families, ASP Conf. Ser. 63,62-75), we have identified 14 probable members including the two large S-class, H=8 asteroids, (480) Hansa and (925) Alphonsina. The present osculating elements are centered at a=2.66 au, e=0.06 and i=22.0deg . We will also analyze peculiarities among the osculating orbital elements.

  11. Thankful for Family and Foods! (An ABLE Teaching Unit).

    ERIC Educational Resources Information Center

    Barringer, Mary Dean; And Others

    The teaching unit focuses on a month (November) of primary grade learning activities which focus on being thankful for food, family, and friends. Concepts stressed throughout the unit include: We are all part of the large family of Americans; Families are made up of a variety of people and our families are usually different from each other;…

  12. Religious Influences on Work-Family Trade-Offs

    ERIC Educational Resources Information Center

    Ammons, Samantha K.; Edgell, Penny

    2007-01-01

    Despite a large body of research on the influences of religion on family life and gender ideology, few studies examined how religion affects work-family strategies. One set of strategies involves making employment or family trade-off--strategies of devoting time or attention to either work or family in a situation in which one cannot devote the…

  13. A novel mutation in the TMC1 gene causes non-syndromic hearing loss in a Moroccan family.

    PubMed

    Bakhchane, Amina; Charoute, Hicham; Nahili, Halima; Roky, Rachida; Rouba, Hassan; Charif, Majida; Lenaers, Guy; Barakat, Abdelhamid

    2015-12-10

    Autosomal recessive non-syndromic hearing loss (ARNSHL) is one of the most common genetic diseases in human and is subject to important genetic heterogeneity, rendering molecular diagnosis difficult. Whole-exome sequencing is thus a powerful strategy for this purpose. After excluding GJB2 mutation and other common mutations associated with hearing loss in Morocco, whole-exome sequencing was performed to study the genetic causes of one sibling with ARSHNL in a consanguineous Moroccan family. After filtering data and Sanger sequencing validation, one novel pathogenic homozygous mutation c.1810C>G (p.Arg604Gly) was identified in TMC1, a gene reported to cause deafness in various populations. Thus, we identified here the first mutation in the TMC1 gene in the Moroccan population causing non-syndromic hearing loss. PMID:26226225

  14. A novel gene insertion combined with a missense mutation causing factor VII deficiency in two unrelated Chinese families.

    PubMed

    Hao, Xiuping; Cheng, XiaoLi; Wang, Yingyu; Yang, LiHong; Xie, Yaosheng; Wang, Mingshan; Jin, Yanhui

    2015-09-01

    Hereditary coagulation factor VII (FVII) deficiency is a rare bleeding disorder characterized by reduced FVII activity (FVII:C) and inconsistent FVII antigen (FVII:Ag). In our study, two pregnant probands were diagnosed with FVII deficiency, based on the tests that FVII:C were both 3% and FVII:Ag were less than 7.5%. Gene sequencing revealed the same compound mutations, a recurrent missense mutation p.Arg277Cys and a novel insertion mutation g.11520-11521insT. What is more, haplotype analysis of SNPs excluded the possibility of consanguinity between the two families. According to the model, we speculated that although the insertion mutation was close to the carboxy-terminal, it induced the protein extension and affected the 3' untranslated region of F7 gene, which is significant to posttranscriptional regulation. Hypothetically, the stability or translational efficiency of mRNA may be influenced, resulting in reducing FVII:C. PMID:26083983

  15. Frequency of alterations in the MEFV gene and clinical signs in familial Mediterranean fever in Central Anatolia, Turkey.

    PubMed

    Ceylan, G G; Ceylan, C; Ozturk, E

    2012-01-01

    Familial Mediterranean fever is a recessive autoinflammatory disease that is frequent in Armenians, Jews, Arabs, and Turks. The MEFV gene is responsible for this disease. We looked for MEFV gene variations (polymorphism and mutations) in a population that resides in Central Anatolia, Turkey. DNA was extracted from peripheral blood leukocytes of 802 familial Mediterranean fever patients. The DNA sequence data were examined for approximately 150 different mutations and polymorphisms, including single nucleotide polymorphisms in different exons of the MEFV gene. The male:female ratio of these patients was 1.44:1. Mutations were detected in 48.1% of the patients; 7.5% were homozygous, 11.1% were compound heterozygous and 31.5% had only one identifiable mutant allele. No mutations were detected in 51.9% of the patients. The main clinical characteristics of the patients were: abdominal pain in 20.6%, arthritis in 22.9% and amyloidosis in 4.6%. Sixty-six percent of patients had a family history of familial Mediterranean fever; 19.4% of the patients were found to have parental consanguinity. We conclude that the genetics of familial Mediterranean fever is more complex than has previously been reported; heterozygous patients presenting a severe phenotype should be further analyzed for less common secondary MEFV mutations, using gene sequencing. PMID:22614345

  16. Hematopoietic stem cell transplantation from non-sibling matched family donors for patients with thalassemia major in Jordan.

    PubMed

    Hussein, Ayad Ahmed; Al-Zaben, Abdulhadi; Khattab, Eman; Haroun, Anas; Frangoul, Haydar

    2016-02-01

    There are limited data on the outcome of patients with thalassemia receiving HSCT from non-sibling matched family donors. Of the 341 patients with thalassemia major that underwent donor search at our center from January 2003 to December 2011, 236 (69.2%) had fully matched family donor of which 28 patients (8.2%) had non-sibling matched family donors identified. We report on seven patients with a median age of eight yr (4-21) who underwent myeloablative (n = 4) or RIC (n = 3) HSCT. The median age of the donors was 33 yr (4-47), three were parents, two first cousins, one paternal uncle, and one paternal aunt. All patients achieved primary neutrophil and platelet engraftment at a median of 18 (13-20) and 16 days (11-20), respectively. One patient developed grade II acute GVHD, and two patients developed limited chronic GVHD. One patient experienced secondary GF requiring a second transplant. At a median follow-up of 69 months (7-110), all patients are alive and thalassemia free. Our data emphasize the need for extended family HLA typing for patients with thalassemia major in regions where there is high rate of consanguinity. Transplant from non-sibling matched family donor can result in excellent outcome. PMID:26493691

  17. Family and family therapy in Russia.

    PubMed

    Bebtschuk, Marina; Smirnova, Daria; Khayretdinov, Oleg

    2012-04-01

    This article represents the information about family and family therapy in the context of culture, traditions and contemporary changes of social situations in Russia. The legislation of family rights are mentioned within items about marriage and family in the Constitution, Civil Code and Family Code of the Russian Federation which has changed during recent years. The definition of family and description of family structure are given through the prism of the current demographic situation, dynamics of statistics of marriage and divorce rates, mental disorders, disabilities and such phenomena as social abandonment. The actual curriculum, teaching of family therapy and its disadvantages, system of continuous education, supervision and initiatives of the Institute of Integrative Family Therapy in improvement of preparing of specialists who can provide qualified psychosocial assistance for the family according to the actual needs of society are noted. The directions of state and private practice of family counselling and therapy both for psychiatric patients and medical patients, for adults and children in a family systemic approach are highlighted with an indication of the spectrum of techniques and methods used by Russian professionals. The main obstacles and perspectives of development of family therapy in Russia are summarized. PMID:22515460

  18. Glycogenosis type II: protein and DNA analysis in five South African families from various ethnic origins.

    PubMed Central

    Van der Ploeg, A T; Hoefsloot, L H; Hoogeveen-Westerveld, M; Petersen, E M; Reuser, A J

    1989-01-01

    The molecular nature of lysosomal alpha-glucosidase deficiency was studied in five South African families with glycogenosis type II. Distinct ethnic origins were represented. Two new mutant acid alpha-glucosidase alleles were discovered. In two infantile patients from a consanguineous Indian family we found for the first time an acid alpha-glucosidase precursor of reduced size. The mutant precursor appeared normally glycosylated and phosphorylated but was not processed to mature enzyme. Abnormalities of the mRNA were not obvious, but digestion of genomic DNA with HindIII, BglII, and StuI revealed for each enzyme a fragment of increased length. Heterozygosity was demonstrated in the parents. Complete lack of acid alpha-glucosidase mRNA, as well as deficiency of precursor synthesis, was observed in two black baby girls from unrelated families. In these cases the length of all restriction-enzyme fragments was normal. Reduced enzyme synthesis but normal processing was registered in juvenile and young adult Cape colored patients. The extensive heterogeneity of glycogenosis type II is emphasized in these studies on various ethnic groups. The newly discovered mutants are valuable for the understanding of clinical diversity as a result of allelic variation. Images Figure 1 Figure 2 Figure 3 Figure 4 PMID:2658562

  19. Linkage disequilibrium mapping places the gene causing familial Mediterranean fever close to D16S246

    SciTech Connect

    Levy, E. N.; Aksentijevich, I.; Pras, E.

    1996-03-01

    This report presents refined genetic mapping data for the gene causing familial Mediterranean fever (FMF), a recessively inherited disorder of inflammation. We sampled 65 Jewish, Armenian, and Arab families and typed them for eight markers from chromosome 16p. Using a new algorithm that permits multipoint calculations for a dense map of markers in consanguineous families, we obtained a maximal LOD score of 49.2 at a location 1.6 cM centromeric to D16S246. A specific haplotype at D16S283-D16S94-D16S246 was found in 76% of Moroccan and 32% of non-Moroccan Jewish carrier chromosomes, but this haplotype was not overrepresented in Armenian or Arab FMF carriers. Moreover, the 2.5-kb allele at D16S246 was significantly associated with FMF in Moroccan and non-Moroccan Jews but not in Armenians or Arabs. Since the Moroccan Jewish community represents a relatively recently established and genetically isolated founder population, we analyzed the Moroccan linkage-disequilibrium data by using Luria-Delbruck formulas and simulations based on a Poisson branching process. These methods place the FMF susceptibility gene within 0.305 cM of D16S246 (2-LOD-unit range 0.02-0.64 cM). 41 refs., 3 figs., 5 tabs.

  20. Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family.

    PubMed

    Okutman, Ozlem; Muller, Jean; Baert, Yoni; Serdarogullari, Munevver; Gultomruk, Meral; Piton, Amélie; Rombaut, Charlotte; Benkhalifa, Moncef; Teletin, Marius; Skory, Valerie; Bakircioglu, Emre; Goossens, Ellen; Bahceci, Mustafa; Viville, Stéphane

    2015-10-01

    Infertility is a global healthcare problem, and despite long years of assisted reproductive activities, a significant number of cases remain idiopathic. Our currently restricted understanding of basic mechanisms driving human gametogenesis severely limits the improvement of clinical care for infertile patients. Using exome sequencing, we identified a nonsense mutation leading to a premature stop in the TEX15 locus (c.2130T>G, p.Y710*) in a consanguineous Turkish family comprising eight siblings in which three brothers were identified as infertile. TEX15 displays testis-specific expression, maps to chromosome 8, contains four exons and encodes a 2789-amino acid protein with uncertain function. The mutation, which should lead to early translational termination at the first exon of TEX15, co-segregated with the infertility phenotype, and our data strongly suggest that it is the cause of spermatogenic defects in the family. All three affected brothers presented a phenotype reminiscent of the one observed in KO mice. Indeed, previously reported results demonstrated that disruption of the orthologous gene in mice caused a drastic reduction in testis size and meiotic arrest in the first wave of spermatogenesis in males while female KO mice were fertile. The data from our study of one Turkish family suggested that the identified mutation correlates with a decrease in sperm count over time. A diagnostic test identifying the mutation in man could provide an indication of spermatogenic failure and prompt patients to undertake sperm cryopreservation at an early age. PMID:26199321

  1. The Reconstituted Family

    PubMed Central

    Talbot, Yves

    1981-01-01

    The reconstituted or step-family is becoming more prevalent. The physician who cares for families should be acquainted with the different aspects of such family structure and family functioning. This will enable professionals to better understand and assist their patients, by anticipating the different stresses related to the new family formation, and supporting their adaptation. PMID:21289836

  2. The Changing Family Structure.

    ERIC Educational Resources Information Center

    Bernard van Leer Foundation Newsletter, 1993

    1993-01-01

    This newsletter issue contains feature articles and short reports on how and why family structures are undergoing substantial change in many parts of the world. These articles include: (1) "The Changing Family Structure," a review of how families are changing and why; (2) "Peru: Families in the Andes"; (3) "Thailand: Families of the Garbage Dump";…

  3. Genetic homogeneity in Sjoegren-Larsson syndrome: Linkage to chromosome 17p in families of different non-Swedish ethnic origins

    SciTech Connect

    Rogers, G.R.; Lee, M.; Compton, J.G.

    1995-11-01

    Sjoegren-Larsson syndrome (SLS) is a rare, autosomal recessive disorder that is characterized by congenital ichthyosis, mental retardation, and spastic diplegia or tetraplegia. Three United States families, three Egyptian families, and one Israeli Arab family were investigated for linkage of the SLS gene to a region of chromosome 17. Pairwise and multipoint linkage analysis with nine markers mapped the SLS gene to the same region of the genome as that reported in Swedish SLS pedigrees. Examination of recombinants by haplotype analysis showed that the gene lies in the region containing the markers D17S953, D17S805, D17S689, and D17S842. D17S805 is pericentromeric on 17p. Patients in two consanguineous Egyptian families were homozygous at the nine marker loci tested, and another patient from a third family was homozygous for eight of the nine, suggesting that within each of these families the region of chromosome 17 carrying the SLS gene is identical by descent. Linkage of the SLS gene to chromosome 17p in families of Arabic, mixed European, Native American, and Swedish descent provides evidence for a single SLS locus and should prove useful for diagnosis and carrier detection in worldwide cases. 25 refs., 4 figs., 1 tab.

  4. Families with congenital heart disease.

    PubMed Central

    Emery, J L

    1989-01-01

    Families with congenital heart deformities appear to have more difficulties and stress than those with other deformities. Some problems are intrinsic to the deformity but others are largely related to communication difficulties between the groups doing home support and those in supraregional centres. PMID:2923468

  5. Family Capital: Implications for Interventions with Families

    ERIC Educational Resources Information Center

    Belcher, John R.; Peckuonis, Edward V.; Deforge, Bruce R.

    2011-01-01

    Social capital has been extensively discussed in the literature as building blocks that individuals and communities utilize to leverage system resources. Similarly, some families also create capital, which can enable members of the family, such as children, to successfully negotiate the outside world. Families in poverty confront serious…

  6. Bounding CKM Mixing with a Fourth Family

    SciTech Connect

    Chanowitz, Michael S.

    2009-04-22

    CKM mixing between third family quarks and a possible fourth family is constrained by global fits to the precision electroweak data. The dominant constraint is from nondecoupling oblique corrections rather than the vertex correction to Z {yields} {bar b}b used in previous analyses. The possibility of large mixing suggested by some recent analyses of FCNC processes is excluded, but 3-4 mixing of the same order as the Cabbibo mixing of the first two families is allowed.

  7. Family Reunion Health Guide

    MedlinePLUS

    ... Phone (Continued) 1. Send a Kidney Health Message Hi Family, I came across this information and thought ... mails to family members. Before the Reunion 1. Hi family! Taking care of your kidneys is important. ...

  8. Family Activities for Fitness

    ERIC Educational Resources Information Center

    Grosse, Susan J.

    2009-01-01

    This article discusses how families can increase family togetherness and improve physical fitness. The author provides easy ways to implement family friendly activities for improving and maintaining physical health. These activities include: walking, backyard games, and fitness challenges.

  9. Characterization of familial breast cancer in Saudi Arabia

    PubMed Central

    2015-01-01

    Background The contribution of genetic factors to the development of breast cancer in the admixed and consanguineous population of the western region of Saudi Arabia is thought to be significant as the disease is early onset. The current protocols of continuous clinical follow-up of relatives of such patients are costly and cause a burden on the usually over-stretched medical resources. Discovering the significant contribution of BRCA1/2 mutations to breast cancer susceptibility allowed for the design of genetic tests that allows the medical practitioner to focus the care for those who need it most. However, BRCA1/2 mutations do not account for all breast cancer susceptibility genes and there are other genetic factors, known and unknown that may play a role in the development of such disease. The advent of whole-exome sequencing is offering a unique opportunity to identify the breast cancer susceptibility genes in each family of sufferers. The polymorphisms/mutations identified will then allow for personalizing the genetic screening tests accordingly. To this end, we have performed whole-exome sequencing of seven breast cancer patients with positive family history of the disease using the Agilent SureSelect™ Whole-Exome Enrichment kit and sequencing on the SOLiD™ platform. Results We have identified several coding single nucleotide variations that were either novel or rare affecting genes controlling DNA repair in the BRCA1/2 pathway. Conclusion The disruption of DNA repair pathways is very likely to contribute to breast cancer susceptibility in the Saudi population. PMID:25923920

  10. Family boundary characteristics, work-family conflict and life satisfaction: A moderated mediation model.

    PubMed

    Qiu, Lin; Fan, Jinyan

    2015-10-01

    Although work-family border and boundary theory suggest individuals' boundary characteristics influence their work-family relationship, it is largely unknown how boundary flexibility and permeability mutually influence work-family conflict and subsequent employee outcomes. Moreover, the existing work-family conflict research has been mainly conducted in the United States and other Western countries. To address these gaps in the work-family literature, the present study examines a moderated mediation model regarding how family boundary characteristics may influence individuals' work-family conflict and life satisfaction with a sample of 278 Chinese full-time employees. Results showed that employees' family flexibility negatively related to their perceived work interference with family (WIF) and family interference with work (FIW), and both these two relationships were augmented by individuals' family permeability. In addition, WIF mediated the relationship between family flexibility and life satisfaction; the indirect effect of family flexibility on life satisfaction via WIF was stronger for individuals with higher family permeability. The theoretical and managerial implications of these findings are discussed. PMID:25331584

  11. Familial mesothelioma: a report of two families

    SciTech Connect

    Hammar, S.P.; Bockus, D.; Remington, F.; Freidman, S.; LaZerte, G.

    1989-02-01

    Five reports of familial mesothelioma in which mesotheliomas occurred in two or more family members have been recorded in the medical literature. In this report, we describe two examples of familial mesothelioma. In one family, three brothers who worked in the asbestos insulation industry developed mesothelioma. In the second family, the father, who was occupationally exposed to asbestos, died from a tubulopapillary peritoneal mesothelioma 11 years before his son died from an identical histologic type of peritoneal mesothelioma. Our report, as with those previously recorded, suggests that genetic factors may be important in the genesis of some mesotheliomas.

  12. 'I don't see any point in telling them': attitudes to sharing genetic information in the family and carrier testing of relatives among British Pakistani adults referred to a genetics clinic.

    PubMed

    Shaw, Alison; Hurst, Jane A

    2009-04-01

    The sharing of genetic information following the diagnosis of a genetic condition can be important for managing familial risks for genetic conditions. This paper explores factors that impede or facilitate the sharing of genetic information within a sample of British Pakistani families. It draws from research investigating understandings of genetics and inheritance, attitudes to prenatal diagnosis and risk communication in the family that used methods of participant observation and interview with adults from 66 families of Pakistani origin referred to a genetics clinic in southern England. We found a lack of English often restricted one partner's access to genetic information and partners fluent in English sometimes withheld information to protect a partner (usually the wife) from blame, stigma or feelings of marital insecurity. Many couples felt genetic information was private to them as a couple and were unwilling to share it with the wider family, commenting on its potentially stigmatizing and emotionally and socially disruptive effects on themselves, their child and their marriage, as well as on the marriage prospects of other family members. Those who sought carrier testing because of a family history did so when considering their own marriage or parenting, sometimes on the insistence of an affected relative, but did not readily discuss carrier testing with other relatives. Despite the complex consanguinity in some families, a family-based approach to risk management is not necessarily any easier among British Pakistanis than other ethnic groups. PMID:19052940

  13. Resources for the Family Day Care Provider.

    ERIC Educational Resources Information Center

    Brown, Jeanne, Ed.; And Others

    The 34 brief articles in this sourcebook for family day care providers are presented mainly in two large sections: (1) management of family day care business, and (2) interaction with children. Many of these articles pose and provide answers to questions that are likely to occur to child caregivers, such as "Does the IRS really expect me to keep…

  14. Family Child Care Licensing Study, 1998.

    ERIC Educational Resources Information Center

    Children's Foundation, Washington, DC.

    This report details a survey of state child care regulatory agencies. Data on both small family child care homes (FCCH) and group or large family child care homes (LCCH or GCCH) are included and organized into 22 categories: (1) number of regulated homes; (2) definitions and regulatory requirements; (3) unannounced inspection procedure; (4)…

  15. Family Child Care Licensing Study, 1997.

    ERIC Educational Resources Information Center

    Children's Foundation, Washington, DC.

    This report details the findings of an annual survey of state child care regulatory agencies. The survey gathered data on both small family child care homes and group or large family child care homes in each of the 50 states, the District of Columbia, Puerto Rico and the Virgin Islands. The report's introduction lists the survey categories and…

  16. Strengthening Family Practices for Latino Families

    PubMed Central

    Chartier, Karen G.; Negroni, Lirio K.; Hesselbrock, Michie N.

    2010-01-01

    The study examined the effectiveness of a culturally-adapted Strengthening Families Program (SFP) for Latinos to reduce risks for alcohol and drug use in children. Latino families, predominantly Puerto Rican, with a 9–12 year old child and a parent(s) with a substance abuse problem participated in the study. Pre- and post-tests were conducted with each family. Parental stress, parent-child dysfunctional relations, and child behavior problems were reduced in the families receiving the intervention; family hardiness and family attachment were improved. Findings contribute to the validation of the SFP with Latinos, and can be used to inform social work practice with Puerto Rican families. PMID:20871785

  17. Incidence of Wife Abuse in Incestuous Families.

    ERIC Educational Resources Information Center

    Truesdell, Donna L.; And Others

    1986-01-01

    Investigates a largely uncharted dynamic in the literature--the incidence of wife abuse among incestuous families--and suggests that professional caregivers reevaluate conventional treatment modalities that are based on certain assumptions regarding the mother's role in incest. (Author)

  18. [The press and family planning].

    PubMed

    Abraham De D'ornellas, R

    1987-01-01

    The treatment in the press of family planning hinges on two fundamental factors: the taboo of the leftist groups and the taboo of the Catholic Church, whose head is against abortion under any circumstances. Leftist views insinuate that family planning is the genocidal plan of North American imperialists against the Third World and, in particular, against Latin America. This genocidal plan is supposed to subject poor populations to international schemes. In the press family planning is often treated in a sanctimonious fashion, lumping it together with topics like pornography, sex, and violence. In 1983 the daily newspaper Expreso published a supplement running every week for almost three months about the issue of population, which dealt fairly extensively with such topics as population and housing, education, employment, and urban proliferation, as well as responsible parenthood and child survival. In addition, there was a detailed description of contraceptive methods. In October 1986 another surprising thing happened: the President of Peru talked about the topic of family planning, which at the time was an act of courage. Since then much has changed; the whole world is interested in family planning and certain aspects of population. Since October 1986 more has been published in this domain than during the preceding 20 years. In contrast, the Church reacted differently to this issue: after some initial caution, the conference of Peruvian bishops attacked all methods of modern contraceptives and private institutions of family planning. The information boom in family planning will certainly continue. At the moment this flood of articles and editorials about the issue is an expression of the anxiety of families related to uncontrolled reproduction and the fear of overpopulation in large cities devoid of minimal services. PMID:12281466

  19. Unequal VH gene rearrangement frequency within the large VH7183 gene family is not due to recombination signal sequence variation, and mapping of the genes shows a bias of rearrangement based on chromosomal location.

    PubMed

    Williams, G S; Martinez, A; Montalbano, A; Tang, A; Mauhar, A; Ogwaro, K M; Merz, D; Chevillard, C; Riblet, R; Feeney, A J

    2001-07-01

    Much of the nonrandom usage of V, D, and J genes in the Ab repertoire is due to different frequencies with which gene segments undergo V(D)J rearrangement. The recombination signal sequences flanking each segment are seldom identical with consensus sequences, and this natural variation in recombination signal sequence (RSS) accounts for some differences in rearrangement frequencies in vivo. Here, we have sequenced the RSS of 19 individual V(H)7183 genes, revealing that the majority have one of two closely related RSS. One group has a consensus heptamer, and the other has a nonconsensus heptamer. In vitro recombination substrate studies show that the RSS with the nonconsensus heptamer, which include the frequently rearranging 81X, rearrange less well than the RSS with the consensus heptamer. Although 81X differs from the other 7183-I genes at three positions in the spacer, this does not significantly increase its recombination potency in vitro. The rearrangement frequency of all members of the family was determined in microMT mice, and there was no correlation between the in vitro recombination potential and V(H) gene rearrangement frequency in vivo. Furthermore, genes with identical RSS rearrange at different frequencies in vivo. This demonstrates that other factors can override differences in RSS potency in vivo. We have also determined the gene order of all V(H)7183 genes in a bacterial artificial chromosome contig and show that most of the frequently rearranging genes are in the 3' half of the region. This suggests that chromosomal location plays an important role in nonrandom rearrangement of the V(H)7183 genes. PMID:11418657

  20. THE FAMILY FLAVIVIRIDAE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The family Flaviviridae, commonly referred to as the flavivirus family, contains viruses important to both human and veterinary medicine. The term flavivirus can be confusing because it is used both to refer to the family and one of the three genera within that family. The proper name of the viral...

  1. Black Families. Third Edition.

    ERIC Educational Resources Information Center

    McAdoo, Harriette Pipes, Ed.

    The chapters of this collection explore the experiences of black families in the United States and Africa, today and in the past. They are: (1) "African American Families: A Historical Note" (John Hope Franklin); (2) "African American Families and Family Values" (Niara Sudarkasa); (3) "Old-Time Religion: Benches Can't Say 'Amen'" (William Harrison…

  2. [Teaching about Family Law].

    ERIC Educational Resources Information Center

    Ryan, John Paul, Ed.

    1992-01-01

    This issue of "Focus on Law Studies""contains a special emphasis on teaching about law and the family", in the form of the following three articles: "Teaching Family Law: Growing Pains and All" (Susan Frelich Appleton); "The Family Goes to Court: Including Law in a Sociological Perspective on the Family" (Mary Ann Lamanna); and Michael Grossberg's…

  3. Family Day Care.

    ERIC Educational Resources Information Center

    Seefeldt, Carol, Ed.; Dittmann, Laura L., Ed.

    This handbook is intended to provide information for the family seeking day care for its children, the family wishing to begin a family day care service, and an agency considering implementing a network of family day care homes. The first section of the handbook is especially intended for parents who are trying to decide which type of day care…

  4. Black Families. Third Edition.

    ERIC Educational Resources Information Center

    McAdoo, Harriette Pipes, Ed.

    The chapters of this collection explore the experiences of black families in the United States and Africa, today and in the past. They are: (1) "African American Families: A Historical Note" (John Hope Franklin); (2) "African American Families and Family Values" (Niara Sudarkasa); (3) "Old-Time Religion: Benches Can't Say 'Amen'" (William Harrison…

  5. Families in Transition .

    ERIC Educational Resources Information Center

    Bundy, Michael L., Ed.; Gumaer, James, Ed.

    1984-01-01

    Focuses on disrupted families and the role of the school counselor in helping children adjust. Describes characteristics of healthy families, and discusses the transition to the blended family, effects of divorce groups on children's classroom behavior, counseling children in stepfamilies, single-parent families, and parenting strengths of single…

  6. Family Participation in Policymaking.

    ERIC Educational Resources Information Center

    Caplan, Elizabeth, Ed.; Blankenship, Kelly, Ed.; McManus, Marilyn, Ed.

    1998-01-01

    This bulletin focuses on family participation in mental health policymaking and highlights state efforts to increase family involvement. Articles include: (1) "Promoting Family Member Involvement in Children's Mental Health Policy Making Bodies," which describes how different states are promoting family member involvement in various statutory and…

  7. Familial colorectal cancer.

    PubMed

    Lung, M S; Trainer, A H; Campbell, I; Lipton, L

    2015-05-01

    Identifying individuals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected individual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz-Jeghers syndrome. An individual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up. PMID:25955461

  8. Singing about family planning.

    PubMed

    Emah, E

    1993-01-01

    The Nigerian Family Health services project teamed up with the Johns Hopkins University's Population Communication Services to produce songs called "Choices" and "Wait for Me." The songs, which were about sexual responsibility, were performed by popular music stars King Sunny Ade and Onyeka Onwenu and appeared under King Sonny Ade's long playing albums in 1989. Teaching sexual responsibility through song was suggested in focus group discussions. Findings indicated that young people were responsive to messages about sexual responsibility, postponing sex or saying "no," male sexual responsibility, and children by informed choice and not chance among married couples. An impact assessment of the songs was conducted in February, 1991. Survey findings revealed that 64% of urban and 22% of rural respondents recalled having heard the songs and seen the videos. 48% of urban youth discussed the songs with friends, and 27% discussed the songs with sexual partners. 90% of respondents reported agreement with the message that couples should have only the number of children that they can care for, and that couples should practice family planning. The target population that was affected most by the songs was aged less than 35 years. The strategy of using songs to teach youth responsible parenting appears to be a reliable strategy for mass education and mobilization. There is mass support from among members of the National Council for Women's Societies, the Planned Parenthood Federation of Nigeria, and Coca Cola Corporation, as well as the public at large. PMID:12318626

  9. Split families unified

    NASA Astrophysics Data System (ADS)

    Craig, Nathaniel; Dimopoulos, Savas; Gherghetta, Tony

    2012-04-01

    We present a simple supersymmetric model of split families consistent with flavor limits that preserves the successful prediction of gauge coupling unification and naturally accounts for the Higgs mass. The model provides an intricate connection between the Standard Model flavor hierarchy, supersymmetric flavor problem, unification and the Higgs mass. In particular unification favors a naturally large Higgs mass from D-term corrections to the quartic couplings in the Higgs potential. The unification scale is lowered with a stable proton that can account for the success of b - τ Yukawa coupling unification. The sparticle spectrum is similar to that of natural supersymmetry, as motivated by the supersymmetric flavor problem and recent LHC bounds, with a heavy scalar particle spectrum except for a moderately light stop required for viable electroweak symmetry breaking. Finally, Higgs production and decays, NLSP decays, and new states associated with extending the Standard Model gauge group above the TeV scale provide signatures for experimental searches at the LHC.

  10. The utility of exome sequencing for genetic diagnosis in a familial microcephaly epilepsy syndrome

    PubMed Central

    2014-01-01

    Background Despite remarkable advances in genetic testing, many adults with syndromic epilepsy remain without a molecular diagnosis. The challenge in providing genetic testing for this patient population lies in the extensive genetic heterogeneity associated with epilepsy. Even for the subset of epilepsy patients that present with a defining feature, such as microcephaly, the number of possible genes that would require interrogation by Sanger sequencing is extensive and often prohibitively expensive. Case presentation We report a family of French Canadian descent with four adult children affected with severe intellectual disability, epilepsy and microcephaly born to consanguineous parents and evaluated by the Genetics Service to provide informed genetic counseling to unaffected family members regarding possible recurrence risks. We used whole-exome sequencing (WES) of DNA from one affected sibling as a first-line diagnostic tool and compared the prioritization of variants using two strategies: 1) focusing on genes with homozygous variants; and, 2) focusing on genes associated with microcephaly. Both approaches prioritized the same homozygous novel frameshift mutation (p.Arg608Serfs*26) in WDR62, a gene known to cause autosomal recessive primary microcephaly. Sanger sequencing confirmed the presence of the homozygous mutation in the other three affected siblings. Conclusions WES and subsequent filtering of the rare variants in a single affected family member led to the rapid and cost-effective identification of a novel homozygous frameshift mutation in WDR62, thereby explaining the severe neurodevelopmental disorder in this family and facilitating genetic counseling. Our findings support WES as an effective first-line diagnostic tool in families presenting with rare genetically heterogeneous neurological disorders. PMID:24479948

  11. La maladie de Wilson: à propos d'un cas familial

    PubMed Central

    Mouzari, Yassine; Abdelkhalek, Ryme; El Asri, Fouad; Reda, Karim; Oubaaz, Abedelbarre

    2014-01-01

    La maladie de Wilson est une maladie rare autosomique récessive due à une diminution de l’élimination du cuivre dans la bile et son accumulation toxique dans les organes en particulier le cerveau, le foie, la cornée et le rein d'où son hétérogénéité clinique. Les manifestations ophtalmologiques représentent des critères diagnostiques importants. Le traitement précoce permet une réversibilité des déficits; non traitée la maladie de Wilson est létale. Nous rapportons un cas familial de la maladie de Wilson: deux membres d'une fratrie issus d'un mariage consanguin étaient atteints de la maladie de Wilson dans ses trois formes cliniques: hépatique, neurologique et psychiatrique. Les manifestations ophtalmologiques de la maladie de Wilson sont l'anneau de Keyser Fleischer et la cataracte en tournesol, l'atteinte hépatique se manifeste par une hépatite chronique et une cirrhose, la symptomatologie neurologique et psychiatrique est variée; on retrouve à l'IRM une atteinte prédominante aux noyaux gris centraux. Le diagnostic positif de la maladie de Wilson est fait sur la triade: présence de l'anneau de Keyser Fleischer, céruloplasmine sanguine basse et augmentation de la cuprurie de 24 heures. Le traitement précoce basé sur les chélateurs de cuivre permet la réversibilité des lésions. Le pronostic dépend de la sévérité de la maladie lors du diagonstic et de la qualité de la prise en charge. Ce cas familial de la maladie de Wilson démontre l'importance du dépistage des membres pré symptomatique par un examen ophtalmologique et général rigoureux. PMID:25426217

  12. Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy

    SciTech Connect

    Thomas, P.M.; Cote, G.J.; Hallman, D.M.; Mathew, P.M.

    1995-02-01

    Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a rare, autosomal recessive disease of unregulated insulin secretion, defined by elevations in serum insulin despite severe hypoglycemia. We used the homozygosity gene-mapping strategy to localize this disorder to the region of chromosome 11p between markers D11S1334 and D11S899 (maximum LOD score 5.02 [{theta} = 0] at marker D11S926) in five consanguineous families of Saudi Arabian origin. These results extend those of a recent report that also placed PHHI on chromosome 11p, between markers D11S926 and D11S928. Comparison of the boundaries of these two overlapping regions allows the PHHI locus to be assigned to the 4-cM region between the markers D11S926 and D11S899. Identification of this gene may allow a better understanding of other disorders of glucose homeostasis, by providing insight into the regulation of insulin release. 37 refs., 2 figs., 4 tabs.

  13. Familial hypocalciuric hypercalcemia associated with mutation in the human Ca{sup 2+}-sensing receptor gene

    SciTech Connect

    Aida, Kaoru; Koishi, Sawako; Inoue, Masaharu

    1995-09-01

    Familial hypocalciuric hypercalcemia (FHH) is generally characterized by lifelong hypercalcemia without hypercalciuria and is inherited in an autosomal dominant manner. Affected individuals show abnormal parathyroid and renal responses to changes in the extracellular calcium concentration. A Japanese FHH family was screened for mutations in the Ca{sup 2+} -sensing receptor gene by the polymerase chain reaction and single strand conformation polymorphism. The proband with hypercalcemia showed an abnormal pattern in exon 1 of the gene, whereas her two sisters with normocalcemia showed a normal pattern. The consanguineous parents with borderline serum calcium concentrations showed both patterns. Nucleotide sequence analysis identified a G{yields}C point mutation at nucleotide 118 that resulted in the conversion of the normal codon for proline into a codon for alanine at amino acid 40 (numbered according to the bovine complementary DNA). The proband was homozygous for the mutation, and the parents were heterozygous. These results imply that this mutation in the human Ca{sup 2+}-sensing receptor gene causes FHH and that the dosage of the gene defect determines disease phenotype. 33 refs., 4 figs., 1 tab.

  14. Novel Deletion of SERPINF1 Causes Autosomal Recessive Osteogenesis Imperfecta Type VI in Two Brazilian Families

    PubMed Central

    Moldenhauer Minillo, Renata; Sobreira, Nara; de Fatima de Faria Soares, Maria; Jurgens, Julie; Ling, Hua; Hetrick, Kurt N.; Doheny, Kimberly F.; Valle, David; Brunoni, Decio; Alvarez Perez, Ana B.

    2014-01-01

    Autosomal recessive osteogenesis imperfecta (OI) accounts for 10% of all OI cases, and, currently, mutations in 10 genes (CRTAP, LEPRE1, PPIB, SERPINH1, FKBP10, SERPINF1, SP7, BMP1, TMEM38B, and WNT1) are known to be responsible for this form of the disease. PEDF is a secreted glycoprotein of the serpin superfamily that maintains bone homeostasis and regulates osteoid mineralization, and it is encoded by SERPINF1, currently associated with OI type VI (MIM 172860). Here, we report a consanguineous Brazilian family in which multiple individuals from at least 4 generations are affected with a severe form of OI, and we also report an unrelated individual from the same small city in Brazil with a similar but more severe phenotype. In both families the same homozygous SERPINF1 19-bp deletion was identified which is not known in the literature yet. We described intra- and interfamilial clinical and radiological phenotypic variability of OI type VI caused by the same homozygous SERPINF1 19-bp deletion and suggest a founder effect. Furthermore, the SERPINF1 genotypes/phenotypes reported so far in the literature are reviewed. PMID:25565926

  15. Family Allowances and Fertility: Socioeconomic Differences

    PubMed Central

    SCHELLEKENS, JONA

    2009-01-01

    This article explores socioeconomic differences in the effect of family allowances on fertility. Although several studies have examined the relationship between cash benefits and fertility, few studies have addressed the possible differential effects of cash benefits on families of different income or education levels. I reconstructed the birth histories of women in the past two Israeli censuses of 1983 and 1995 to study socioeconomic differences in the effect of family allowances up to the seventh parity. The results indicate that family allowances have a significant effect at every parity. Using female education as an indicator of socioeconomic status, I find that socioeconomic status is a significant modifier of the effect of family allowances. Family allowances seem to have a relatively large impact on more-educated women. PMID:19771939

  16. AIDS and the family: families take care.

    PubMed

    1994-01-01

    In 1994, the International Year of the Family, the WHO's Global Program on AIDS (GPA) is marking World AIDS Day under the banner AIDS and the Family. Traditional and non-traditional families have a crucial role to play in addressing the HIV/AIDS pandemic. In the run-up to World AIDS Day--and on 1 December itself--GPA urges the world to focus on how families of all kinds are affected by AIDS, on how they can be more effective in prevention and care, and on how they can contribute to global efforts against the disease. For GPA, any group of people linked by feelings of trust, mutual support and a common destiny may be seen as a family. The concept need not be limited to ties of blood, marriage, sexual partnership or adoption. In this light, religious congregations, workers' associations, support groups of people with HIV/AIDS, gangs of street children, circles of drug injectors, collectives of sex workers and networks of governmental, nongovernmental and intergovernmental organizations may all be regarded as families within the over-arching family of humankind. Every kind of family should take care to protect its members from HIV. And all families should take care of those among them who fall ill with AIDS. Families take care. "Families whose bonds are based on love, trust, nurturing and openness are best placed to protect their members from infection and give compassionate care and support to those affected by HIV or AIDS," says Dr. Hiroshi Nakajima, Director-General of the WHO [World Health Organization]. PMID:12287963

  17. Making sense of nuclear localization: a zinc-finger protein encoded by a cytoplasmically replicating plant RNA virus acts a transcription factor: a novel function for a member of large family of viral proteins.

    PubMed

    Lukhovitskaya, Nina I; Gushchin, Vladimir A; Solovyev, Andrey G; Savenkov, Eugene I

    2013-08-01

    Recent studies have uncovered numerous nucleus-localized proteins encoded by plant RNA viruses. Whereas for some of these viruses nuclear (or, more specifically, nucleolar) passage of the proteins is needed for the virus movement within the plant or suppression of host defense, the nuclear function of these proteins remains largely unknown. Recently, the situation has been clarified for one group of plant RNA viruses, the Carlaviruses. Being positive-stranded RNA viruses, carlaviruses multiply exclusively in the cytoplasm. Chrysanthemum virus B (CVB, a carlavirus) encodes a zinc-finger protein p12 targeted to the nucleus in a nuclear localization signal-dependent manner. In a recent work, we demonstrated that p12 directly interacts with chromatin and plant promoters, thus, acts as a eukaryotic transcription factor (TF) and activates expression of a host TF involved in regulation of cell size and proliferation to favor virus infection. Therefore our studies identified a novel nuclear stage of in CVB infection involving modulation of host gene expression and plant development. Whereas it is well established that any RNA virus actively replicating in the cell causes changes in the transcriptome, our study expanded this view by showing that some positive-stranded RNA viruses can directly manipulate host transcription by encoding eukaryotic TFs. PMID:23759549

  18. Strengthening Family Practices for Latino Families

    ERIC Educational Resources Information Center

    Chartier, Karen G.; Negroni, Lirio K.; Hesselbrock, Michie N.

    2010-01-01

    This study examined the effectiveness of a culturally adapted Strengthening Families Program (SFP) for Latinos to reduce risks for alcohol and drug use in children. Latino families, predominantly Puerto Rican, with a 9- to 12-year-old child and a parent(s) with a substance abuse problem participated in the study. Pre- and post-tests were conducted…

  19. Strengthening Family Practices for Latino Families

    ERIC Educational Resources Information Center

    Chartier, Karen G.; Negroni, Lirio K.; Hesselbrock, Michie N.

    2010-01-01

    This study examined the effectiveness of a culturally adapted Strengthening Families Program (SFP) for Latinos to reduce risks for alcohol and drug use in children. Latino families, predominantly Puerto Rican, with a 9- to 12-year-old child and a parent(s) with a substance abuse problem participated in the study. Pre- and post-tests were conducted…

  20. Family perspective on a family care program.

    PubMed

    Shimizu, Helena Eri; Rosales, Carlos

    2008-01-01

    This study aimed at assessing the family's perspective on a family care program to better understand the challenges and potential capacities for changing the health care model. A qualitative study was carried out to assess the Family Health Program in the city of São Sebastião, Brasília, Brazil. Data was collected through direct systematic observations of the workflow developed by the program's team, and through focal groups with family members. The discourse of the collective subject was used in data analysis and showed that health prevention and promotion actions and the relationship between providers and consumers were positively evaluated while access to health services, drugs and providers was negatively evaluated. There is no assurance of comprehensive and continuous care to the family, which points to the need of reviewing the strategies of health service organization for more effective involvement of the community to meet their health needs. PMID:19061026

  1. Invest in Family*

    PubMed Central

    Shah, Nilesh; De Sousa, Avinash

    2015-01-01

    The family is an integral part of one's life. It is very essential that every individual employed or unemployed invests time therein. The family is a source of support and growth for an individual, and the lack of family support or loneliness may be a causative factor in the genesis of psychiatric disorders, especially depression. In India, family plays a paramount role when it comes to mental health of the individual. Tips on how one should invest time in one's family along with the role of a family in one's personal and social structure are discussed. PMID:25838732

  2. Work and Family: 1992. Status Report and Outlook.

    ERIC Educational Resources Information Center

    Galinsky, Ellen

    Many parents are currently struggling to balance job and family responsibilities. Such attempts bring about changes in work and individual attitudes. This report presents the status of work and family in 1992, as well as the nature and direction of workplace changes to accommodate families. The report indicates that large United States companies…

  3. Families: It's About Time! = Les familles ont besoin de temps!

    ERIC Educational Resources Information Center

    McCloskey, Donna, Ed.

    1997-01-01

    This document presents a broad view of the Great Canadian Family--all of Canada's families, large and small, "traditional" and otherwise. The issue also examines the challenges of family life at the end of the twentieth century, in two major articles. The first article, "Of Wings and Roots" (Alan Mirabelli and Robert Glossop), presents an overview…

  4. [Familial choices and procreative behavior of the clientele of familial planning centers].

    PubMed

    Texier, G

    1972-01-01

    This is the final article in a series on a survey of 710 couples who consulted for family planning in Lyons and Paris in 1968, Agreement before marriage on planned family size was correlated with success in achieving this plan, especially in the young, well educated, and in rightists. The number of children was directly related to desired family size, but a large proportion of those without a plan had uuplanned children. Factors tending toward larger desired family size were religious practice, higher education, and income. Factors associated with larger existing families were lower education and income, religous practice, female unemployment, longer duration of marriage, and use of traditional contrceptive methods. Among those with only elementary education, the proportion with 3 or more children remained constant with rising income, but among those with postsecondary education the proportion of large families was closely correlated with income. Couples who considered their families complete or who considered their family planning successful were overrepresented by the well educated, while couples with incomplete families or characterized by imperfect planning were more often secondary school graduates. Success in family planning was only apparent in many cases, since these results were often achieved by abortion. PMID:4636768

  5. Genetic heterogeneity of familial hemiplegic migraine

    SciTech Connect

    Joutel, A.; Ducros, A.; Vahedi, K.

    1994-09-01

    Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of migraine with aura, characterized by the occurrence of a transient hemiplegia during the aura. We previously mapped the affected gene to the short arm of chromosome 19, within a 30 cM interval bracketed by D19S216 and D19S215. Linkage analysis conducted on 2 large FHM pedigrees did not show evidence of heterogeneity, despite their clinical differences due to the presence in one family of a cerebellar ataxia and a nystagmus. Herein we report linkage data on 9 additional FHM families including 2 other ones with cerebellar ataxia. Analysis was conducted with a set of 7 markers spanning the D19S216-D19S215 interval. Two point and multipoint lodscores analysis as well as HOMOG testing provided significant evidence for genetic heterogenity. Strong evidence of linkage was obtained in 3 families and absence of linkage in 6 families. Thus within the 11 families so far tested, 5 were linked, including those with an associated cerebellar ataxia. We could not find any clinical difference between the {open_quotes}pure{close_quotes} FHM families whether or not they were linked. This study also allowed us to establish that the most likely location of the gene is a 12 cM interval bracketed by D19S413 and D19S226. One of the unlinked family was large enough to conduct genetic mapping of the affected gene. Data will be presented at the meeting.

  6. Charcot-Marie-Tooth Disease Type 4H Resulting from Compound Heterozygous Mutations in FGD4 from Nonconsanguineous Korean Families.

    PubMed

    Hyun, Young Se; Lee, Jinho; Kim, Hye Jin; Hong, Young Bin; Koo, Heasoo; Smith, Alec S T; Kim, Deok-Ho; Choi, Byung-Ok; Chung, Ki Wha

    2015-11-01

    Charcot-Marie-Tooth disease type 4H (CMT4H) is an autosomal recessive demyelinating subtype of peripheral enuropathies caused by mutations in the FGD4 gene. Most CMT4H patients are in consanguineous Mediterranean families characterized by early onset and slow progression. We identified two CMT4H patients from a Korean CMT cohort, and performed a detailed genetic and clinical analysis in both cases. Both patients from nonconsanguineous families showed characteristic clinical manifestations of CMT4H including early onset, scoliosis, areflexia, and slow disease progression. Exome sequencing revealed novel compound heterozygous mutations in FGD4 as the underlying cause in both families (p.Arg468Gln and c.1512-2A>C in FC73, p.Met345Thr and c.2043+1G>A (p.Trp663Trpfs*30) in FC646). The missense mutations were located in highly conserved RhoGEF and PH domains which were predicted to be pathogenic in nature by in silico modeling. The CMT4H occurrence frequency was calculated to 0.7% in the Korean demyelinating CMT patients. This study is the first report of CMT4H in Korea. FGD4 assay could be considered as a means of molecular diagnosis for sporadic cases of demyelinating CMT with slow progression. PMID:26400421

  7. Identification of a Novel MYO15A Mutation in a Chinese Family with Autosomal Recessive Nonsyndromic Hearing Loss

    PubMed Central

    Xia, Hong; Huang, Xiangjun; Guo, Yi; Hu, Pengzhi; He, Guangxiang; Deng, Xiong; Xu, Hongbo; Yang, Zhijian; Deng, Hao

    2015-01-01

    Autosomal recessive nonsyndromic hearing loss (ARNSHL) is a genetically heterogeneous sensorineural disorder, generally manifested with prelingual hearing loss and absence of other clinical manifestations. The aim of this study is to identify the pathogenic gene in a four-generation consanguineous Chinese family with ARNSHL. A novel homozygous variant, c.9316dupC (p.H3106Pfs*2), in the myoxin XVa gene (MYO15A) was identified by exome sequencing and Sanger sequencing. The homozygous MYO15A c.9316dupC variant co-segregated with the phenotypes in the ARNSHL family and was absent in two hundred normal controls. The variant was predicted to interfere with the formation of the Myosin XVa-whirlin-Eps8 complex at the tip of stereocilia, which is indispensable for stereocilia elongation. Our data suggest that the homozygous MYO15A c.9316dupC variant might be the pathogenic mutation, and exome sequencing is a powerful molecular diagnostic strategy for ARNSHL, an extremely heterogeneous disorder. Our findings extend the mutation spectrum of the MYO15A gene and have important implications for genetic counseling for the family. PMID:26308726

  8. Examining the family-centred approach to genetic testing and counselling among UK Pakistanis: a community perspective.

    PubMed

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

    2013-01-01

    WHO advice suggests a family-centred approach for managing the elevated risk of recessively inherited disorders in consanguineous communities, whilst emerging policy recommends community engagement as an integral component of genetic service development. This paper explores the feasibility of the family-centred approach in the UK Pakistani origin community. The study took place within a context of debate in the media, professional and lay circles about cousin marriage causing disability in children. Using qualitative methods, a total of six single-sex focus group discussions (n = 50) were conducted in three UK cities with a high settlement of people of Pakistani origin. Tape-recorded transcripts were analysed using framework analysis. Kinship networks within Pakistani origin communities are being sustained and marriage between close blood relatives continues to take place alongside other marriage options. Study participants were critical of what was perceived as a prevalent notion that cousin marriage causes disability in children. They were willing to discuss cousin marriage and disability, share genetic information and engage with genetic issues. A desire for accurate information and a public informed about genetic issues was articulated whilst ineffective communication of genetic risk information undermined professionals in their support role. This study suggests a community that is embracing change, one in which kinship networks are still active and genetic information exchange is taking place. At the community level, these are conditions supportive of the family-centred approach to genetic testing and counselling. PMID:23086468

  9. Clinical, laboratory, and immunological studies of a family with a high prevalence of generalized prepubertal and juvenile periodontitis.

    PubMed

    López, N J

    1992-05-01

    A study of a consanguineous family with a high prevalence of localized juvenile periodontitis (LJP) and generalized prepubertal periodontitis (GPP) was done over a 7-and-a-half year period. The parents had adult periodontitis, while 2 daughters, aged 13 and 15, had LJP. Furthermore, 2 other daughters, ages 14 and 10, and a son, aged 9, were affected by GPP. Two remaining siblings were not affected. Clinical and radiographic examinations on all family members were done, and chemotaxis for blood neutrophils was assessed. Laboratory tests, immunological examinations, and evaluation for neutrophil functions were done on the GPP patients. Microbiological cultures were performed on 2 of the GPP patients, as well as in the mother. The mother, the 2 LJP patients, and 1 of the unaffected siblings had depressed PMN chemotaxis. The other family members, including the 3 GPP patients, had normal PMN chemotaxis. GPP patients did not have any systemic disease, and evidence of major defects in the immunological functions was not detected. LJP patients were successfully treated with root planing, subgingival curettage, and tetracycline therapy. Intensive periodontal therapy, combined with systemic administration of antibiotics, was not effective in halting periodontal tissue destruction in the 3 GPP patients. Results indicate that the underlying cause of GPP is not always related to leukocyte dysfunction. Since Actinobacillus actinomycetemcomitans was the most frequent pathogen found in subgingival microflora of 2 of the GPP patients, it is assumed that it may play a key role in the etiology of GPP. PMID:1527690

  10. Familial Pulmonary Fibrosis

    MedlinePLUS

    ... is two or more primary biological family members (parent, child, or sibling) with the diagnosis of IPF or ... when two or more primary biological family members (parent, child, or sibling) have the diagnosis of an Idiopathic ...

  11. Familial Pulmonary Fibrosis

    MedlinePLUS

    ... are here: Health Information > Condition Information Familial Pulmonary Fibrosis: Overview When two or more members within the ... Programs and Services Doctors Who Treat Familial Pulmonary Fibrosis No doctors are currently listed for this condition. ...

  12. Family Learning Vacation.

    ERIC Educational Resources Information Center

    Carbin, Clifton F.

    1986-01-01

    "Family learning vacations" 5-10 day summer residential programs for families with deaf children, are described. Guidelines for establishing such a program are given concerning rationale, physical plant, eligibility, scheduling, parent activities, children's activities, and evaluation. (Author/DB)

  13. Assessing Postpartum Family Functioning

    PubMed Central

    Midmer, Deana; Talbot, Yves

    1988-01-01

    The birth of a child requires adaptation and reorganization within the family system in order to accommodate the new family member and to allow the family to continue in its psychosocial development. Knowledge of the normative and transitional changes required at this stage of family life will enhance family practitioners' understanding of some of the common concerns and complaints related to them by various family members during the postpartum period. The Family FIRO model represents a helpful conceptual framework to increase the family physician's understanding of the issues of inclusion, control, and intimacy that are highlighted during the transition to parenthood. The authors briefly present this model and discuss its application to postpartum adjustment and its implications for health-care professionals. PMID:21253238

  14. Fatherhood and Family Support.

    ERIC Educational Resources Information Center

    Goetz, Kathy, Ed.

    1996-01-01

    On the assumption that fathers have been relatively absent from family support programs, this publication of the Family Resource Coalition addresses the role of fathers in family support programs, examines the impact of fathers on their children, and describes programs involving fathers successfully. Articles include: (1) "What's Behind the…

  15. Families and Assisted Living*

    PubMed Central

    Gaugler, Joseph E.; Kane, Robert L.

    2008-01-01

    Purpose Despite growing research on assisted living (AL) as a residential care option for older adults, the social ramifications of residents' transitions to assisted living is relatively unexplored. This article examines family involvement in AL, including family structures of residents, types of involvement from family members living outside the AL, and outcomes for these family members. Design and Methods We reviewed current literature utilizing the MEDLINE, PSYCINFO, and CINAHL databases to identify AL studies that examined issues pertaining to families or informal care. Following the screening of abstracts, 180 reports were retrieved for further review, and 62 studies were selected for inclusion. Results Families visit residents frequently and provide a wide range of instrumental assistance but provide only minimal personal care. Studies of family outcomes indicated relatively high satisfaction, but potential care burden as well. Implications How family care and involvement occurs in AL in relation to formal care provision and whether various types of formal-informal care integration influence family outcomes remains unclear. We suggest a research agenda that attempts to tease out causal relationships for family involvement, differentiate family roles, and implement longitudinal analyses for a range of family outcomes. PMID:18162571

  16. Doing Better for Families

    ERIC Educational Resources Information Center

    OECD Publishing (NJ3), 2011

    2011-01-01

    All OECD governments want to give parents more choice in their work and family decisions. This book looks at the different ways in which governments support families. It seeks to provide answers to questions like: Is spending on family benefits going up, and how does it vary by the age of the child? Has the crisis affected public support for…

  17. Establishing Family Math.

    ERIC Educational Resources Information Center

    Bobango, Janet, Milgram, Joel

    1993-01-01

    The Family Math Program is an outgrowth of the Equals Program at the Lawrence Hall of Science at UC Berkeley. Piloted in 1982 in Richmond, California, this widespread program boasts a simple philosophy: Families "doing math" will get the same result as families who read--improved skills and enjoyment. The program also confronts parental math…

  18. Learning from Latino Families

    ERIC Educational Resources Information Center

    Auerbach, Susan

    2011-01-01

    As a researcher in parent engagement in school and former parent activist, the author shares three lessons for sparking more authentic partnerships between schools and immigrant families. First, schools need to move away from deficit thinking and validate families' cultures. In the case of Latino immigrant families, this entails understanding…

  19. The Family Leukemia Association

    ERIC Educational Resources Information Center

    Pollitt, Eleanor

    1976-01-01

    An association of families of children with leukemia, the Family Leukemia Association (FLA), was recently established in Toronto. This paper discusses (a) philosophy of the FLA; (b) formative years of this organization; (c) problems encountered by leukemic children and their families; and (d) the FLA's past and future educational and social…

  20. The Family Leukemia Association

    ERIC Educational Resources Information Center

    Pollitt, Eleanor

    1976-01-01

    An association of families of children with leukemia, the Family Leukemia Association (FLA), was recently established in Toronto. This paper discusses (a) philosophy of the FLA; (b) formative years of this organization; (c) problems encountered by leukemic children and their families; and (d) the FLA's past and future educational and social…

  1. Learning from Latino Families

    ERIC Educational Resources Information Center

    Auerbach, Susan

    2011-01-01

    As a researcher in parent engagement in school and former parent activist, the author shares three lessons for sparking more authentic partnerships between schools and immigrant families. First, schools need to move away from deficit thinking and validate families' cultures. In the case of Latino immigrant families, this entails understanding…

  2. Focus on the Family.

    ERIC Educational Resources Information Center

    Hardy, James M.

    This research attempts to evaluate the YMCA's program in terms of its effect upon the family members it serves. The study was designed to: (1) classify, by descriptive types, the various kinds of YMCA operations which serve the family, identifying their characteristic differences; (2) examine and describe operating practices of family YMCAs…

  3. Year of the Family.

    ERIC Educational Resources Information Center

    California Agriculture, 1994

    1994-01-01

    This special issue focuses on problems and challenges confronting the California family and on research and extension efforts to provide at least partial answers. Research briefs by staff include "Challenges Confront the California Family" (state trends in poverty, divorce, single-parent families, child abuse, delinquency, teen births, limited…

  4. Family Customs and Traditions.

    ERIC Educational Resources Information Center

    MacGregor, Cynthia

    Recognizing the importance of maintaining open communication with immediate and extended family members, this book provides a compilation of ideas for family traditions and customs that are grounded in compassion and human kindness. The traditions were gathered from families in the United States and Canada who responded to advertisements in…

  5. The Resiliency of Families.

    ERIC Educational Resources Information Center

    Morrison, T. R.

    According to researchers, the family may be changing but it is still one of the central institutions in society. Studies report a shift in more than 20 attitudes and values, most of which relate to the context of family life. Specifically, these include attitudes toward marriage, divorce, childbearing, childrearing, working women, family violence,…

  6. Family Customs and Traditions.

    ERIC Educational Resources Information Center

    MacGregor, Cynthia

    Recognizing the importance of maintaining open communication with immediate and extended family members, this book provides a compilation of ideas for family traditions and customs that are grounded in compassion and human kindness. The traditions were gathered from families in the United States and Canada who responded to advertisements in…

  7. Family Violence: An Overview.

    ERIC Educational Resources Information Center

    National Center on Child Abuse and Neglect (DHHS/OHDS), Washington, DC.

    Family violence is a widespread problem; research has shown multiple factors are associated with family violence. Types of family violence include spouse abuse; elder abuse and neglect; child abuse and neglect; parent abuse; and sibling abuse. There are three types of spouse abuse: physical abuse, sexual violence, and psychological/emotional…

  8. Family Issues for the Nineties.

    ERIC Educational Resources Information Center

    Mirabelli, Alan

    This presentation reviews the characteristics of the Canadian family at present. Discussion focuses on divorce, family structure, reproductive technology, fertility, family size, family mobility, family support, government role, women's participation in the labor force, daily family routines, television viewing, work and the family, the need for…

  9. Genetic heterogeneity of familial hemiplegic migraine

    SciTech Connect

    Joutel, A.; Ducros, A.; Delrieu, O.; Maziaceck, J.; Tournier-Lasserve, E.; Vahedi, K. |; Bousser, M.G.; Ponsot, G.; Gouttiere, F.; Labauge, P.; Mancini, J.

    1994-12-01

    Familial hemiplegic migraine (FHM) is an autosomal dominant variety of migraine with aura. We previously mapped a gene for this disorder to the short arm of chromosome 19, within a 30-cM interval bracketed by D19S216 and D19S215. Linkage analysis conducted on two large pedigrees did not show any evidence of heterogeneity, despite their clinical differences due to the presence, in one family, of cerebellar ataxia and nystagmus. Herein we report linkage data on seven additional FHM families including another one with cerebellar ataxia. Analysis was conducted with a set of seven markers spanning the D19S216-D19S215 interval. Two-point and multipoint strong evidence for genetic heterogeneity. Strong evidence of linkage was obtained in two families and of absence of linkage in four families. The posterior probability of being of the linked type was >.95 in the first two families and <.01 in four other ones. It was not possible to draw any firm conclusion for the last family. Thus, within the nine families so far tested, four were linked, including those with associated cerebellar ataxia. We could not find any clinical difference between the pure FHM families regardless of whether they were linked. In addition to the demonstration of genetic heterogeneity of FHM, this study also allowed us to establish that the most likely location of the gene was within an interval of 12 cM between D19S413 and D19S226.

  10. Family Spirituality and Family Health Among Korean-American Elderly Couples.

    PubMed

    Kim, Suk-Sun; Kim-Godwin, Yeoun Soo; Koenig, Harold G

    2016-04-01

    Spirituality has been regarded as an individual and private matter; consequently, research on spirituality as a family phenomenon has been largely neglected. In addition, most published research has been focused on Western cultures. The purpose of this study was to explore the experience of family spirituality and how it influences health among Korean-American elderly couples who are the first generation to reside in the Southeastern USA. A thematic and interpretive data analysis method was used. Thirteen elderly couples (N = 26) participated in in-depth individual interviews in Korean with the primary author. Interviews were audio-taped, transcribed, and then translated by two bilingual researchers with a background in Korean and American culture. Three main themes of family spirituality were identified: (1) family togetherness, (2) family interdependence, and (3) family coping. Also, participants reported that family spirituality strengthened family health by fostering family commitment, improving emotional well-being, developing new healthy behaviors, and providing healing experiences. This finding implies that healthcare providers need to assess family spiritual issues of elderly couples to maximize their strengths for coping with health problems. As our society becomes more culturally diverse, healthcare providers should seek to understand family spirituality from different cultural perspectives to develop a more holistic approach to care. PMID:26330374

  11. The incestoid family.

    PubMed

    Braun-Scharm, H; Frank, R

    1989-01-01

    Following a short overall view on family therapeutic models of close family systems and on incest family models, the concept "incestoid family" is conceived. In this way, families should be exemplified in which it is true that no manifest incest occurs, but by going from one generation to another, relationships between parents and children, resembling a relationship between partners and the constellation of subliminal enticement and seduction situations promote pseudosexual behaviour patterns; the most conspicuous symptom of such a family is hyper- as well as hyposexualised behaviour in children and young people. Definitive and conceptual demarcations to oedipal and incestuous structures were undertaken. Four case descriptions should illustrate the clinic of incestoid families. PMID:2487482

  12. Familial Aggregation and Childhood Blood Pressure

    PubMed Central

    Xu, Xiaojing; Su, Shaoyong; Snieder, Harold

    2015-01-01

    There is growing concern about elevated blood pressure (BP) in children. The evidence for familial aggregation of childhood BP is substantial. Twin studies have shown that a large part of the familial aggregation of childhood BP is due to genes. The first part of this review provides the latest progress in gene finding for childhood BP, focusing on the combined effects of multiple loci identified from the genome-wide association studies on adult BP. We further review the evidence on the contribution of the genetic components of other family risk factors to the familial aggregation of childhood BP including obesity, birth weight, sleep quality, sodium intake, parental smoking, and socioeconomic status. At the end, we emphasize the promise of using genomic-relatedness-matrix restricted maximum likelihood (GREML) analysis, a method that uses genome-wide data from unrelated individuals, in answering a number of unsolved questions in the familial aggregation of childhood BP. PMID:25432901

  13. Family Instability and Child Well-Being*

    PubMed Central

    Fomby, Paula; Cherlin, Andrew J.

    2011-01-01

    Past research suggests that children who experience multiple transitions in family structure may face worse developmental outcomes than children raised in stable two-parent families and perhaps even children raised in stable, single-parent families. However, multiple transitions and negative child outcomes may be associated because of common causal factors such as parents’ antecedent behaviors and attributes. Using a nationally-representative, two-generation longitudinal survey that includes detailed information on children’s behavioral and cognitive development, family history, and mother’s attributes prior to the child’s birth, we examine these alternative hypotheses. Our results suggest that, for white children, the association between the number of family structure transitions and cognitive outcomes is largely explained by mother’s prior characteristics but that the association between the number of transitions and behavioral outcomes may be causal in part. We find no robust effects of number of transitions for black children. PMID:21918579

  14. Supervisor referrals to work-family programs.

    PubMed

    Casper, Wendy J; Fox, Kevin E; Sitzmann, Traci M; Landy, Ann L

    2004-04-01

    Supervisors play an important role in determining whether employees use work-family programs. Yet little research has examined the factors that relate to supervisor perceptions of and behaviors surrounding work-family programs. This study builds on past research, the theory of reasoned action, and expectancy theory to explore factors that contribute to supervisors' decisions to refer subordinates to work-family programs. Usable surveys assessing perceptions of work-family programs were completed and returned by 1972 managers in a large government agency. Results revealed that program awareness and instrumentality perceptions both contributed uniquely to predicting the frequency of supervisors' referrals to work-family programs. Supportive attitudes also predicted referrals, but only through their shared relationship with instrumentality perceptions. PMID:15053713

  15. Improving Youth Mental Health through Family-Based Prevention In Family Homeless Shelters

    PubMed Central

    Lynn, Cynthia J.; Acri, Mary C.; Goldstein, Leah; Bannon, William; Beharie, Nisha; McKay, Mary M.

    2014-01-01

    This exploratory study examines changes in suicidal ideation among a sample (N = 28) of homeless youth, ages 11-14, residing within family shelters in a large metropolitan area. Changes in suicidal ideation from pretest to posttest are compared across two group approaches to delivering HIV prevention. Youth and their families participating in the HOPE Family Program, incorporating a family strengthening approach, are compared to those receiving a traditional health education-only approach. Multivariate analyses reveal that youth in the HOPE Family Program were 13 times more likely to report a decrease of suicidal ideation. These findings indicate that health education programs integrating a family strengthening approach hold promise for positively impacting mental health outcomes for vulnerable youth. PMID:25157200

  16. The putative chemoreceptor families of C. elegans.

    PubMed Central

    Robertson, Hugh M; Thomas, James H

    2006-01-01

    Chemoreception of environmental stimuli is a major sensory system in small soil nematodes like C. elegans. As in other animals, chemoreception is mediated in C. elegans by members of the seven-transmembrane G-protein-coupled receptor class (7TM GPCRs). We summarize the many large putative chemoreceptor gene families, including the str family (which includes odr-10, the only receptor with an identified ligand), and the sra, srab, srb, srbc, srd, sre, srg, srh, sri, srj, srm, srr, srsx, srt, sru, srv, srw, srx, srxa, and srz families. Together these comprise +/-1280 apparently intact genes and +/-420 apparent pseudogenes, about 7% of the total gene count of C. elegans. These genes are unusually clustered on chromosomes, both within and between families, and are enigmatically concentrated on the large chromosome V. Comparative studies with C. briggsae have revealed extraordinary divergence of the chemoreceptor repertoire between the two species, including frequent amplifications of subfamilies in C. elegans and positive selection in the srz family. The size and complexity of the chemoreceptor gene families also facilitate studies of promoter elements using paralogous and orthologous comparisons, as well as other aspects of gene family and genome evolution. PMID:18050473

  17. 24 CFR 982.515 - Family share: Family responsibility.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 24 Housing and Urban Development 4 2012-04-01 2012-04-01 false Family share: Family responsibility... Assistance Payment § 982.515 Family share: Family responsibility. (a) The family share is calculated by subtracting the amount of the housing assistance payment from the gross rent. (b) The family rent to owner...

  18. 24 CFR 982.515 - Family share: Family responsibility.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 24 Housing and Urban Development 4 2013-04-01 2013-04-01 false Family share: Family responsibility... Assistance Payment § 982.515 Family share: Family responsibility. (a) The family share is calculated by subtracting the amount of the housing assistance payment from the gross rent. (b) The family rent to owner...

  19. 24 CFR 982.515 - Family share: Family responsibility.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 24 Housing and Urban Development 4 2014-04-01 2014-04-01 false Family share: Family responsibility... Assistance Payment § 982.515 Family share: Family responsibility. (a) The family share is calculated by subtracting the amount of the housing assistance payment from the gross rent. (b) The family rent to owner...

  20. 24 CFR 982.515 - Family share: Family responsibility.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 24 Housing and Urban Development 4 2010-04-01 2010-04-01 false Family share: Family responsibility... Assistance Payment § 982.515 Family share: Family responsibility. (a) The family share is calculated by subtracting the amount of the housing assistance payment from the gross rent. (b) The family rent to owner...