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Sample records for family syndrome kindreds

  1. Inheritance of nevus number and size in melanoma and dysplastic nevus syndrome kindreds.

    PubMed

    Goldgar, D E; Cannon-Albright, L A; Meyer, L J; Piepkorn, M W; Zone, J J; Skolnick, M H

    1991-12-01

    Previous studies of the genetics of melanoma have focused on the dysplastic nevus syndrome (DNS). The variability in clinical and histopathological expression of affected individuals, however, has made definition and diagnosis of the syndrome difficult and subjective. Independent of the DNS, case-control studies have demonstrated the total number of nevi to be a significant risk factor for melanoma. In this article, we report results of genetic analyses of two quantitative nevus phenotypes that can be measured objectively in all subjects: the total number of nevi on an individual (TNN) and total nevus density (TND), a derived phenotype which incorporates both number and size of nevi. Ten kindreds ascertained for multiple cases of DNS-melanoma (multiplex ascertainment) and 16 kindreds and 19 solitary cases ascertained from a sequential list of melanoma cases without regard for family history (simplex ascertainment) were studied. Both phenotypes exhibited increased levels in relatives of probands compared with those in spouse controls. While neither TNN nor TND exhibited evidence for a major factor in the simplex pedigrees, a major factor was strongly indicated in the multiplex kindreds for TND. When both phenotypes were examined in more detail in the multiplex kindreds, the phenotype incorporating nevus size, TND, fit a mendelian pattern of inheritance better than the TNN. Significant residual familial correlations were found for both phenotypes. Parameter estimates from the best fitting genetic model indicated that a major gene may be responsible for 55% of the phenotypic variability of TND in the multiplex kindreds. PMID:1770551

  2. Second locus for Hirschsprung disease/Waardenburg syndrome in a large Mennonite kindred

    SciTech Connect

    Dow, E.; Cross, S.; Williamson, R.; Mulligan, L.M.; Lyonnet, S.; Wolgemuth, D.J.; Mascari, M.; Ladda, R.

    1994-10-15

    We have studied a large Mennonite kindred in which 20 members were affected with Hirschburg disease (HSCR), 5 of whom had one or more manifestations of Waardenburg syndrome (WS) type II (WS2). Eleven additional relatives had signs of WS2 without HSCR. Since HSCR and WS2 each represent perturbations of neural crest migration/differentiation, this large pedigree with apparent cosegregation of HSCR and WS2 offered an opportunity to search for linkage between these loci, candidate genes, and random DNA markers, particularly in view of recent discoveries of genes for Waardenburg syndrome type I (WS1) and Hirschsprung disease (c-ret). We have examined the following possible linked markers in 69 relatives in this family: the c-ret gene (HSCR); the human PAX3 gene (HuP2) on chromosome 2q (WS1) and placental alkaline phosphatase (ALPP) on chromosome 2q (linked to WS1); argininosuccinate synthetase (ASS) on chromosome 9q, close to ABO blood groups which have shown weak linkage to WS; and the {beta}1 GABA receptor gene (GABARB1) on chromosome 4q13-11, close to c-kit, deletions of which cause piebaldism. Linkage between any of these loci and HSCR/WS in this kindred was excluded, demonstrating that there is at least one further locus for HSCR other than c-ret. 45 refs., 1 fig., 3 tabs.

  3. Clinical analysis of a large kindred with the pallister ulnar-mammary syndrome

    SciTech Connect

    Bamshad, M.; Root, S.; Carey, J.C.

    1996-11-11

    The ulnar-mammary syndrome (UMS) is an autosomal dominant disorder characterized by posterior limb deficiencies or duplications, apocrine/mammary gland hypoplasia and/or dysfunction, abnormal dentition, delayed puberty in males, and genital anomalies. We present the clinical descriptions of 33 members of a six generation kindred with UMS. The number of affected individuals in this family is more than the sum of all previously reported cases of UMS. The clinical expression of UMS is highly variable. While most patients have limb deficiencies, the range of abnormalities extends from hypoplasia of the terminal phalanx of the 5th digit to complete absence of the ulna and 3rd, 4th, and 5th digits. Moreover, affected individuals may have posterior digital duplications with or without contralateral limb deficiencies. Apocrine gland abnormalities range from diminished axillary perspiration with normal breast development and lactation, to complete absence of the breasts and no axillary perspiration. Dental abnormalities include misplaced or absent teeth. Affected males consistently undergo delayed puberty, and both sexes have diminished to absent axillary hair. Imperforate hymen were seen in some affected women. A gene for UMS was mapped to chromosome area 12q23-q24.1. A mutation in the gene causing UMS can interfere with limb patterning in the proximal/distal, anterior/posterior, and dorsal/ventral axes. This mutation disturbs development of the posterior elements of forearm, wrist, and hand while growth and development of the anterior elements remain normal. 24 refs., 4 figs., 1 tab.

  4. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region

    SciTech Connect

    Kamino, K.; Anderson, L.; O'dahl, S.; Nemens, E.; Bird, T.D.; Schellenberg, G.D.; Wijsman, E.M.; Kukall, W.; Larson, E. ); Heston, L.L.

    1992-11-01

    A large number of familial Alzheimer disease (FAD) kindreds were examined to determine whether mutations in the amyloid precursor protein (APP) gene could be responsible for the disease. Previous studies have identified three mutations at APP codon 717 which are pathogenic for Alzheimer disease (AD). Samples from affected subjects were examined for mutations in exons 16 and 17 of the APP gene. A combination of direct sequencing and single-strand conformational polymorphism analysis was used. Sporadic AD and normal controls were also examined by the same methods. Five sequence variants were identified. One variant at APP codon 693 resulted in a Glu[yields]Gly change. This is the same codon as the hereditary cerebral hemorrhage with amyloidosis-Dutch type Glu[yields]Gln mutation. Another single-base change at APP codon 708 did not alter the amino acid encoded at this site. Two point mutations and a 6-bp deletion were identified in the intronic sequences surrounding exon 17. None of the variants could be unambigously determined to be responsible for FAD. The larger families were also analyzed by testing for linkage of FAD to a highly polymorphic short tandem repeat marker (D21S210) that is tightly linked to APP. Highly negative LOD scores were obtained for the family groups tested, and linkage was formally excluded beyond [theta] = .10 for the Volga German kindreds, [theta] = .20 for early-onset non-Volga Germans, and [theta] = .10 for late-onset families. LOD scores for linkage of FAD to markers centromeric to APP (D21S1/S11, D21S13, and D21S215) were also negative in the three family groups. These studies show that APP mutations account for AD in only a small fraction of FAD kindreds. 49 refs., 6 figs., 4 tabs.

  5. Cystic fibrosis in a large kindred family in Qatar.

    PubMed

    Abdul Wahab, A; Dawod, S T; al Thani, G

    2000-09-01

    We describe 45 patients with cystic fibrosis (CF), diagnosed between June 1987 and May 1999, seen at the Hamad Medical Corporation, Qatar in the Arabian Gulf. Twenty-six of 32 families in the study were related and belonged to the same Bedouin tribe. The parents of 98% of these cases were consanguineous. Metabolic alkalosis and/or hypo-electrolytaemia were found in a large proportion of infants with CF. Cystic fibrosis in Qatari children is phenotypically variable with mild to moderate respiratory symptoms, and none of them died during this study. Among the non-Arabic-Asian patients, pulmonary symptoms were more severe, Pseudomonas colonization was earlier, pancreatic insufficiency occurred in infancy and four died in early life. PMID:11064773

  6. Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s

    PubMed Central

    Johnson, Todd A.; Tsunoda, Tatsuhiko; Behner, Dusty; Hoffman, Harriet; Hesdorffer, Mary; Nasu, Masaki; Napolitano, Andrea; Powers, Amy; Minaai, Michael; Baumann, Francine; Bryant-Greenwood, Peter; Lauk, Olivia; Kirschner, Michaela B.; Weder, Walter; Opitz, Isabelle; Pass, Harvey I.; Gaudino, Giovanni; Pastorino, Sandra; Yang, Haining

    2015-01-01

    We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies). PMID:26683624

  7. Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s.

    PubMed

    Carbone, Michele; Flores, Erin G; Emi, Mitsuru; Johnson, Todd A; Tsunoda, Tatsuhiko; Behner, Dusty; Hoffman, Harriet; Hesdorffer, Mary; Nasu, Masaki; Napolitano, Andrea; Powers, Amy; Minaai, Michael; Baumann, Francine; Bryant-Greenwood, Peter; Lauk, Olivia; Kirschner, Michaela B; Weder, Walter; Opitz, Isabelle; Pass, Harvey I; Gaudino, Giovanni; Pastorino, Sandra; Yang, Haining

    2015-12-01

    We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies). PMID:26683624

  8. Neuropathology of two members of a German-American kindred (Family C) with late onset parkinsonism.

    PubMed

    Wszolek, Z K; Gwinn-Hardy, K; Wszolek, E K; Muenter, M D; Pfeiffer, R F; Rodnitzky, R L; Uitti, R J; McComb, R D; Gasser, T; Dickson, D W

    2002-04-01

    We present genealogical and longitudinal clinical observations and autopsy findings of a previously reported kindred, Family C (German-American), with late-onset autosomal dominant parkinsonism with evidence for linkage on chromosome 2p13. The clinical phenotype includes the cardinal features of idiopathic Parkinson's disease. In addition, postural tremor and dementia are detected in some individuals. Two members of the kindred, one affected and one unaffected have recently come to autopsy. The unaffected family member was an 82-year-old woman whose brain showed only mild age-related pathology and no evidence of subclinical Lewy body disease. In contrast, the affected family member was an 83-year-old man whose brain had neuronal loss, gliosis and Lewy bodies in the substantia nigra and other monoaminergic brain stem nuclei, as well as the basal forebrain and amygdala. Lewy bodies and Lewy neurites had a distribution typical of cases of idiopathic Parkinson's disease. Thus, the clinical and pathological findings in this family with autosomal dominant parkinsonism are similar to those of sporadic Parkinson's disease. PMID:11904753

  9. Familial idiopathic gonadotropin deficiency not linked to gene for gonadotropin-releasing hormone (GnRH) in Brazilian kindred

    SciTech Connect

    Faraco, J.; Francke, U.; Toledo, S.

    1994-09-01

    Familial idiopathic gonadotropin deficiency (FIGD) is an autosomal recessive disorder which results in failure to develop secondary sexual characteristics. The origin is a hypothalamic defect resulting in insufficient secretion of gonadotropin-releasing hormone GnRH (also called LHRH, luteinizing hormone releasing hormone) and follicle-stimuating hormone (FSH). FIGD has been determined to be a separate entity from Kallmann syndrome which presents with hypogonadism as well as anosmia. The FIGD phenotype appears to be analogous to the phenotype of the hpg (hypogonadal) mouse. Because the hpg phenotype is the result of a structurally abnormal GnRH gene, we have studied the GnRH gene in individuals from a previously reported Brazilian FIGD family. An informative dimorphic marker in the signal peptide sequence of the GnRH gene allowed assessment of linkage between the disease gene and the GnRH locus in this pedigree. We have concluded that the GnRH locus is not linked to the disease-causing mutation in these hypogonadal individuals. Recent evidence suggests that neuropeptide Y (NPY) may play a role in the initiation of puberty. We hypothesize that mutations in NPY may result in failure to secrete GnRH. We have characterized three diallelic frequent-cutter restriction fragment length polymorphisms within the human NPY locus, and are currently using these markers to determine if the NPY gene is linked to, and possibly the site of the disease mutation in this kindred.

  10. Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy

    PubMed Central

    Chen, Hui; Zhou, Xueya; Wang, Jing; Wang, Xi; Liu, Liyang; Wu, Shinan; Li, Tengyan; Chen, Si; Yang, Jingwen; Sham, Pak Chung; Zhu, Guangming; Zhang, Xuegong; Wang, Binbin

    2016-01-01

    Inherited neuropathies show considerable heterogeneity in clinical manifestations and genetic etiologies, and are therefore often difficult to diagnose. Whole-exome sequencing (WES) has been widely adopted to make definite diagnosis of unclear conditions, with proven efficacy in optimizing patients’ management. In this study, a large Chinese kindred segregating autosomal dominant polyneuropathy with incomplete penetrance was ascertained through a patient who was initially diagnosed as Charcot-Marie-Tooth disease. To investigate the genetic cause, forty-six living family members were genotyped by SNP microarrays, and one confirmed patient was subject to WES. Through systematic computational prioritization, we identified a missense mutation c.G148T in TTR gene which results in a p.V50L substitution known to cause transthyretin-related familial amyloid polyneuropathy. Co-segregation analysis and clinical follow-up confirmed the new diagnosis, which suggested new therapeutic options to the patients and informed high risk family members. This study confirms WES as a powerful tool in translational medicine, and further demostrates the practical utility of gene prioritization in narrowing the scope of causative mutation. PMID:27212199

  11. Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy.

    PubMed

    Chen, Hui; Zhou, Xueya; Wang, Jing; Wang, Xi; Liu, Liyang; Wu, Shinan; Li, Tengyan; Chen, Si; Yang, Jingwen; Sham, Pak Chung; Zhu, Guangming; Zhang, Xuegong; Wang, Binbin

    2016-01-01

    Inherited neuropathies show considerable heterogeneity in clinical manifestations and genetic etiologies, and are therefore often difficult to diagnose. Whole-exome sequencing (WES) has been widely adopted to make definite diagnosis of unclear conditions, with proven efficacy in optimizing patients' management. In this study, a large Chinese kindred segregating autosomal dominant polyneuropathy with incomplete penetrance was ascertained through a patient who was initially diagnosed as Charcot-Marie-Tooth disease. To investigate the genetic cause, forty-six living family members were genotyped by SNP microarrays, and one confirmed patient was subject to WES. Through systematic computational prioritization, we identified a missense mutation c.G148T in TTR gene which results in a p.V50L substitution known to cause transthyretin-related familial amyloid polyneuropathy. Co-segregation analysis and clinical follow-up confirmed the new diagnosis, which suggested new therapeutic options to the patients and informed high risk family members. This study confirms WES as a powerful tool in translational medicine, and further demostrates the practical utility of gene prioritization in narrowing the scope of causative mutation. PMID:27212199

  12. Nephritogenic antigen determinants in epidermal and renal basement membranes of kindreds with Alport-type familial nephritis.

    PubMed Central

    Kashtan, C; Fish, A J; Kleppel, M; Yoshioka, K; Michael, A F

    1986-01-01

    We probed epidermal basement membranes (EBM) of acid-urea denatured skin from members of kindreds with Alport-type familial nephritis (FN) for the presence of antigens reactive with Goodpasture sera (GPS) and serum (FNS) from an Alport patient who developed anti-glomerular basement membrane (GBM) nephritis in a renal allograft. By immunoblotting, GPS reacted primarily with the 28,000 molecular weight (mol wt) monomer but also the 24,000 mol wt and 26,000 mol wt monomers of the noncollagenous globular domain (NC1) of type IV collagen from normal human GBM, while FNS identified only the 26,000-mol wt monomer. FNS reacted with EBM of 12 controls and nine unaffected male kindred members but not EBM of eight affected males. Five affected females exhibited interrupted reactivity of FNS with EBM. GPS showed variable reactivity with EBM and was not discriminating with respect to Alport-type FN. FNS did not stain renal basement members of five affected males. However, the EBM, tubular basement membrane, and Bowman's capsules of affected males contained antigens reactive with GPS. These immunochemical studies suggest that the FNS antigen is distinct from Goodpasture antigen(s). The expression of FNS antigen located on the NC1 domain of type IV collagen is altered in basement membranes of patients with Alport-type FN, and the distribution of this antigenic anomaly within kindreds suggests X-linked dominant transmission of a defective gene. Images PMID:2428839

  13. Manifestations of juvenile polyposis syndrome in SMAD4 mutation carriers of a kindred.

    PubMed

    Schwetz, Verena; Uhrig, Sabine; Spuller, Ekkehard; Deutschmann, Andrea; Högenauer, Christoph

    2012-08-01

    The autosomal dominantly inherited juvenile polyposis syndrome (JPS) leads to the development of multiple hamartomatous polyps in the gastrointestinal tract and is a precancerous condition. In a large family with a newly identified SMAD4 mutation (c.543delC), we describe the clinical manifestations of JPS. Nine affected SMAD4 mutation-positive family members were screened and treated for manifestations of JPS. Two family members were symptomatic at the time of diagnosis; seven were asymptomatic - independent of the severity of the manifestation. Each mutation carrier presented with colonic juvenile polyps, seven out of nine with additional gastric manifestations. One asymptomatic patient had early gastric cancer; another patient had a villous adenoma with high-grade intraepithelial neoplasia in the colon. Three patients had biliary lesions including a bile duct hamartoma in one and gallbladder polyps in two. Three patients had gastrointestinal vascular malformations. All mutation carriers were affected by JPS. Interestingly, the manifestations and their severity differed considerably between the patients, suggesting secondary factors influencing JPS manifestations such as Helicobacter pylori infection. PMID:22617360

  14. Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus.

    PubMed Central

    Rittig, S.; Robertson, G. L.; Siggaard, C.; Kovács, L.; Gregersen, N.; Nyborg, J.; Pedersen, E. B.

    1996-01-01

    Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder characterized by progressive postnatal deficiency of arginine vasopressin as a result of mutation in the gene that encodes the hormone. To determine the extent of mutations in the coding region that produce the phenotype, we studied members of 17 unrelated kindreds with the disorder. We sequenced all 3 exons of the gene by using a rapid, direct dye-terminator method and found the causative mutation in each kindred. In four kindreds, the mutations were each identical to mutations described in other affected families. In the other 13 kindreds each mutation was unique. There were two missense mutations that altered the cleavage region of the signal peptide, seven missense mutations in exon 2, which codes for the conserved portion of the protein, one nonsense mutation in exon 2, and three nonsense mutations in exon 3. These findings, together with the clinical features of FNDI, suggest that each of the mutations exerts an effect by directing the production of a pre-prohormone that cannot be folded, processed, or degraded properly and eventually destroys vasopressinergic neurons. Images Figure 3 PMID:8554046

  15. Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus

    SciTech Connect

    Rittig, S.; Siggaard, C.; Pedersen, E.B.

    1996-01-01

    Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder characterized by progressive postnatal deficiency of arginine vasopressin as a result of mutation in the gene that encodes the hormone. To determine the extent of mutations in the coding region that produce the phenotype, we studied members of 17 unrelated kindreds with the disorder. We sequenced all 3 exons of the gene by using a rapid, direct dye-terminator method and found the causative mutation in each kindred. In four kindreds, the mutations were each identical to mutations described in other affected families. In the other 13 kindreds each mutation was unique. There were two missense mutations that altered the cleavage region of the signal peptide, seven missense mutations in exon 2, which codes for the conserved portion of the protein, one nonsense mutation in exon 2, and three nonsense mutations in exon 3. These findings, together with the clinical features of FNDI, suggest that each of the mutations exerts an effect by directing the production of a pre-prohormone that cannot be folded, processed, or degraded properly and eventually destroys vasopressinergic neurons. 63 refs., 5 figs., 6 tabs.

  16. Apolipoprotein C-II and C-III metabolism in a kindred of familial hypobetalipoproteinemia

    SciTech Connect

    Malmendier, C.L.; Delcroix, C.; Lontie, J.F.; Dubois, D.Y. )

    1991-01-01

    Three affected members of a kindred with asymptomatic hypobetalipoproteinemia (HBL) showed low levels of triglycerides, low-density lipoprotein (LDL)-cholesterol, and apolipoproteins (apo) B, C-II, and C-III. Turnover of iodine-labeled apo C-II and apo C-III associated in vitro to plasma lipoproteins was studied after intravenous injection. Radioactivity in plasma and lipoproteins (95% recovered in high-density lipoprotein (HDL) density range) and in 24-hour urine samples was observed for 16 days. A parallelism of the slowest slopes of plasma decay curves was observed between apo C-II and apo C-III, indicating a partial common catabolic route. Urine/plasma radioactivity ratio (U/P) varied with time, suggesting heterogeneity of metabolic pathways. A new compartmental model using the SAAM program was built, not only fitting simultaneously plasma and urine data, but also taking into account the partial common metabolism of lipoprotein particles (LP) containing apo C-II and apo C-III. The low apo C-II and C-III plasma concentrations observed in HBL compared with normal resulted from both an increased catabolism and a reduced synthesis, these changes being more marked for apo C-III. The modifications in the rate constants of the different pathways calculated from the new model are in favor of an increased direct removal of particles following the fast pathway, likely in the very-low-density lipoprotein (VLDL) density range.

  17. POLE and POLD1 mutations in 529 kindred with familial colorectal cancer and/or polyposis: review of reported cases and recommendations for genetic testing and surveillance

    PubMed Central

    Bellido, Fernando; Pineda, Marta; Aiza, Gemma; Valdés-Mas, Rafael; Navarro, Matilde; Puente, Diana A.; Pons, Tirso; González, Sara; Iglesias, Silvia; Darder, Esther; Piñol, Virginia; Soto, José Luís; Valencia, Alfonso; Blanco, Ignacio; Urioste, Miguel; Brunet, Joan; Lázaro, Conxi; Capellá, Gabriel; Puente, Xose S.; Valle, Laura

    2016-01-01

    Purpose: Germ-line mutations in the exonuclease domains of POLE and POLD1 have been recently associated with polyposis and colorectal cancer (CRC) predisposition. Here, we aimed to gain a better understanding of the phenotypic characteristics of this syndrome to establish specific criteria for POLE and POLD1 mutation screening and to help define the clinical management of mutation carriers. Genet Med 18 4, 325–332. Methods: The exonuclease domains of POLE and POLD1 were studied in 529 kindred, 441 with familial nonpolyposis CRC and 88 with polyposis, by using pooled DNA amplification and massively parallel sequencing. Genet Med 18 4, 325–332. Results: Seven novel or rare genetic variants were identified. In addition to the POLE p.L424V recurrent mutation in a patient with polyposis, CRC and oligodendroglioma, six novel or rare POLD1 variants (four of them, p.D316H, p.D316G, p.R409W, and p.L474P, with strong evidence for pathogenicity) were identified in nonpolyposis CRC families. Phenotypic data from these and previously reported POLE/POLD1 carriers point to an associated phenotype characterized by attenuated or oligo-adenomatous colorectal polyposis, CRC, and probably brain tumors. In addition, POLD1 mutations predispose to endometrial and breast tumors. Genet Med 18 4, 325–332. Conclusion: Our results widen the phenotypic spectrum of the POLE/POLD1-associated syndrome and identify novel pathogenic variants. We propose guidelines for genetic testing and surveillance recommendations. Genet Med 18 4, 325–332. PMID:26133394

  18. A deleterious RNF43 germline mutation in a severely affected serrated polyposis kindred

    PubMed Central

    Taupin, Douglas; Lam, Wesley; Rangiah, David; McCallum, Larissa; Whittle, Belinda; Zhang, Yafei; Andrews, Daniel; Field, Matthew; Goodnow, Christopher C; Cook, Matthew C

    2015-01-01

    We report a germline nonsense mutation within the extracellular domain of the RING finger ubiquitin ligase RNF43, segregating with a severe form of serrated polyposis within a kindred. The finding provides evidence that inherited RNF43 mutations define a familial cancer syndrome. PMID:27081527

  19. Familial unilateral Brown syndrome

    PubMed Central

    Kenawy, Nihal; Pilz, Daniela T

    2008-01-01

    We present a two-generation family with Brown syndrome. The proband was a six and a half-year-old female who presented with a history of failure of dextro-elevation of her left eye. A full ophthalmic evaluation was consistent with a left Brown syndrome. Family history revealed that her mother was operated on as a child for left Brown syndrome and examination of her four and a half-year-old sibling showed similar affection in the left eye. Autosomal dominant inheritance has been postulated in this condition. To our knowledge this is the first report of three members of a two-generation family with left-sided Brown syndrome. Genetic counseling of Brown syndrome cases is advised; nevertheless, identification of the responsible gene should shed more light on its genetics. PMID:18711279

  20. Genetic mapping of the gene for Usher syndrome: Linkage analysis in a large Samaritan kindred

    SciTech Connect

    Bonne-Tamir, B.; Korostishevsky, M.; Kalinsky, H.; Seroussi, E.; Beker, R.; Weiss, S. ); Godel, V. )

    1994-03-01

    Usher syndrome is a group of autosomal recessive disorders associated with congenital sensorineural deafness and progressive visual loss due to retinitis pigmentosa. Sixteen members of the small inbred Samaritan isolate with autosomal recessive deafness from 59 individuals including parents and affected and nonaffected sibs were typed for markers on chromosomes 1q and 11q for which linkage has recently been established for Usher syndrome types II and I. Statistically significant linkage was observed with four markers on 11q (D11S533, D11S527, OMP, and INT2) with a maximum six-point location score of 11.61 at the D11S533 locus. Analysis of haplotypes supports the notion that the mutation arose only once in an ancestral chromosome carrying a specific haplotype. The availability of markers closely linked to the disease locus allows indirect genotype analysis and identifies all carriers of the gene within the community. Furthermore, the detection of complete linkage disequilibrium between the D11S533 marker and the Usher gene suggests that these loci are either identical or adjacent and narrows the critical region to which physical mapping efforts are currently directed. 35 refs., 2 figs., 6 tabs.

  1. A{sup -2} {yields} G transition at the 3{prime} acceptor splice site of IVS17 characterizes the COL2A1 gene mutation in the original Stickler syndrome kindred

    SciTech Connect

    Williams, C.J.; Ganguly, A.; Considine, E.

    1996-06-14

    Hereditary progressive arthro-ophthalmopathy, or {open_quotes}Stickler syndrome,{close_quotes} is an autosomal dominant osteochondrodysplasia characterized by a variety of ocular and skeletal anomalies which frequently lead to retinal detachment and precocious osteoarthritis. A variety of mutations in the COL2A1 gene have been identified in {open_quotes}Stickler{close_quotes} families; in most cases studied thus far, the consequence of mutation is the premature generation of a stop codon. We report here the characterization of a COL2A1 gene mutation in the original kindred described by Stickler et al. Conformational sensitive gel electrophoresis (CSGE) was used to screen for mutations in the entire COL2A1 gene in an affected member from the kindred. A prominent heteroduplex species was noted in the polymerase chain reaction (PCR) product from a region of the gene including exons 17 to 20. Direct sequencing of PCR-amplified genomic DNA resulted in the identification of a base substitution at the A{sup -2} position of the 3{prime} splice acceptor site of IVS17. Sequencing of DNA from affected and unaffected family members confirmed that the mutation segregated with the disease phenotype. Reverse transcriptase-PCR analysis of poly A+ RNA demonstrated that the mutant allele utilized a cryptic splice site in exon 18 of the gene, eliminating 16 bp at the start of exon 18. This frameshift eventually results in a premature termination codon. These findings are the first report of a splice site mutation in classical Stickler syndrome and they provide a satisfying historical context in which to view COL2A1 mutations in this dysplasia. 25 refs., 3 figs., 1 tab.

  2. Jackson-Weiss syndrome: Clinical and radiological findings in a large kindred and exclusion of the gene from 7p21 and 5qter

    SciTech Connect

    Ades, L.C.; Haan, E.A.; Mulley, J.C.; Senga, I.P.; Morris, L.L.; David, D.J.

    1994-06-01

    We describe the clinical and radiological manifestations of the Jackson-Weiss syndrome (JWS) in a large South Australian kindred. Radiological abnormalities not previously described in the hands include coned epiphyses, distal and middle phalangeal hypoplasia, and carpal bone malsegmentation. New radiological findings in the feet include coned epiphyses, hallux valgus, phalangeal, tarso-navicular and calcaneo-navicular fusions, and uniform absence of metatarsal fusions. Absence of linkage to eight markers along the short arm of chromosome 7 excluded allelian between JWS and Saethre-Chotzen syndrome at 7p21. No linkage was detected to D5S211, excluding allelism to another recently described cephalosyndactyly syndrome mapping to 5qter. 35 refs., 5 figs., 4 tabs.

  3. Retrospective molecular detection of Transthyretin Met 111 mutation in a Danish kindred with familial amyloid cardiomyopathy, using DNA from formalin-fixed and paraffin-embedded tissues.

    PubMed

    Nordvåg, B Y; Ranløv, I; Riise, H M; Husby, G; el-Gewely, M R

    1993-10-01

    Severe familial amyloid cardiomyopathy (FAC) in a Danish kindred is associated with a specific mutation (Met for Leu 111) in the transthyretin (TTR) gene. The mutation causes the loss of a DdeI restriction site in the gene, allowing molecular diagnostic studies. We studied formalin-fixed, paraffin-embedded tissues, up to 39 years old, from 29 family members of this kindred. DNA was partially purified from deparaffinized tissue sections and a DNA sequence of the TTR gene flanking the mutation site was amplified by the polymerase chain reaction (PCR), followed by restriction enzyme analysis. Amplified DNA was obtained from tissues representing 23 of the 29 persons. Ten out of the 23 family members were found to carry the TTR Met 111 mutation, whereas 13 were not affected. The results were consistent with known clinical data and with corresponding serum TTR examinations. This retrospective study shows that archival tissues can be used to confirm the diagnosis and disease pattern in members of families affected by hereditary diseases. PMID:8406434

  4. Familial atypical multiple mole melanoma (FAMMM) syndrome: history, genetics, and heterogeneity.

    PubMed

    Lynch, Henry T; Shaw, Trudy G

    2016-07-01

    Approximately 5-10 % of cutaneous melanoma occurs in kindreds with a hereditary predisposition. Mutations in the CDKN2A gene are found to occur in approximately 20-40 % of these kindreds. The first historical mention of what is now called the familial atypical multiple mole melanoma syndrome appears to be from 1820, with more reports throughout the 1950s, 1960s, and later years. In 1991, Lynch and Fusaro described an association between familial multiple mole melanoma and pancreatic cancer and work continues to elucidate the syndrome's genotypic and phenotypic heterogeneity. Individuals at risk for familial melanoma need periodic screenings. Unfortunately, adequate screening for pancreatic cancer does not currently exist, but pancreatic cancer's prominence in the hereditary setting will hopefully act as a stimulus for development of novel screening measures. PMID:26892865

  5. Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): Codon 178 mutation and codon 129 polymorphism

    SciTech Connect

    Medori, R.; Tritschler, H.J. )

    1993-10-01

    Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp) [yields] AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. The authors confirmed the 178[sup Asn] mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced perfusion in the basal ganglia on single photon emission computerized tomography. Some FFI features differ from the clinical and neuropathologic findings associated with 178[sup Asn] reported elsewhere. However, additional intragenic mutations accounting for the phenotypic differences were not observed in two affected individuals. In other sporadic and familial forms of Creutzfeldt-Jakob disease and Gerstmann-Straeussler syndrome, Met or Val homozygosity at polymorphic codon 129 is associated with a more severe phenotype, younger age at onset, and faster progression. In FFI, young and old individuals at disease onset had 129[sup Met/Val]. Moreover, of five 178[sup Asn] individuals who are above age-at-onset range and who are well, two have 129[sup Met] and three have 129[sup Met/Val], suggesting that polymorphic site 129 does not modulate FFI phenotypic expression. Genetic heterogeneity and environment may play an important role in inter- and intrafamilial variability of the 178[sup Asn] mutation. 32 refs., 5 figs., 1 tab.

  6. Prion protein gene analysis in three kindreds with fatal familial insomnia (FFI): codon 178 mutation and codon 129 polymorphism.

    PubMed Central

    Medori, R; Tritschler, H J

    1993-01-01

    Fatal familial insomnia (FFI) is a disease linked to a GAC(Asp)-->AAC(Asn) mutation in codon 178 of the prion protein (PrP) gene. FFI is characterized clinically by untreatable progressive insomnia, dysautonomia, and motor dysfunctions and is characterized pathologically by selective thalamic atrophy. We confirmed the 178Asn mutation in the PrP gene of a third FFI family of French ancestry. Three family members who are under 40 years of age and who inherited the mutation showed only reduced perfusion in the basal ganglia on single photon emission computerized tomography. Some FFI features differ from the clinical and neuropathologic findings associated with 178Asn reported elsewhere. However, additional intragenic mutations accounting for the phenotypic differences were not observed in two affected individuals. In other sporadic and familial forms of Creutzfeldt-Jakob disease and Gerstmann-Sträussler syndrome, Met or Val homozygosity at polymorphic codon 129 is associated with a more severe phenotype, younger age at onset, and faster progression. In FFI, young and old individuals at disease onset had 129Met/Val. Moreover, of five 178Asn individuals who are above age-at-onset range and who are well, two have 129Met and three have 129Met/Val, suggesting that polymorphic site 129 does not modulate FFI phenotypic expression. Genetic heterogeneity and environment may play an important role in inter- and intrafamilial variability of the 178Asn mutation. Images Figure 2 Figure 3 Figure 4 Figure 5 PMID:8105681

  7. 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.

  8. Clinical spectrum of Kufor-Rakeb syndrome in the Chilean kindred with ATP13A2 mutations.

    PubMed

    Behrens, Maria I; Brüggemann, Norbert; Chana, Pedro; Venegas, Pablo; Kägi, Marianne; Parrao, Teresa; Orellana, Patricia; Garrido, Cristian; Rojas, Cecilia V; Hauke, Jan; Hahnen, Eric; González, Rafael; Seleme, Nicolas; Fernández, Verónica; Schmidt, Alexander; Binkofski, Ferdinand; Kömpf, Detlef; Kubisch, Christian; Hagenah, Johann; Klein, Christine; Ramirez, Alfredo

    2010-09-15

    We report the clinical features of the original Chilean family with Kufor-Rakeb syndrome (KRS) that led to the discovery of the ATP13A2 gene at the PARK9 locus. KRS is a rare juvenile-onset autosomal recessive disease characterized by progressive Parkinsonism, pyramidal signs, and cognitive decline in addition to vertical gaze palsy and facial-faucial-finger minimyoclonus. Neurological and neuropsychological examination during a 10-year period, videotaping, neuroimaging, and measurement of DNA methylation of the ATP13A2 promoter region were performed. The youngest 5 of 17 children of nonconsanguineous parents, carrying compound-heterozygous ATP13A2 mutations, had normal development until ages ∼10 to 12 years, when school performance deteriorated and slowness, rigidity, and frequent falls developed. Examination revealed bradykinesia, subtle postural/action tremor, cogwheel rigidity, spasticity, upward gaze palsy, smooth pursuit with saccadic intrusions, and dementia. Additional signs included facial-faucial-finger minimyoclonus, absent postural reflexes, visual/auditory hallucinations, and insomnia. Levodopa response could not be fully judged in this family. T2* magnetic resonance imaging sequences revealed marked diffuse hypointensity of the caudate (head and body) and lenticular nucleus bilaterally. Disease progression was slow including epilepsy, cachexia, and anarthria. Four affected members died after 28.5 ± 5.5 (mean ± SD) years of disease. Two heterozygous carriers, the mother and eldest sibling, showed jerky perioral muscle contractions and clumsiness of hand movements. There was no significant correlation between DNA methylation of the ATP13A2 promoter region and disease progression. The marked caudate and lenticular nucleus T2*-hypointensity suggests that KRS might belong to the family of neurodegenerative diseases associated with brain iron accumulation. PMID:20683840

  9. LDLR gene synonymous mutation c.1813C>T results in mRNA splicing variation in a kindred with familial hypercholesterolaemia.

    PubMed

    Ho, Clement K M; Musa, Fathel Rahman; Bell, Christine; Walker, Simon W

    2015-11-01

    Familial hypercholesterolaemia, one of the most common inherited diseases in the general population, is associated with mutations in at least three different genes including the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and protein convertase subtilisin/kexin type 9 (PCSK9) genes. In this report, we describe an unclassified DNA variant (c.1813C>T; p.Leu605Leu) within exon 12 of the LDLR gene in a kindred in which familial hypercholesterolaemia is associated with c.1813C>T heterozygosity. In silico analysis suggested that c.1813C>T might affect splicing of the LDLR gene by creating a cryptic donor splice site, which was confirmed by RT-PCR coupled with cDNA sequencing, to result in the loss of 34 base pairs in the coding sequence. The latter truncated mRNA is predicted to generate a frameshift leading to a premature stop at codon 652 and early termination of the low density lipoprotein receptor polypeptide chain, and thus provides a molecular basis for the hypercholesterolaemic phenotype. This case report highlights the emerging utility of RNA studies for the molecular diagnosis of familial hypercholesterolaemia in patients with potential mRNA splicing variants. PMID:25624525

  10. Senior-Loken syndrome secondary to NPHP5/IQCB1 mutation in an Iranian family

    PubMed Central

    Haghighi, Alireza; Al-Hamed, Mohamed; Al-Hissi, Safa; Hynes, Ann-Marie; Sharifian, Maryam; Roozbeh, Jamshid; Saleh-Gohari, Nasrollah

    2011-01-01

    Senior-Loken syndrome (SLS) is a rare autosomal recessive disease characterized by nephronophthisis and early-onset retinal degeneration. We used a large Iranian family with SLS to establish a molecular genetic diagnosis. Following clinical evaluation, we undertook homozygosity mapping in two affected family members and mutational analysis in known SLS genes coinciding with regions of homozygosity. In a region of homozygosity coinciding with a known SLS locus on chromosome 3q21.1, we found a homozygous non-sense mutation R332X in NPHP5/IQCB1. This is the first report of a molecular genetic diagnosis in an Iranian kindred with SLS. PMID:25984213

  11. Familial cancer syndromes and clusters.

    PubMed

    Birch, J M

    1994-07-01

    The study of rare families in which a variety of cancers occur, usually at an early age and with patterns consistent with a common hereditary mechanism, has contributed much to our understanding of the process of carcinogenesis. So far, genes identified as having a role in cancer predisposition in these families have also been important in the histogenesis of sporadic cancers. In the two most clearly defined cancer family syndromes, the Li-Fraumeni syndrome and Lynch syndrome II, the genes involved predispose to diverse but specific constellations of cancers. Genes associated with site-specific familial cancer clusters may also give rise to increased susceptibility to other cancers, and site-specific clusters may represent one end of a spectrum. A consistent feature of familial cancer syndromes is the variable expression within and between families. A challenge for the future will be to determine other factors which may interact with the principal genes involved, giving rise to this variability. PMID:7987644

  12. Familial Adrenocortical Carcinoma in Association With Lynch Syndrome

    PubMed Central

    Challis, Benjamin G.; Kandasamy, Narayanan; Powlson, Andrew S.; Koulouri, Olympia; Annamalai, Anand Kumar; Happerfield, Lisa; Marker, Alison J.; Arends, Mark J.; Nik-Zainal, Serena

    2016-01-01

    Context: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Although the majority of childhood ACC arises in the context of inherited cancer susceptibility syndromes, it remains less clear whether a hereditary tumor predisposition exists for the development of ACC in adults. Here, we report the first occurrence of familial ACC in a kindred with Lynch syndrome resulting from a pathogenic germline MSH2 mutation. Case: A 54-year-old female with a history of ovarian and colorectal malignancy was found to have an ACC. A detailed family history revealed her mother had died of ACC and her sister had previously been diagnosed with endometrial and colorectal cancers. A unifying diagnosis of Lynch syndrome was considered, and immunohistochemical analyses demonstrated loss of MSH2 and MSH6 expression in both AACs (proband and her mother) and in the endometrial carcinoma of her sister. Subsequent genetic screening confirmed the presence of a germline MSH2 mutation (resulting in deletions of exons 1–3) in the proband and her sister. Conclusion: Our findings provide strong support for the recent proposal that ACC should be considered a Lynch syndrome-associated tumor and included in the Amsterdam II clinical diagnostic criteria. We also suggest that screening for ACC should be considered in cancer surveillance strategies directed at individuals with germline mutations in DNA mismatch repair genes. PMID:27144940

  13. Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V).

    PubMed

    Abdul Wahab, A; Al Thani, G; Dawod, S T; Kambouris, M; Al Hamed, M

    2001-04-01

    Twenty-nine subjects (17 families) with cystic fibrosis belonging to the same Bedouin tribe were screened for cystic fibrosis transmembrane regulator gene mutations (CFTR). Homozygous I1234V mutation in exon 19 was identified in all families with a relatively high rate of consanguinity (96.6 per cent). The homozygous I1234V mutation tended to present with a variable degree of pulmonary disease, pancreatic insufficiency and electrolyte imbalance. Homozygous I1234V was found to be a common mutation in the studied Bedouin tribe in Qatar. PMID:11336127

  14. Mitochondrial encephalomyopathy: variable clinical expression within a single kindred.

    PubMed Central

    Crimmins, D; Morris, J G; Walker, G L; Sue, C M; Byrne, E; Stevens, S; Jean-Francis, B; Yiannikas, C; Pamphlett, R

    1993-01-01

    The clinical manifestations of mitochondrial encephalomyopathy are described in four generations of a single kindred. The age of onset of major neurological disturbance varied from 3-70 years. In some patients, deafness was the only manifestation; in others, recurrent bouts of status epilepticus associated with focal neurological deficits and headache, caused severe disability or death. Examples of all three adult forms of mitochondrial encephalomyopathy: MELAS, MERFF and Kearns Sayre syndrome, were represented within the kindred. Associated features included deafness, short stature, non-insulin-dependent diabetes mellitus, migraine, peptic ulceration and severe constipation. The nt 3243 A-G MELAS mutation was detected in two members of the kindred. This study highlights the diversity of clinical expression of a mitochondrial mutation within a single kindred. Images PMID:8350109

  15. Current status of familial gastrointestinal polyposis syndromes

    PubMed Central

    Jung, Ioan; Gurzu, Simona; Turdean, Gligore Sabin

    2015-01-01

    Because of the rarity of familial gastrointestinal cancer-predisposing syndromes, their exploration in literature is not extensive. In this review, an update of the clinicopathological and molecular criteria of gastrointestinal familial polyposis syndromes with potential malignant transformation is performed. In addition, a guide for screening and surveillance was synthesized and a distribution of gene mutations according to the specific syndromes and geographic distribution was included. The following inherited polyposes syndromes were analyzed: familial adenomatous polyposis, the hamartomatous familial polyposes (Juvenile polyposis, Peutz-Jeghers syndrome, Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, hereditary mixed polyposis syndrome, Gorlin syndrome, Birt-Hogg-Dube syndrome, neurofibromatosis type I and multiple endocrine neoplasia syndrome 2B), Li-Fraumeni syndrome, and MUTYH-associated adenomatous polyposis. For proper medical care, subspecialization of gastroenterologists, pathologists, and genticists in the field of familial diseases should be introduced in the medical curriculum. PMID:26600934

  16. Neuropsychological profile of a large kindred with familial Alzheimer's disease caused by the E280A single presenilin-1 mutation.

    PubMed

    Ardila, A; Lopera, F; Rosselli, M; Moreno, S; Madrigal, L; Arango-Lasprilla, J C; Arcos, M; Murcia, C; Arango-Viana, J C; Ossa, J; Goate, A; Kosik, K S

    2000-08-01

    It was hypothesized that subjective memory complaints represent the earliest sign of dementia in carriers of the presenilin-1 (PS1) mutation. A total of 122 subjects (44 males, 78 females) were included in this study. Forty of them were positive for the mutation in the PS1 gene (mutation positive, MP) whereas 82 showed negative results (mutation negative, MN). Subjects were active, functionally normal, even though some of them complained of memory difficulties. Two groups of neuropsychological instruments were administered: (a) The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological test battery (Morris et al., 1989), and (b) some additional neuropsychological tests (Raven Test, Wechsler Memory Scale, Rey-Osterrieth Complex Figure, Boston Naming Test, Naming of Categories, Boston Diagnostic Aphasia Examination, Memory of Three Phrases, Knopman Test, Digit Symbol, and Visual "A" Cancellation Test). Performance in both groups was quite similar. In a secondary analysis, the MP group was subdivided into two subgroups: without and with memory complaints. When comparing both subgroups, a better performance in the first subgroup was found throughout the different subtests. Statistically significant differences were observed in the following test scores: Mini-Mental State Examination, Naming Test (Low Frequency), Memory of Words Test, Recall of Drawings, Wechsler Memory Scale (Logical Memory, Associative Learning, and Total Score), Rey-Osterrieth Complex Figure (Immediate Recall Condition), Boston Diagnostic Aphasia Examination (Complex Ideational Material Subtest), Memory of Three Phrases Test, Serial Verbal Learning (maximum score and Delayed Recall), Knopman Test (First Trial, Second Trial, and Recall after 5 Minutes), Digit Symbol, and Visual "A" Cancellation Test (Additions). Results supported the hypothesis that memory complaints represent the earliest symptom of familial Alzheimer's disease. In addition to the memory difficulties

  17. Can a familial gastrointestinal tumour syndrome be allelic with Waardenburg syndrome?

    PubMed

    Vilain, R E; Dudding, T; Braye, S G; Groombridge, C; Meldrum, C; Spigelman, A D; Ackland, S; Ashman, L; Scott, R J

    2011-06-01

    Familial gastrointestinal stromal tumours (GISTs) are rare but otherwise well-characterized tumour syndromes, most commonly occurring on a background of germline-activating mutations in the tyrosine kinase receptor c-KIT. The associated clinical spectrum reflects the constitutive activation of this gene product across a number of cell lines, generating gain-of-function phenotypes in interstitial cells of Cajal (GIST and dysphagia), mast cells (mastocytosis) and melanocytes (hyperpigmentation). We report a three-generation kindred harbouring a c-KIT germline-activating mutation resulting in multifocal GISTs, dysphagia and a complex melanocyte hyperpigmentation and hypopigmentation disorder, the latter with features typical of those observed in Waardenburg type 2 syndrome (WS2F). Sequencing of genes known to be causative for WS [microphthalmia transcription factor (MITF), Pax3, Sox10, SNAI2 ] failed to show any candidate mutations to explain this complex cutaneous depigmentation phenotype. Our case report conclusively expands the clinical spectrum of familial GISTs and shows a hitherto unrecognized link to WS. Possible mechanisms responsible for this novel cause of WS2F will be discussed. PMID:20636395

  18. Craniosynostosis suggestive of Saethre-Chotzen syndrome: Clinical description of a large kindred and exclusion of candidate regions on 7p

    SciTech Connect

    von Gernet, S.; Muehlbauer, W.; Fairley, J.

    1996-05-03

    We describe the clinical manifestations of an autosomal dominant form of craniosynostosis in a large family with eight affected relatives. Unilateral or bilateral coronal synostosis, low frontal hair line, strabismus, ptosis, and partial cutaneous syndactyly of fingers and toes are findings suggestive of the diagnosis of Saethre-Chotzen syndrome. The disease locus was excluded from the two adjacent Saethre-Chotzen candidate regions on 7p by linkage analysis with markers D7S664 and D7S507. This indicates heterogeneity of Saethre-Chotzen syndrome with a locus outside the candidate regions on 7p. 30 refs., 6 figs., 2 tabs.

  19. Legius syndrome in fourteen families.

    PubMed

    Denayer, Ellen; Chmara, Magdalena; Brems, Hilde; Kievit, Anneke Maat; van Bever, Yolande; Van den Ouweland, Ans M W; Van Minkelen, Rick; de Goede-Bolder, Arja; Oostenbrink, Rianne; Lakeman, Phillis; Beert, Eline; Ishizaki, Takuma; Mori, Tomoaki; Keymolen, Kathelijn; Van den Ende, Jenneke; Mangold, Elisabeth; Peltonen, Sirkku; Brice, Glen; Rankin, Julia; Van Spaendonck-Zwarts, Karin Y; Yoshimura, Akihiko; Legius, Eric

    2011-01-01

    Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome. PMID:21089071

  20. Legius Syndrome in Fourteen Families

    PubMed Central

    Denayer, Ellen; Chmara, Magdalena; Brems, Hilde; Kievit, Anneke Maat; van Bever, Yolande; Van den Ouweland, Ans MW; Van Minkelen, Rick; de Goede-Bolder, Arja; Oostenbrink, Rianne; Lakeman, Phillis; Beert, Eline; Ishizaki, Takuma; Mori, Tomoaki; Keymolen, Kathelijn; Van den Ende, Jenneke; Mangold, Elisabeth; Peltonen, Sirkku; Brice, Glen; Rankin, Julia; Van Spaendonck-Zwarts, Karin Y; Yoshimura, Akihiko; Legius, Eric

    2011-01-01

    Legius syndrome presents as an autosomal dominant condition characterized by café-au-lait macules with or without freckling and sometimes a Noonan-like appearance and/or learning difficulties. It is caused by germline loss-of-function SPRED1 mutations and is a member of the RAS-MAPK pathway syndromes. Most mutations result in a truncated protein and only a few inactivating missense mutations have been reported. Since only a limited number of patients has been reported up until now, the full clinical and mutational spectrum is still unknown. We report mutation data and clinical details in fourteen new families with Legius syndrome. Six novel germline mutations are described. The Trp31Cys mutation is a new pathogenic SPRED1 missense mutation. Clinical details in the 14 families confirmed the absence of neurofibromas, and Lisch nodules, and the absence of a high prevalence of central nervous system tumors. We report white matter T2 hyperintensities on brain MRI scans in 2 patients and a potential association between postaxial polydactyly and Legius syndrome. © 2010 Wiley-Liss, Inc. PMID:21089071

  1. Family perspectives about Down syndrome.

    PubMed

    Skotko, Brian G; Levine, Susan P; Macklin, Eric A; Goldstein, Richard D

    2016-04-01

    National medical organizations recommend that during prenatal counseling sessions, healthcare providers discuss how having a child with Down syndrome (DS) might impact the family unit. Few studies, to date, have surveyed families about their life experiences. For this investigation, we examined 41 family attitudes, which were obtained from mailed questionnaires completed by 1,961 parents/guardians, 761 brothers/sisters, and 283 people with DS who were members of six DS non-profit organizations, chosen for their size, ethnic/racial diversities, and geographic distribution throughout the United States. About 83% of families reported to all being proud of the family member with DS, and 87% reported to all feeling love for the member with DS. Younger siblings (ages 9-11) were more likely to feel embarrassed by their sibling with DS if their parents/guardians also did. If one or more parents/guardians felt that their children without DS did have a good relationship with their child with DS, siblings were more likely to report that they loved and liked their brother/sister with DS. Overall, our data demonstrate that positive themes tend to dominate within modern-day families who have members with DS, although challenges were not insignificant for some. PMID:26692378

  2. 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.

  3. Familial Hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3.

    PubMed Central

    MacRae, C A; Ghaisas, N; Kass, S; Donnelly, S; Basson, C T; Watkins, H C; Anan, R; Thierfelder, L H; McGarry, K; Rowland, E

    1995-01-01

    We have mapped a disease locus for Wolff-Parkinson-White syndrome (WPW) and familial hypertrophic cardiomyopathy (FHC) segregating in a large kindred to chromosome 7 band q3. Although WPW syndrome and FHC have been observed in members of the same family in prior studies, the relationship between these two diseases has remained enigmatic. A large family with 25 surviving individuals who are affected by one or both of these conditions was studied. The disease locus is closely linked to loci D7S688, D7S505, and D7S483 (maximum two point LOD score at D7S505 was 7.80 at theta = 0). While four different FHC loci have been described this is the first locus that can be mutated to cause both WPW and/or FHC. PMID:7657794

  4. Identification of compound heterozygous KCNJ1 mutations (encoding ROMK) in a kindred with Bartter's syndrome and a functional analysis of their pathogenicity.

    PubMed

    Srivastava, Shalabh; Li, Dimin; Edwards, Noel; Hynes, Ann-M; Wood, Katrina; Al-Hamed, Mohamed; Wroe, Anna C; Reaich, David; Moochhala, Shabbir H; Welling, Paul A; Sayer, John A

    2013-11-01

    A multiplex family was identified with biochemical and clinical features suggestive of Bartter's syndrome (BS). The eldest sibling presented with developmental delay and rickets at 4 years of age with evidence of hypercalciuria and hypokalemia. The second sibling presented at 1 year of age with urinary tract infections, polyuria, and polydipsia. The third child was born after a premature delivery with a history of polyhydramnios and neonatal hypocalcemia. Following corrective treatment she also developed hypercalciuria and a hypokalemic metabolic alkalosis. There was evidence of secondary hyperreninemia and hyperaldosteronism in all three siblings consistent with BS. Known BS genes were screened and functional assays of ROMK (alias KCNJ1, Kir1.1) were carried out in Xenopus oocytes. We detected compound heterozygous missense changes in KCNJ1, encoding the potassium channel ROMK. The S219R/L220F mutation was segregated from father and mother, respectively. In silico modeling of the missense mutations suggested deleterious changes. Studies in Xenopus oocytes revealed that both S219R and L220F had a deleterious effect on ROMK-mediated potassium currents. Coinjection to mimic the compound heterozygosity produced a synergistic decrease in channel function and revealed a loss of PKA-dependent stabilization of PIP2 binding. In conclusion, in a multiplex family with BS, we identified compound heterozygous mutations in KCNJ1. Functional studies of ROMK confirmed the pathogenicity of these mutations and defined the mechanism of channel dysfunction. PMID:24400161

  5. Modeling Family Adaptation to Fragile X Syndrome

    ERIC Educational Resources Information Center

    Raspa, Melissa; Bailey, Donald, Jr.; Bann, Carla; Bishop, Ellen

    2014-01-01

    Using data from a survey of 1,099 families who have a child with Fragile X syndrome, we examined adaptation across 7 dimensions of family life: parenting knowledge, social support, social life, financial impact, well-being, quality of life, and overall impact. Results illustrate that although families report a high quality of life, they struggle…

  6. Familial 'sleep apnea plus' syndrome: report of a family.

    PubMed

    Manon-Espaillat, R; Gothe, B; Adams, N; Newman, C; Ruff, R

    1988-02-01

    We describe a familial disorder consisting of sleep apnea, anosmia, colorblindness, partial complex seizures, and cognitive dysfunction. The phenotypic expression of the syndrome suggests an autosomal dominant inheritance with incomplete penetrance. PMID:3257550

  7. Endocrine neoplasms in familial syndromes of hyperparathyroidism.

    PubMed

    Li, Yulong; Simonds, William F

    2015-06-01

    Familial syndromes of hyperparathyroidism, including multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2A (MEN2A), and the hyperparathyroidism-jaw tumor (HPT-JT), comprise 2-5% of primary hyperparathyroidism cases. Familial syndromes of hyperparathyroidism are also associated with a range of endocrine and nonendocrine tumors, including potential malignancies. Complications of the associated neoplasms are the major causes of morbidities and mortalities in these familial syndromes, e.g., parathyroid carcinoma in HPT-JT syndrome; thymic, bronchial, and enteropancreatic neuroendocrine tumors in MEN1; and medullary thyroid cancer and pheochromocytoma in MEN2A. Because of the different underlying mechanisms of neoplasia, these familial tumors may have different characteristics compared with their sporadic counterparts. Large-scale clinical trials are frequently lacking due to the rarity of these diseases. With technological advances and the development of new medications, the natural history, diagnosis, and management of these syndromes are also evolving. In this article, we summarize the recent knowledge on endocrine neoplasms in three familial hyperparathyroidism syndromes, with an emphasis on disease characteristics, molecular pathogenesis, recent developments in biochemical and radiological evaluation, and expert opinions on surgical and medical therapies. Because these familial hyperparathyroidism syndromes are associated with a wide variety of tumors in different organs, this review is focused on those endocrine neoplasms with malignant potential. PMID:27207564

  8. Homozygous HAX1 mutations in severe congenital neutropenia patients with sporadic disease: a novel mutation in two unrelated British kindreds.

    PubMed

    Smith, Bradley N; Ancliff, Phil J; Pizzey, Arnold; Khwaja, Asim; Linch, David C; Gale, Rosemary E

    2009-03-01

    Patients with autosomal dominant (AD), sporadic and X-linked severe congenital neutropenia (SCN) may have mutations in the elastase 2 (ELA2) or Wiskott-Aldrich syndrome (WAS) genes. Homozygous mutations in the HAX1 gene have recently been reported in autosomal recessive (AR) cases of primarily Middle-Eastern descent and the original Kostmann family. We screened 109 predominantly Caucasian SCN kindreds for mutations in these genes; 33 (30%) had 24 different ELA2 mutations, five of them novel, two kindreds (2%) had WAS mutations and four kindreds (4%) had three different HAX1 mutations, two of them novel. One HAX1 mutation (p.Ser43LeufsX11) was found in an AR Ashkenazi Jewish kindred, the other (p.Glu31LysfsX54) in two unrelated British patients with sporadic disease. Microsatellite analysis of the HAX1 locus revealed a common haplotype (maximum distance 4.1 Megabases) for the p.Glu31LysfsX54 patients, suggesting a possible ancestral founder. In functional assays, the level of spontaneous and staurosporine-induced apoptosis was increased in neutrophils from both p.Ser43LeufsX11 patients but not a p.Glu31LysfsX54 patient, suggesting the possible presence of modifying factors. The low incidence of HAX1 mutations in our study suggests that the frequency may vary between racial groups but suggests that irrespective of inheritance or racial origin, SCN patients should be screened for HAX1 mutations. PMID:19036076

  9. Marfan syndrome affecting a whole Sudanese family

    PubMed Central

    Elmahdi, Laila M; Ali, Sulafa KM

    2013-01-01

    Marfan syndrome (MS, OMIM 154700) is an autosomal dominant disorder of fibrous connective tissue with striking pleiotropism and clinical variability. The cardinal features occur in skeletal, ocular, and cardiovascular systems. We describe a Sudanese family with the father and all his 4 children manifesting the syndrome. To our knowledge, there were no previously reported MS cases from Sudan.

  10. High-density genetic and physical mapping of DNA markers near the X-linked Alport syndrome locus: definition and use of flanking polymorphic markers.

    PubMed

    Barker, D F; Fain, P R; Goldgar, D E; Dietz-Band, J N; Turco, A E; Kashtan, C E; Gregory, M C; Tryggvason, K; Skolnick, M H; Atkin, C L

    1991-12-01

    To refine the genetic and physical mapping of the locus for Alport syndrome (ATS), 22 X-chromosome restriction fragment length polymorphism (RFLP) markers that fall between Xq21.3 and Xq25 were tested for genetic linkage with the disease and also mapped with respect to a series of physical breakpoints in this region. The location of the COL4A5 gene, which has recently been shown to be mutated in at least some families with Alport syndrome, was determined with respect to the same physical breakpoints. Two large Utah kindreds were included in the genetic studies, kindreds P and C, with 125 and 63 potentially informative meioses, respectively. Both kindreds have essentially identical nephritis; however, kindred P has sensorineural hearing loss associated with the nephritis, while kindred C does not. A mutation in COL4A5 has been demonstrated for kindred P, but no change in this gene has yet been detected for kindred C. Twelve informative probes did not recombine with the disease locus in either kindred (theta = 0.0, with combined lod scores for the two kindreds ranging from 7.7 to 30.0). The closest markers that could be demonstrated to flank the disease locus were the same for each kindred and thus the locations of the mutations causing the two disease phenotypes are not distinguishable at the current level of genetic resolution. The flanking markers are also useful for the resolution of questionable diagnoses and allow accurate estimates for these families of the rate of sporadic hematuria in noncarrier females (7%) and the penetrance of hematuria for carrier females (93%). PMID:1684566

  11. Genetic linkage analysis in 26 families with Bardet-Biedl syndrome

    SciTech Connect

    Wright, A.F.; Bruford, E.A.; Mansfield, D.C.

    1994-09-01

    Bardet-Biedl syndrome is an autosomal recessive disorder characterized by polydactyly, obesity, hypogonadism, retinitis pigmentosa, renal anomalies and mental retardation. Clinical heterogeneity is quite marked both within and between families. Linkage has been reported between Bardet-Biedl syndrome and the D16408 marker in chromosomal region 16q21 in an extended Bedouin kindred and, more recently, in a subset of 17 out of 31 families using the PYGM/D11S913 markers in chromosomal region 11q13. We have analyzed linkage to the 16q21 and 11q13 regions and used markers covering chromosomes 2, 3, 17 and 18 in a set of 26 Bardet-Biedl families, each containing at least two affected individuals, with a total of 57 affected members. Evidence of linkage to the D11S527 locus has been identified assuming linkage homogeneity with a lod score of 2.72 at a recombination fraction of 0.11 (95% limits 0.03-0.25).

  12. A Japanese family with popliteal pterygium syndrome

    PubMed Central

    Katsube, Motoki; Yoshiura, Koh-ichiro; Kusumoto, Kenji

    2015-01-01

    We investigated a family in which the mother and a daughter suffered from popliteal pterygium syndrome (PPS). Mutation in the interferon regulatory factor 6 (IRF6) gene was detected in the mother and daughter. This is the second report of a family case with mutation in the IRF6 gene in Japanese patients with PPS.

  13. A family with Wagner syndrome with uveitis and a new versican mutation

    PubMed Central

    Rothschild, Pierre-Raphaël; Brézin, Antoine P.; Nedelec, Brigitte; des Roziers, Cyril Burin; Ghiotti, Tiffany; Orhant, Lucie; Boimard, Mathieu

    2013-01-01

    Purpose To report the clinical and molecular findings of a kindred with Wagner syndrome (WS) revealed by intraocular inflammatory features. Methods Eight available family members underwent complete ophthalmologic examination, including laser flare cell meter measurements. Collagen, type II, alpha 1, versican (VCAN), frizzled family receptor 4, low density lipoprotein receptor-related protein 5, tetraspanin 12, and Norrie disease (pseudoglioma) genes were screened with direct sequencing. Results The index case was initially referred for unexplained severe and chronic postoperative bilateral uveitis following a standard cataract surgery procedure. Clinical examination of the proband revealed an optically empty vitreous with avascular vitreous strands and veils, features highly suggestive of WS. The systematic familial ophthalmologic examination identified three additional unsuspected affected family members who also presented with the WS phenotype, including uveitis for one of them. We identified a novel c.4004–6T>A nucleotide substitution at the acceptor splice site of intron 7 of the VCAN gene that segregated with the disease phenotype. Conclusions We present a family with WS with typical WS features and intraocular inflammatory manifestations associated with a novel splice site VCAN mutation. Beyond the structural role in the retinal-vitreous architecture, versican is also emerging as a pivotal mediator of the inflammatory response, supporting uveitis predisposition as a clinical manifestation of WS. PMID:24174867

  14. A common DLX3 gene mutation is responsible for tricho-dento-osseous syndrome in Virginia and North Carolina families.

    PubMed

    Price, J A; Wright, J T; Kula, K; Bowden, D W; Hart, T C

    1998-10-01

    Tricho-dento-osseous syndrome (TDO) is characterised by a variable clinical phenotype primarily affecting the hair, teeth, and bone. Different clinical features are observed between and within TDO families. It is not known whether the variable clinical features are the result of genetic heterogeneity or clinical variability. A gene for TDO was localised recently to chromosome 17q21 in four North Carolina families, and a 4 bp deletion in the human distal-less 3 gene (DLX3) was identified in all affected members. A previous genetic linkage study in a large Virginia kindred with TDO indicated possible linkage to the ABO, Gc, and Kell blood group loci. To examine whether TDO exhibits genetic heterogeneity, we have performed molecular genetic analysis to determine whether affected members of this Virginia kindred have the DLX3 gene deletion identified in North Carolina families. Results show that affected subjects (n=3) from the Virginia family have the same four nucleotide deletion previously identified in the North Carolina families. A common haplotype for three genetic markers surrounding the DLX3 gene was identified in all affected subjects in the North Carolina and Virginia families. These findings suggest that all people with TDO who have been evaluated have inherited the same DLX3 gene deletion mutation from a common ancestor. The variable clinical phenotype observed in these North Carolina and Virginia families, which share a common gene mutation, suggests that clinical variability is not the result of genetic heterogeneity at the major locus, but may reflect genetic heterogeneity at other epigenetic loci or contributing environmental factors or both. PMID:9783705

  15. Family Demands, Social Support and Family Functioning in Taiwanese Families Rearing Children with Down Syndrome

    ERIC Educational Resources Information Center

    Hsiao, C-Y.

    2014-01-01

    Background: Down syndrome (DS) affects not only children but also their families. Much remains to be learned about factors that influence how families of children with DS function, especially families in non-Western populations. The purpose of this cross-sectional, correlational study was to examine how family demographics, family demands and…

  16. Concordance of phenotypic expression and gender identity in a large kindred with a mutation in the androgen receptor.

    PubMed

    Hooper, H T; Figueiredo, B C; Pavan-Senn, C C; De Lacerda, L; Sandrini, R; Mengarelli, J K; Japp, K; Karaviti, L P

    2004-03-01

    A 14-year-old female presented to the Pediatric Endocrine Clinic, Universidade Federal o Parana Curitiba, Brazil, for obesity. A few years later, despite normal breast development, the patient had failed to menstruate and lacked pubic and axillary hair. Laboratory analyses revealed high levels of testosterone. Karyotype analysis was XY. Direct sequencing of her genomic DNA showed a G to T transition at nucleotide 2089 at exon 2 in the androgen receptor gene, resulting in a substitution of Phe for Cys at position 576. This mutation disrupts the first Zn finger critical to DNA binding and transcriptional activity and results in complete androgen-insensitivity syndrome (CAIS). This individual was part of 700-member multigenerational kindred of German origin living in small villages in Southern Brazil. Family members who gave informed consent were screened using a polymerase chain reaction-based method. Nineteen CAIS-affected individuals and carriers were identified. All presented with infertility and lack of or sparse pubic hair. The prevalence of common AIS within the kindred greatly exceeds that of the general population and is due in part to their isolated familial and community structures. All individuals are genuinely feminine in their appearance, sex behavior, gender identity, and integration within their communities. We conclude that CAIS leads to complete feminization of XY individuals and results in individuals who are psychologically and socially established and integrated as women within the familial and cultural contexts of their communities. PMID:14756668

  17. Most Families Cherish a Child with Down Syndrome, Survey Finds

    MedlinePlus

    ... nih.gov/medlineplus/news/fullstory_157878.html Most Families Cherish a Child With Down Syndrome, Survey Finds ... 21, 2016 MONDAY, March 21, 2016 (HealthDay News) -- Families of children with Down syndrome face challenges, but ...

  18. A Family History Study of Asperger Syndrome

    ERIC Educational Resources Information Center

    Ghaziuddin, Mohammad

    2005-01-01

    Asperger syndrome (AS) is a childhood-onset disorder often described as a mild variant of autism. Although classified as a distinct disorder in the DSM-IV, its overlap with autism continues to be a matter of ongoing debate. While the family genetic origins of autism are well established, few studies have investigated this topic in AS using current…

  19. Munchausen Syndrome by Proxy: A Family Affair.

    ERIC Educational Resources Information Center

    Mehl, Albert L.; And Others

    1990-01-01

    The article reports on a case of Munchausen syndrome by proxy in which chronic illicit insulin was administered to a one-year-old child by her mother. Factitious illnesses continued despite psychiatric intervention. Retrospective review of medical records suggested 30 previous episodes of factitious illness within the family. (DB)

  20. Familial hypothalamic digoxin deficiency syndrome.

    PubMed

    Kurup, Ravi Kumar; Kurup, Parameswara Achutha

    2004-01-01

    The case report of a family with coexistence of hypotension, recurrent respiratory infection, motor tics, obsessive-compulsive disorder (OCD), major depressive disorder, early onset osteoporosis, low body mass index, bulimia nervosa, and healthy aging with longevity is described. The family members had hyposexual behavior and less tendency toward spirituality. They did not have insomnia, but they did display tendency toward increased somnolence. No addictive behavior was observed. The family demonstrated a high level of bonding and affectionate behavior, and they were less creative, with an average intelligence quotient (IQ). There was a total absence of vascular thrombosis, systemic neoplasms and neuronal degeneration in the indexed family. All members of the indexed family were left hemispheric dominant. The levels of serum digoxin, HMG-CoA reductase activity, and dolichol were found to be decreased in the members of the indexed family, with a corresponding increase in red blood cell (RBC) Na(+)-K+ ATPase activity, serum ubiquinone and magnesium levels. There was increase in tyrosine catabolites and a reduction in tryptophan catabolites in the serum. The total and individual glycosaminoglycan fractions, carbohydrate residues of glycoproteins, activity of glycosaminoglycans (GAG) degrading enzymes, and glycohydrolases were decreased in the serum. The concentration of RBC membrane total GAG and carbohydrate residues of glycoproteins increased, while the cholesterol: phospholipid ratio of the membrane decreased. The activity of free radical scavenging enzymes were increased, while the concentration of free radicals decreased significantly. The same biochemical patterns were observed in left hemispheric dominance as opposed to right hemispheric dominance. The significance of these findings in the pathogenesis of these disorders is discussed. PMID:14990764

  1. Familial CRC—Beyond the Lynch Syndrome

    PubMed Central

    Stoffel, Elena M.; Kastrinos, Fay

    2013-01-01

    Although 30% of individuals diagnosed with CRC report a family history of the disease, only 5–6% carry germline mutations in genes associated with known hereditary cancer syndromes. The evaluation and management of families affected with CRC can be complicated by variability in disease phenotypes and limited sensitivity of genetic tests. In this review we examine what is currently known about familial CRC and what we have yet to learn, and explore how novel genomic approaches might be used to identify additional genetic and epigenetic factors implicated in heritable risk for cancer. PMID:23962553

  2. Two distinct origins of a common BRCA1 mutation in breast-ovarian cancer families: a genetic study of 15 185delAG-mutation kindreds.

    PubMed Central

    Berman, D. B.; Wagner-Costalas, J.; Schultz, D. C.; Lynch, H. T.; Daly, M.; Godwin, A. K.

    1996-01-01

    We screened 163 women from breast-ovarian cancer-prone families, as well as 178 individuals affected with breast and/or ovarian cancer but unselected for family history, for germ-line mutations in exon 2 of BRCA1, by SSCP analysis and direct sequencing. A total of 25 mutations were detected. Thirteen of 64 Jewish Ashkenazi women and 2 non-Jewish individuals were found to possess the 185delAG mutation. Haplotype data for all 15 individuals, with markers intragenic to BRCA1, suggest that the Jewish Ashkenazi individuals share a common ancestry that is distinct from the lineage shared by the other two women. These data provide the first evidence of two distinct lines of transmission for the 185delAG mutation, only one of which has its origins in the Jewish Ashkenazi population. Our screening also uncovered 10 affected individuals with an 11-bp deletion at nucleotide 188 of BRCA1 (188del11), 4 of whom are Ashkenazi Jews. This is only the third reported mutation detected within the Jewish Ashkenazi population and may represent the second most common alteration in BRCA1 found in Ashkenazi Jews in the United States. The observed overrepresentation of specific mutations within a subgroup of the general population may eventually contribute to the development of inexpensive and routine tests for BRCA1 mutations, as well as to the elucidation of other contributory factors (e.g., diet, environment, and chemical exposures) that may play a key role in cancer initiation and development. The implications of the mutational data, as well as the role that founder effect, demographic history, and penetrance play in the resulting observed phenomena, are discussed. Images Figure 1 Figure 2 Figure 3 PMID:8651293

  3. Genetics of familial intrahepatic cholestasis syndromes

    PubMed Central

    van Mil, S W C; Houwen, R; Klomp, L

    2005-01-01

    Bile acids and bile salts have essential functions in the liver and in the small intestine. Their synthesis in the liver provides a metabolic pathway for the catabolism of cholesterol and their detergent properties promote the solubilisation of essential nutrients and vitamins in the small intestine. Inherited conditions that prevent the synthesis of bile acids or their excretion cause cholestasis, or impaired bile flow. These disorders generally lead to severe human liver disease, underscoring the essential role of bile acids in metabolism. Recent advances in the elucidation of gene defects underlying familial cholestasis syndromes has greatly increased knowledge about the process of bile flow. The expression of key proteins involved in bile flow is tightly regulated by transcription factors of the nuclear hormone receptor family, which function as sensors of bile acids and cholesterol. Here we review the genetics of familial cholestasis disorders, the functions of the affected genes in bile flow, and their regulation by bile acids and cholesterol. PMID:15937079

  4. Familial Turner syndrome: the importance of information.

    PubMed

    Periquito, Isabel; Carrusca, Catarina; Morgado, Joana; Robalo, Brígida; Pereira, Carla; de Lurdes Sampaio, Maria

    2016-05-01

    Turner syndrome is a common genetic disorder with an incidence of 1 in 2500 live births. Spontaneous fertility is rare in such patients and is most likely in women with mosaicism or very distal Xp deletions. The authors report an unusual case of familial Turner syndrome in a woman with mosaicism 45,X/46,Xdel(Xp) karyotype with three documented spontaneous pregnancies, which resulted in two daughters with 46,Xdel(X)(p11.4)mat karyotype and a healthy son. The mother was first diagnosed by the age of 11 and did not receive contraceptive medication, due to information that she would be infertile. Both daughters were referred to an endocrinology unit and are now under growth hormone treatment, and have been growing in the 3rd percentile. This family illustrates the complexity and difficulties in counseling, follow-up and treatment in Turner syndrome, namely referring to a tertiary center, fertility and treatment such as growth hormone and hormonal replacement, due to the heterogeneity of the clinical spectrum. PMID:26824976

  5. Familial syndromes associated with neuroendocrine tumours

    PubMed Central

    Komarowska, Hanna; Czarnywojtek, Agata; Waligórska-Stachura, Joanna; Bączyk, Maciej; Ziemnicka, Katarzyna; Fischbach, Jakub; Wrotkowska, Elżbieta; Ruchała, Marek

    2015-01-01

    Neuroendocrine tumours may be associated with familial syndromes. At least eight inherited syndromes predisposing to endocrine neoplasia have been identified. Two of these are considered to be major factors predisposing to benign and malignant endocrine tumours, designated multiple endocrine neoplasia type 1 and type 2 (MEN1 and MEN2). Five other autosomal dominant diseases show more heterogeneous clinical patterns, such as the Carney complex, hyperparathyroidism-jaw tumour syndrome, Von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis. The molecular and cellular interactions underlying the development of most endocrine cells and related organs represent one of the more complex pathways not yet to be deciphered. Almost all endocrine cells are derived from the endoderm and neuroectoderm. It is suggested that within the first few weeks of human development there are complex interactions between, firstly, the major genes involved in the initiation of progenitor-cell differentiation, secondly, factors secreted by the surrounding mesenchyme, and thirdly, a series of genes controlling cell differentiation, proliferation and migration. Together these represent a formula for the harmonious development of endocrine glands and tissue. PMID:26557756

  6. A Korean Family with the Muenke Syndrome

    PubMed Central

    Yu, Jae Eun; Park, Dong Ha

    2010-01-01

    The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members. PMID:20592905

  7. A Korean family with the Muenke syndrome.

    PubMed

    Yu, Jae Eun; Park, Dong Ha; Yoon, Soo Han

    2010-07-01

    The Muenke syndrome (MS) is characterized by unicoronal or bicoronal craniosynostosis, midfacial hypoplasia, ocular hypertelorism, and a variety of minor abnormalities associated with a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. The birth prevalence is approximately one in 10,000 live births, accounting for 8-10% of patients with coronal synostosis. Although MS is a relatively common diagnosis in patients with craniosynostosis syndromes, with autosomal dominant inheritance, there has been no report of MS, in an affected Korean family with typical cephalo-facial morphology that has been confirmed by molecular studies. Here, we report a familial case of MS in a female patient with a Pro250Arg mutation in exon 7 (IgII-IGIII linker domain) of the FGFR3 gene. This patient had mild midfacial hypoplasia, hypertelorism, downslanting palpebral fissures, a beak shaped nose, plagio-brachycephaly, and mild neurodevelopmental delay. The same mutation was confirmed in the patient's mother, two of the mother's sisters and the maternal grandfather. The severity of the cephalo-facial anomalies was variable among these family members. PMID:20592905

  8. A study of a family with leopard syndrome.

    PubMed

    Loyd, D W; Tsuang, M T; Benge, J W

    1982-03-01

    We report a family with multiple lentigines syndrome and a manic-like psychosis. The psychosis and multiple lentigines syndrome are genetically unrelated, since the psychosis occurred in a maternal half-sibling of the propositus, while multiple lentigines syndrome occurred in the father of the propositus. The propositus also had Gilbert's syndrome and mitral valve prolapse. No other family members personally examined had either of these last two disorders. PMID:7061405

  9. Black Kindreds: Parenthood and Personal Kinship Networks Among Blacks "On Aid."

    ERIC Educational Resources Information Center

    Stack, Carol B.

    This study suggests that jural parenthood, i.e. socially recognized parenthood, is the basis of the creation of personal kinship networks, commonly referred to as personal kindreds. From 1968 to 1970, field work was conducted among second generation welfare families in an urban black community in a midwestern city in the United States. The…

  10. [Families with recurrent cases of Waardenburg-Klein syndrome].

    PubMed

    Bliumina, M G; Moskovkina, A G

    1985-06-01

    Deaf children with the type I Waardenburg--Klein syndrome were studied. Secondary cases were found in 14 unrelated and 1 incest families. In 10 families probands and all their affected relatives had the type I Waardenburg--Klein syndrome. In 4 families patients were discovered with both type I and type II syndromes. In an incest family the proband seemed to have the type III, while his mother and father (sibs) had type II and their grandmother the type I syndrome. These results contradict the hypothesis claiming the origin of different types of Waardenburg--Klein syndrome to be due to the action of different genes. It is proposed that types I and II, or all types of the syndrome are caused by a single dominant gene. Potential mechanisms for clinical polymorphism of Waardenburg--Klein syndrome are related to incomplete penetrance and varying expression of this gene. PMID:4029612

  11. Linkage analysis in familial Angelman syndrome

    SciTech Connect

    Wagstaff, J. ); Shugart, Y.Y. ); Lalande, M. Howard Hughes Medical Institute, Boston, MA )

    1993-07-01

    Familial Angelman syndrome (AS) can result from mutations in chromosome 15q11q13 that, when transmitted from father to child, result in no phenotypic abnormality but, when transmitted from mother to child, cause AS. These mutations therefore behave neither as dominant nor as recessive mutations but, rather, show an imprinted mode of inheritance. The authors have analyzed two sibling pairs with AS and a larger family with four AS offspring of three sisters with several recently described microsatellite polymorphisms in the AS region. AS siblings inherited the same maternal alleles at the GABRB3 and GABRA5 loci, and the unaffected siblings of AS individuals inherited the other maternal alleles at these loci. In one of the AS sibling pairs, analysis of a recombination event indicates that the mutation responsible for AS is distal to locus D15S63. This result is consistent with a previously described imprinted submicroscopic deletion causing AS, a deletion that includes loci D15S10, D15S113, and GABRB3, all distal to D15S63. The analysis of the larger AS family provides the first clear demonstration of a new mutation in nondeletion AS. Analysis of linkage of AS to GABRB3 in these three families, on the assumption of imprinted inheritance (i.e., penetrance of an AS mutation is 1 if transmitted maternally and is 0 if transmitted paternally), indicates a maximum lod score of 3.52 at 6 = 0. 34 refs., 4 figs., 1 tab.

  12. Fragile X syndrome in incestuous families

    SciTech Connect

    Seemanova, E.

    1996-11-11

    Reed suggested the investigation of children 219 from incestuous unions as a method for calculation of the detrimental heterozygosity of man. Some studies of latent genetics load in man have been based on the comparison of health status of incestuous children with their half-sibs born to the same mothers in matings with nonconsanguineous partners. These studies were limited to the detection of autosomal-recessive genes leading to abnormal phenotypes or mental deficiency in homozygotes. The highest coefficient of inbreeding in human beings is 1/4 in offspring of incestuous matings: hence, the high proportion of affected homozygotes and low incidence of affected individuals among their maternal half-sibs. Mental deficiency in incestuous children represents not only cases of simple recessive inheritance. Recently, we observed three incestuous families in which fragile X syndrome was detected. The fra(X) children were born to carriers from incestuous unions as well as to unrelated partners. Therefore, we recommend use of incestuous children and their maternal half-sibs as a control group for studies estimating latent genetic load after investigation for fra(X). The incidence of fra(X) syndrome is high, and mental retardation in heterozygotes is uncommon. Both of these factors can play a role in the occurrence of incest, and in pregnancy at young age, as well as in multiple partnerships. Families of heterozygotes for fragile X should be excluded from the material for the calculation of human latent detrimental (autosomal-recessive) genetic load. 3 refs., 3 figs.

  13. Familial carpal tunnel syndrome: a report of a Finnish family.

    PubMed

    Mahjneh, I; Saarinen, A; Siivola, J

    2001-12-01

    The existence of familial carpal tunnel syndrome (FCTS) as a separate autonomic entity has been discussed during the last few years. In order to contribute with more data to the literature, we report here the results of clinical. electrophysiological, pathological and radiological studies performed in 5 patients belonging to the same Finnish pedigree. The disease appeared usually before the second decade with numbness and pain on the I--III digits. In most patients symptoms were unilateral but within 2 years they became bilateral. In all patients typical electrophysiological features of median nerve entrapment have been recorded. X-rays of the wrist showed narrow carpal tunnel in all patients. In all patients the possibility of having HNPP as well as familial amyloidosis has been excluded by molecular genetic and pathological studies. All patients underwent surgery and at postoperative stage symptoms were relieved or completely disappeared. Our study supports the theory that FCTS exists as a separate autonomic entity, therefore it is important in front of a sporadic case to investigate the family occurrence of CTS. PMID:11903093

  14. A novel CHST3 allele associated with spondyloepiphyseal dysplasia and hearing loss in Pakistani kindred.

    PubMed

    Waryah, A M; Shahzad, M; Shaikh, H; Sheikh, S A; Channa, N A; Hufnagel, R B; Makhdoom, A; Riazuddin, S; Ahmed, Z M

    2016-07-01

    Skeletal dysplasias (SDs) are highly heterogeneous disorders composed of 40 clinical sub-types that are part of 456 well-delineated syndromes in humans. Here, we enrolled consanguineous kindred from a remote area of Sindh province of Pakistan, with 14 affected individuals suffering with short stature, kyphoscoliosis, joint dislocations, clubfoot, heart valve anomalies and progressive bilateral mixed hearing loss. To identify pathogenic variants in this family, whole exome sequencing (WES) was performed in one affected and one normal individual, which revealed a novel transversion mutation (c.802G>T; p.Glu268*) in CHST3 associated with the phenotype. CHST3 encodes a chondroitin 6-O-sulfotransferase-1 (C6ST-1) enzyme that is essential for the sulfation of proteoglycans found in cartilages. Previously, mutations in CHST3 have largely been reported in sporadic cases of SD, primarily with severe spinal abnormalities, joint dislocations, joint contractures, and clubfoot. Clinical and radiological examination of the affected individuals in this family provides new insights into phenotypic spectrum of CHST3 alleles and disease progression with age. PMID:26572954

  15. Recognizing Family Dynamics in the Treatment of Chronic Fatigue Syndrome

    ERIC Educational Resources Information Center

    Sperry, Len

    2012-01-01

    Chronic fatigue syndrome (CFS) is an increasingly common chronic medical condition that affects not only patients but also their families. Because family dynamics, particularly the family life cycle, can and does influence the disease process, those providing counseling to CFS patients and their families would do well to recognize these dynamics.…

  16. Familial neuroendocrine tumor syndromes: from genetics to clinical practice.

    PubMed

    Sakurai, Akihiro; Katai, Miyuki; Hashizume, Kiyoshi; Fukushima, Yoshimitsu

    2006-01-01

    Thanks to recent developments in molecular biology and cancer genetics, genetic testing has become widely available and useful in several kinds of familial tumor syndrome. However, the impact of genetic testing on medical management is not always straightforward. Clinicians have to consider the psychological impact and ethical complexities of communicating hereditary cancer risk information to families. This review notes some points on genetic counseling before and after genetic testing for familial neuroendocrine tumor syndromes. PMID:17001463

  17. SIDS Family Adjustment Scale: A Method of Assessing Family Adjustment to Sudden Infant Death Syndrome.

    ERIC Educational Resources Information Center

    May, Harold J.; Breme, Frederick J.

    1982-01-01

    Discusses Sudden Infant Death Syndrome (SIDS) and the family's resultant grief process. Explores SIDS as a family crisis, and by identifying the psychological factors or tasks pertinent to family adjustment, proposes a SIDS Family Adjustment Scale which assists in recognizing adaptive and maladaptive grief responses. (Author)

  18. Divorce in families of children with Down Syndrome or Rett Syndrome.

    PubMed

    Lederman, Vivian Renne Gerber; Alves, Bianca dos Santos; Negrão, Juliana; Maria, Juliana Negrão; Schwartzman, José Salomão; D'Antino, Maria Eloisa Famá; Brunoni, Decio

    2015-05-01

    This study evaluates the impact in the stability and management of the marriage of parents of a child with Down or Rett Syndrome. Morbidity of the syndromes and the marital status of the couples before and after the birth of the affected children were considered variables. The divorce rate in families with Down syndrome was 10%, similar to the Brazilian rate population. In Rett Syndrome, the divorce rate was significantly higher, 23.5%. The higher morbidity of Rett Syndrome, and the moment of diagnosis could be relevant factors for the increased divorce rate related to this syndrome. PMID:26017939

  19. Tumour spectrum in the FAMMM syndrome.

    PubMed Central

    Lynch, H. T.; Fusaro, R. M.; Pester, J.; Oosterhuis, J. A.; Went, L. N.; Rumke, P.; Neering, H.; Lynch, J. F.

    1981-01-01

    The Familial Atypical Multiple Mole-Melanoma Syndrome (FAMMM) is characterized by an autosomal dominantly inherited susceptibility to multiple atypical naevi. Patients with this hereditary phenotype show a strong susceptibility to cutaneous malignant melanoma (CMM). Our investigation of an extended Dutch kindred showing the FAMMM phenotype revealed a proband with bilateral intraocular malignant melanoma (IOM) and multiple CMM. The family revealed an array of tumours which included carcinoma of the lung, skin, larynx, and breast in addition to CMM and IOM, which were transmitted vertically through 3 generations. There was male-to-male transmission, and the number of affected males and females was about the same, which was consistent with an autosomal dominant inheritance. Thus the FAMMM syndrome not only indicates a potential for CMM, but a susceptibility to other systemic cancers as well. These observations, though limited to a single kindred, merit a painstaking evaluation of cancer of all anatomical sites in other kindreds showing the FAMMM syndrome. Such studies could yield clues to cancer aetiology, pathogenesis, and control. Images Fig. 2 Fig. 3 Fig. 4 PMID:7295511

  20. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.

    PubMed

    Bull, L N; Carlton, V E; Stricker, N L; Baharloo, S; DeYoung, J A; Freimer, N B; Magid, M S; Kahn, E; Markowitz, J; DiCarlo, F J; McLoughlin, L; Boyle, J T; Dahms, B B; Faught, P R; Fitzgerald, J F; Piccoli, D A; Witzleben, C L; O'Connell, N C; Setchell, K D; Agostini, R M; Kocoshis, S A; Reyes, J; Knisely, A S

    1997-07-01

    Byler disease (ByD) is an autosomal recessive disorder in which cholestasis of onset in infancy leads to hepatic fibrosis and death. Children who have a clinically similar disorder, but are not members of the Amish kindred in which ByD was described, are said to have Byler syndrome (ByS). Controversy exists as to whether ByD and ByS (subtypes of progressive familial intrahepatic cholestasis [PFIC]) represent one clinicopathological entity. The gene for ByD has been mapped to a 19-cM region of 18q21-q22. PFIC caused by a lesion in this region, including ByD, can be designated PFIC-1. Examination of haplotypes in siblings with ByS in two unrelated non-Amish families showed that the gene(s) responsible for their disorder(s) did not lie in the PFIC-1 candidate region. On light microscopy and transmission electron microscopy (TEM), liver tissue differed between Amish children with PFIC-1, who had coarsely granular bile and at presentation had bland intracanalicular cholestasis, and the children with ByS in the two non-Amish families, who had amorphous or finely filamentous bile and at presentation had neonatal hepatitis. Bile acid composition of bile also differed: In the Amish children with PFIC-1 and in one ByS family, the proportional concentration of chenodeoxycholic acid (CDCA) in bile was low compared with normal bile; in the other ByS family, it was only slightly reduced. Genetic analysis and light microscopy and TEM of liver may help distinguish PFIC-1 from other forms of ByS. PMID:9214465

  1. [Asperger's syndrome in family context--review of studies].

    PubMed

    Zmijewska, Anna

    2010-01-01

    In recent years in the face of still growing number of diagnosis of pervasive developmental disorders there has been an increase in number of research in the functioning of family of children with autism or Asperger's Syndrome. Studies concerning families of children with autism have been predominantly occupied with the stress-coping strategies and also with the therapeutic effect of interaction between disabled children and the rest of the family. New studies with families of children with Asperger's Syndrome, apart from the coping styles of parents and the received support, are also examining the properties of the system of these families, like: cohesion, adaptability, organisation, control, expressiveness or conflict. Such a perspective enables researchers to describe the circularity of influences in these families, on the other hand, however, some methodological deficiencies of this research, as well as the lack of longitudinal studies prevent researchers from creating a comprehensive picture of functioning of these families. PMID:21452506

  2. Familial colorectal cancer syndromes: an overview of clinical management.

    PubMed

    Sammour, Tarik; Hayes, Ian P; Hill, Andrew G; Macrae, Finlay A; Winter, Des C

    2015-06-01

    Familial colorectal cancer syndromes pose a complex challenge to the treating clinician. Once a syndrome is recognized, genetic testing is often required to confirm the clinical suspicion. Management from that point is usually based on disease-specific guideline recommendations targeting risk reduction for the patient and their relatives through surgery, surveillance and chemoprophylaxis. The aim of this paper is to provide an up-to-date summary of the most common familial syndromes and their medical and surgical management, with specific emphasis on evidence-based interventions that improve patient outcome, and to present the information in a manner that is easily readable and clinically relevant to the treating clinician. PMID:25779305

  3. Genetics Home Reference: congenital central hypoventilation syndrome

    MedlinePlus

    ... central hypoventilation syndrome: PHOX2B genotype determines risk for sudden death. Pediatr Pulmonol. 2008 Jan;43(1):77-86. ... Rand CM. Congenital central hypoventilation syndrome (CCHS) and sudden infant death syndrome (SIDS): kindred disorders of autonomic regulation. Respir ...

  4. Nonorganic Failure-to-Thrive Syndrome and the Family System.

    ERIC Educational Resources Information Center

    Alderette, Paula; deGraffenried, Donald F.

    1986-01-01

    Argues that nonorganic failure-to-thrive syndrome (NFTT) in infants is the result of family disengagement--the family system's maladaptive style of interaction. Proposes a systems-based approach to diagnosis and to treatment, focusing on the process of disengagement and other interaction factors. (Author/ABB)

  5. Family Therapy of Terroristic Trauma: Psychological Syndromes and Treatment Strategies.

    ERIC Educational Resources Information Center

    Miller, Laurence

    2003-01-01

    Reviews pertinent literature on terroristic trauma and combines this information with the author's experience in treating adults, children, and family victims and survivors of recent terrorist attacks. Describes the psychological syndromes resulting from terrorism and discusses the relevant individual and family therapy modalities for treating…

  6. Families of 30-35-Year Olds with Down's Syndrome

    ERIC Educational Resources Information Center

    Carr, Janet

    2005-01-01

    Background: The families of a population sample of people with Down's syndrome (DS), and of their non-disabled controls, have been followed since early childhood, and the families have now been seen again as their sons and daughters reached age 30 and 35 years. Methods: A semi-structured interview schedule was used, including items from the…

  7. Functional classification and mutation analysis of a synpolydactyly kindred.

    PubMed

    Zhou, Jianda; Chen, Yao; Cao, Ke; Zou, Yonghua; Zhou, Haiyan; Hu, Feng; Ni, Bin; Chen, Yong

    2014-11-01

    The aim of the present study was to analyze a congenital syndactyly/polydactyly kindred and propose a new functional classification method of clinical significance. The modes of inheritance and mutational mechanisms were also determined using genetic analyses. Hand and foot anatomy and functions were measured using photographic images, X-ray imaging and grip ability tests. Genetic analysis comprised the genotyping of polymorphic microsatellite markers at known polydactyly-associated loci and the sequencing of the candidate gene. A functional classification system was devised to divide the clinical features into three types, which included mild, moderate or severe deformity. The family was concluded to have syndactyly type II with autosomal dominant inheritance. The microsatellites, D2S2310 and D2S2314, at the 2q31-32 chromosome, which have previously been associated with synpolydactyly type I, were found to be associated with the disorder in the current family. A 27-bp insertion mutation was identified in the affected individuals in the HOXD13 gene at this locus. The insertion added a further nine alanine residues to the polyalanine stretch within the encoded protein. In conclusion, the functional classification method described in the present study may be used to guide surgical approaches to treatment. A family was identified in whom expansion of the polyalanine tract in the HOXD13 gene causes autosomal dominant hereditary synpolydactyly. PMID:25289061

  8. A second family with CATSHL syndrome: Confirmatory report of another unique FGFR3 syndrome.

    PubMed

    Escobar, Luis F; Tucker, Megan; Bamshad, Michael

    2016-07-01

    Here we describe the second reported family with the CATSHL syndrome, a condition resulting from a unique mutation in the fibroblast growth factor receptor 3 (FGFR3) gene. Our family confirms the consistent and unique phenotype of this condition, and the specificity of the mutation in FGFR3. The CATSHL syndrome appears to be an autosomal dominant disorder with full penetrance. © 2016 Wiley Periodicals, Inc. PMID:27139183

  9. Familial cryptic translocation in Angelman syndrome

    SciTech Connect

    Weyerts, L.K.; Wiley, J.E.; Loud, K.M.

    1994-09-01

    The majority of patients with Angelman syndrome have been shown to have a cytogenetic or molecular deletion on the maternally derived chromosome 15. We report on a case of Angelman syndrome in which this deletion occurs as an unbalanced cryptic translocation involving chromosomes 14 and 15. The proband was diagnosed clinically as having Angelman syndrome. Multiple cytogenetic studies were done without detecting any deletion. When DNA probes (Oncor) specific for the Prader Willi/Angelman locus became available, the patient was restudied and found to be deleted for {open_quotes}region A{close_quotes} (D15S11) but not for {open_quotes}region B{close_quotes} (GABRB3). No other abnormality was detected. The proband`s mother was then studied. The chromosome 15 marker probe and D15S11 were detected on different chromosomes. Using alpha-satellite probes, a cryptic 14;15 translocation was uncovered. This balanced translocation was also found to be carried by the sister of the proband. This case, along with a case presented at the 1993 ASHG meeting, illustrates the need for using acrocentric probes when studying Angelman syndrome patients. The proband was studied using additional probes specific for this region and found to be deleted for SNRPN but not for D15S10. The breakpoint of the translocation in this patient delineates the smallest deletion of the Angelman syndrome region reported to date and therefore may represent the specific gene involved.

  10. Exome sequencing identified new mutations in a Marfan syndrome family

    PubMed Central

    2014-01-01

    Marfan syndrome is a common autosomal dominant hereditary connective tissue disorder. There is no cure for Marfan syndrome currently. Next-generation sequencing (NGS) technology is efficient to identify genetic lesions at the exome level. Here we carried out exome sequencing of two Marfan syndrome patients. Further Sanger sequencing validation in other five members from the same family was also implemented to confirm new variants which may contribute to the pathogenesis of the disease. Two new variants, including one nonsense SNP in the Marfan syndrome gene FBN1 and one missense mutation in exon 15 of LRP1, which may be related to the phenotype of the patients were identified. The exome sequencing analysis provides us a new insight into the molecular events governing pathogenesis of Marfan syndrome. Virtual slide http://www.diagnosticpathology.diagnomx.eu/vs/1229110069114125. PMID:24484584

  11. Rare nonconservative LRP6 mutations are associated with metabolic syndrome.

    PubMed

    Singh, Rajvir; Smith, Emily; Fathzadeh, Mohsen; Liu, Wenzhong; Go, Gwang-Woong; Subrahmanyan, Lakshman; Faramarzi, Saeed; McKenna, William; Mani, Arya

    2013-09-01

    A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2,000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which cosegregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation. PMID:23703864

  12. Rare nonconservative LRP6 mutations are associated with metabolic syndrome

    PubMed Central

    Singh, Rajvir; Smith, Emily; Fathzadeh, Mohsen; Liu, Wenzhong; Go, Gwang-Woong; Subrahmanyan, Lakshman; Faramarzi, Saeed; McKenna, William; Mani, Arya

    2013-01-01

    A rare mutation in LRP6 has been shown to underlie autosomal dominant coronary artery disease (CAD) and metabolic syndrome in an Iranian kindred. The prevalence and spectrum of LRP6 mutations in the disease population of the United States is not known. Two hundred white Americans with early onset familial CAD and metabolic syndrome and 2000 healthy Northern European controls were screened for nonconservative mutations in LRP6. Three novel mutations were identified, which co-segregated with the metabolic traits in the kindreds of the affected subjects and none in the controls. All three mutations reside in the second propeller domain, which plays a critical role in ligand binding. Two of the mutations substituted highly conserved arginines in the second YWTD domain and the third substituted a conserved glycosylation site. The functional characterization of one of the variants showed that it impairs Wnt signaling and acts as a loss of function mutation. PMID:23703864

  13. Family Functioning in Families with a Child with Down Syndrome: A Mixed Methods Approach

    ERIC Educational Resources Information Center

    Povee, K.; Roberts, L.; Bourke, J.; Leonard, H.

    2012-01-01

    Background: This study aimed to explore the factors that predict functioning in families with a child with Down syndrome using a mixed methods design. The quantitative component examined the effect of maladaptive and autism-spectrum behaviours on the functioning of the family while the qualitative component explored the impact of having a child…

  14. Familial hepatopulmonary syndrome in common variable immunodeficiency.

    PubMed

    Holmes, S N; Condliffe, A; Griffiths, W; Baxendale, H; Kumararatne, D S

    2015-04-01

    Common Variable Immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies which lead to a range of complications, including infectious, neoplastic and inflammatory disorders. This report describes monozygotic twin brothers with CVID who developed cryptogenic liver disease and subsequently hepatopulmonary syndrome (HPS). This is the second report of the association of HPS and CVID. Its occurrence in two identical twins implicates a genetic basis. PMID:25708586

  15. Is there a familial link between Down's syndrome and neural tube defects? Population and familial survey

    PubMed Central

    Amorim, Márcia R; Castilla, Eduardo E; Orioli, Iêda M

    2004-01-01

    Objective To verify whether Down's syndrome and neural tube defects arise more often in the same family than expected by chance. Design Population and familial survey. Setting Network of maternity hospitals in the Latin American collaborative study of congenital malformations (ECLAMC) in Argentina, Bolivia, Brazil, Chile, Colombia, Ecuador, Paraguay, Peru, Uruguay, and Venezuela between 1982 and 2000. Probands 2421 cases of neural tube defects, 952 of hydrocephalus, and 3095 of Down's syndrome registered from a total of 1 583 838 live births and stillbirths. Main outcome measures Observed number of cases of Down's syndrome among siblings of probands with a neural tube defect or hydrocephalus and number expected on the basis of maternal age; observed number of cases of neural tube defects or hydrocephalus among siblings of probands with Down's syndrome and number expected according to the prevalence in the same population. Results Five cases of Down's syndrome occurred among 5404 pregnancies previous to a case of neural tube defect or hydrocephalus, compared with 5.13 expected after adjustment by maternal age. Twelve cases of neural tube defect or hydrocephalus occurred among 8066 pregnancies previous to a case of Down's syndrome, compared with 17.18 expected on the basis of the birth prevalence for neural tube defects plus hydrocephalus in the same population. Conclusion No association occurred between families at risk of neural tube defects and those at risk of Down's syndrome. PMID:14662523

  16. Linkage Analysis in Familial Non-Lynch Syndrome Colorectal Cancer Families from Sweden

    PubMed Central

    Lindblom, Annika

    2013-01-01

    Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies. PMID:24349560

  17. Linkage analysis in familial non-Lynch syndrome colorectal cancer families from Sweden.

    PubMed

    Kontham, Vinaykumar; von Holst, Susanna; Lindblom, Annika

    2013-01-01

    Family history is a major risk factor for colorectal cancer and many families segregate the disease as a seemingly monogenic trait. A minority of familial colorectal cancer could be explained by known monogenic genes and genetic loci. Familial polyposis and Lynch syndrome are two syndromes where the predisposing genes are known but numerous families have been tested without finding the predisposing gene. We performed a genome wide linkage analysis in 121 colorectal families with an increased risk of colorectal cancer. The families were ascertained from the department of clinical genetics at the Karolinska University Hospital in Stockholm, Sweden and were considered negative for Familial Polyposis and Lynch syndrome. In total 600 subjects were genotyped using single nucleotide polymorphism array chips. Parametric- and non-parametric linkage analyses were computed using MERLIN in all and subsets of families. No statistically significant result was seen, however, there were suggestive positive HLODs above two in parametric linkage analysis. This was observed in a recessive model for high-risk families, at locus 9q31.1 (HLOD=2.2, rs1338121) and for moderate-risk families, at locus Xp22.33 (LOD=2.2 and HLOD=2.5, rs2306737). Using families with early-onset, recessive analysis suggested one locus on 4p16.3 (LOD=2.2, rs920683) and one on 17p13.2 (LOD/HLOD=2.0, rs884250). No NPL score above two was seen for any of the families. Our linkage study provided additional support for the previously suggested region on chromosome 9 and suggested additional loci to be involved in colorectal cancer risk. Sequencing of genes in the regions will be done in future studies. PMID:24349560

  18. Targeted therapy for hereditary cancer syndromes: hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and Li-Fraumeni syndrome.

    PubMed

    Agarwal, Rishi; Liebe, Sarah; Turski, Michelle L; Vidwans, Smruti J; Janku, Filip; Garrido-Laguna, Ignacio; Munoz, Javier; Schwab, Richard; Rodon, Jordi; Kurzrock, Razelle; Subbiah, Vivek

    2014-12-01

    Cancer genetics has rapidly evolved in the last two decades. Understanding and exploring the several genetic pathways in the cancer cell is the foundation of targeted therapy. Several genomic aberrations have been identified and their role in carcinogenesis is being explored. In contrast to most cancers where these mutations are acquired, patients with hereditary cancer syndromes have inherited genomic aberrations. The understanding of the molecular pathobiology in hereditary cancer syndromes has advanced dramatically. In addition, many molecularly targeted therapies have been developed that could have potential roles in the treatment of patients with hereditary cancer syndromes. In this review, we outline the presentation, molecular biology, and possible targeted therapies for two of the most widely recognized hereditary cancer syndromes -- hereditary breast and ovarian cancer syndrome and hereditary non-polyposis colorectal cancer syndrome (Lynch syndrome). We will also discuss other syndromes such as familial adenomatous polyposis and Li-Fraumeni syndrome (TP53). PMID:25549704

  19. Helping Families Cope with the Severe Stress of Dravet Syndrome.

    PubMed

    Camfield, Peter; Camfield, Carol; Nolan, Kathleen

    2016-06-01

    A child with Dravet syndrome shakes family life to the core. Dravet syndrome usually has three phases: (1) up to 1-1½ years: with episodes of febrile status epilepticus but normal development; (2) age 1½ to ~6-10 years: with frequent seizures of varying types, developmental stagnation, behavioural and sleep problems; (3) after ~10 years: improvement in seizures, deteriorating gait, intellectual disability but some developmental gains. Complete seizure control is rare-simply prescribing medication is inadequate to help families. Based on structured interviews with 24 families and confirmed by more informal discussions with other families, we suggest strategies for coping with this catastrophe. A child with Dravet syndrome usually means that one parent cannot work-financial pressures should be anticipated. In Stage 1, the approach to status should include a written protocol. An indwelling catheter for rapid venous access may be helpful. In Stage 2, assistance finding qualified babysitters is required, and the extended family needs encouragement to help. Appropriate equipment, rescue medication and protocols should travel with the child. Siblings may benefit from a system of one parent "on call." An internet support group provides an invaluable lifeline. In Stage 3, family isolation may be extreme-respite care and personal time for parents are important. Death from status, accidents and SUDEP (sudden unexplained death in epilepsy) occurs in 15%. Fear of SUDEP needs to be addressed. Moving from paediatric to adult care is frightening; an epilepsy transition clinic is useful. Attention to these realities may improve the quality of life for both child and family. PMID:27264140

  20. Screening analysis of candidate gene mutations in a kindred with polycystic liver disease

    PubMed Central

    Jin, Song; Cui, Kai; Sun, Zi-Qiang; Shen, Yang-Yang; Li, Pang; Wang, Zhen-Dan; Li, Fei-Fei; Gong, Ke-Nan; Li, Sheng

    2015-01-01

    AIM: To find potential mutable sites by detecting mutations of the candidate gene in a kindred with polycystic liver disease (PCLD). METHODS: First, we chose a kindred with PCLD and obtained five venous blood samples of this kindred after the family members signed the informed consent form. In the kindred two cases were diagnosed with PCLD, and the left three cases were normal individuals. All the blood samples were preserved at -85 °C. Second, we extracted the genomic DNA from the venous blood samples of the kindred using a QIAamp DNA Mini Kit and then performed long-range polymerase chain reaction (PCR) with different primers. The exons of PKD1 were all sequenced with the forward and reverse primers to ensure the accuracy of the results. Next, we purified the PCR products and directly sequenced them using Big Dye Terminator Chemistry version 3.1. The sequencing reaction was conducted with BiomekFX (Beckman). Finally, we analyzed the results. RESULTS: A total of 42 normal exons were identified in detecting mutations of the PKD1 gene. A synonymous mutation occurred in exon 5. The mutation was a homozygous T in the proband and was C in the reference sequence. This mutation was located in the third codon and did not change the amino acid encoded by the codon. Missense mutations occurred in exons 11 and 35. These mutations were located in the second codon; they changed the amino acid sequence and existed in the dbSNP library. A nonsense mutation occurred in exon 15. The mutation was a heterozygous CT in the proband and was C in the reference sequence. This mutation was located in the first codon and resulted in a termination codon. This mutation had an obvious influence on the encoded protein and changed the length of the protein from 4303 to 2246 amino acids. This was a new mutation that was not present in the dbSNP library. CONCLUSION: The nonsense mutation of exon 15 existed in the proband and in the third individual. Additionally, the proband was heterozygous

  1. Shwachman-Diamond syndrome in a Mexican family.

    PubMed

    Belkind-Gerson, J; Ontiveros-Nevares, P; Ocampo-Roosens, V; Sandoval-Juárez, D

    2001-01-01

    Shwachman-Diamond Syndrome (SDS) is an inherited condition with multisystemic abnormalities including pancreatic exocrine dysfunction, neutropenia, short stature, and skeletal abnormalities. In this report, we describe the case of a 14-year-old female with a history of neutropenia, pancreatic exocrine insufficiency and pancreatic endocrine sufficiency, pancreatic lipomatosis (10), and the development of myeloid leukemia. Postmortem examination revealed a high probability of SDS. We also describe the clinical findings in the patient's six siblings, suggesting this as a familial form of SDS. Because the gene(s) responsible for this syndrome have not yet been identified, genetic confirmation is not yet possible. This is the first report in the literature of a Mexican family with probable SDS. PMID:11440791

  2. Genotype–phenotype correlation in long QT syndrome families

    PubMed Central

    Qureshi, Sameera Fatima; Ali, Altaf; Venkateshwari, Ananthapur; Rao, Hygriv; Jayakrishnan, M.P.; Narasimhan, Calambur; Shenthar, Jayaprakash; Thangaraj, Kumarasamy; Nallari, Pratibha

    2015-01-01

    Heterogeneity in clinical manifestations is a well-known feature in Long QT Syndrome (LQTS). The extent of this phenomenon became evident in families wherein both symptomatic and asymptomatic family members are reported. The study hence warrants genetic testing and/or screening of family members of LQTS probands for risk stratification and prediction. Of the 46 families screened, 18 probands revealed novel variations/compound heterozygosity in the gene/s screened. Families 1–4 revealed probands carrying novel variations in KCNQ1 gene along with compound heterozygosity of risk genotypes of the SCN5A, KCNE1 and NPPA gene/s polymorphisms screened. It was also observed that families- 5, 6 and 7 were typical cases of “anticipation” in which both mother and child were diagnosed with congenital LQTS (cLQTS). Families- 16 and 17 represented aLQTS probands with variations in IKs and INa encoding genes. First degree relatives (FDRs) carrying the same haplotype as the proband were also identified which may help in predictive testing and management of LQTS. Most of the probands exhibiting a family history were found to be genetic compounds which clearly points to the role of cardiac genes and their modifiers in a recessive fashion in LQTS manifestation.

  3. Divorce in Families of Children with Down Syndrome: A Population-Based Study

    ERIC Educational Resources Information Center

    Urbano, Richard C.; Hodapp, Robert M.

    2007-01-01

    In this study, we examined the nature, timing, and correlates of divorce in families of children with Down syndrome (647), other birth defects (10,283) and no identified disability (361,154). Divorce rates among families of children with Down syndrome were lower than in the other two groups. When divorce did occur in the Down syndrome group,…

  4. Large Kindred Evaluation of Mitofusin 2 Novel Mutation, Extremes of Neurologic Presentations, and Preserved Nerve Mitochondria

    PubMed Central

    Klein, Christopher J.; Kimmel, Grace W.; Pittock, Sean J.; Engelstad, JaNean E.; Cunningham, Julie M.; Wu, Yanhong; Dyck, Peter J.

    2013-01-01

    Background Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations. Objective To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred. Patients An American kindred of Northern European and Cherokee American Indian descent. Results Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon β-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls. Conclusions Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological

  5. [Genetic testing and counseling for familial tumor syndromes].

    PubMed

    Katai, Miyuki; Sakurai, Akihiro; Fukushima, Yoshimitsu

    2002-04-01

    Recent developments in molecular biology have increased our understanding of the genetics of familial tumor syndromes. Isolation of the responsible genes has made it possible to identify gene carriers before they manifest clinical symptoms, which enables early detection of disease and at times prophylactic surgery. Indications for genetic testing of susceptible family members, however, should be carefully considered. Genetic counseling must be provided to clients before genetic tests. Patients should be provided with the latest knowledge on the disease and appropriately informed of the benefits and possible problems associated with genetic test, as such information is essential for clients to decide whether they will undergo such tests. Genetic medicine is not sufficiently available at present in Japan. Establishment of genetic services that deal with genetic counseling, family support and ethical, social and legal issues is strongly desired. PMID:11977532

  6. Molecular characterization of WFS1 in an Iranian family with Wolfram syndrome reveals a novel frameshift mutation associated with early symptoms.

    PubMed

    Sobhani, Maryam; Tabatabaiefar, Mohammad Amin; Rajab, Asadollah; Kajbafzadeh, Abdol-Mohammad; Noori-Daloii, Mohammad Reza

    2013-10-10

    Wolfram syndrome (WS) is a rare autosomal recessive neurodegenerative disorder that represents a likely source of childhood diabetes especially among countries in the consanguinity belt. The main responsible gene is WFS1 for which over one hundred mutations have been reported from different ethnic groups. The aim of this study was to identify the molecular etiology of WS and to perform a possible genotype-phenotype correlation in Iranian kindred. An Iranian family with two patients was clinically studied and WS was suspected. Genetic linkage analysis via 5 STR markers was carried out. For identification of mutations, DNA sequencing of WFS1 including all the exons, exon-intron boundaries and the promoter was performed. Linkage analysis indicated linkage to the WFS1 region. After DNA sequencing of WFS1, one novel pathogenic mutation, which causes frameshift alteration c.2177_2178insTCTTC (or c.2173_2177dupTCTTC) in exon eight, was found. The genotype-phenotype correlation analysis suggests that the presence of the homozygous mutation may be associated with early onset of disease symptoms. This study stresses the necessity of considering the molecular analysis of WFS1 in childhood diabetes with some symptoms of WS. PMID:23845777

  7. Familial Aggregation and Segregation Analysis in Families Presenting Autoimmunity, Polyautoimmunity, and Multiple Autoimmune Syndrome

    PubMed Central

    Castiblanco, John; Sarmiento-Monroy, Juan Camilo; Mantilla, Ruben Dario; Rojas-Villarraga, Adriana; Anaya, Juan-Manuel

    2015-01-01

    Studies documenting increased risk of developing autoimmune diseases (ADs) have shown that these conditions share several immunogenetic mechanisms (i.e., the autoimmune tautology). This report explored familial aggregation and segregation of AD, polyautoimmunity, and multiple autoimmune syndrome (MAS) in 210 families. Familial aggregation was examined for first-degree relatives. Segregation analysis was implemented as in S.A.G.E. release 6.3. Data showed differences between late- and early-onset families regarding their age, age of onset, and sex. Familial aggregation of AD in late- and early-onset families was observed. For polyautoimmunity as a trait, only aggregation was observed between sibling pairs in late-onset families. No aggregation was observed for MAS. Segregation analyses for AD suggested major gene(s) with no clear discernible classical known Mendelian transmission in late-onset families, while for polyautoimmunity and MAS no model was implied. Data suggest that polyautoimmunity and MAS are not independent traits and that gender, age, and age of onset are interrelated factors influencing autoimmunity. PMID:26697508

  8. A clinical variant of familial Hermansky-Pudlak syndrome.

    PubMed

    Iannello, Silvia; Fabbri, Giuseppe; Bosco, Paolo; Cavaleri, Antonina; Cantarella, Santi; Camuto, Massimo; Milazzo, Paolina; Romeo, Francesco; Belfiore, Francesco

    2003-01-27

    Hermansky-Pudlak syndrome (HPS) is an autosomal recessive inherited disease consisting of (1) partial oculocutaneous albinism (with nystagmus, strabism, and visual acuity loss), (2) platelet storage pool deficiency (with bleeding diathesis), and (3) disorder of "ceroid" metabolism with a multisystem tissue lysosomal ceroid deposition. HPS is less uncommon in Puerto Rico, where the most important studies have been performed, but is a very rare disease in Europe. HPS basic defect remains unknown, even if an HPS-causing gene was identified in chromosome segment 10q23-q23.3, and several mutations have been reported. The aim of this article is to discuss, on the basis of a review of relevant literature, a new familial HPS clinical variant observed in 2 young sisters (aged 16 and 23 years old, respectively), characterized by the typical symptoms of this syndrome. Our patients also suffered from diffuse interstitial pulmonary disease and an unexpectedly increased platelet aggregation and were prone to bacterial infections. Interestingly, we observed urinary tract abnormality in the younger HPS sister and a porencephalic cyst in the older HPS sister; both of these developmental defects have been reported in the Cross syndrome (or oculocerebral hypopigmentation syndrome). It seems that in our patients, an overlapping of the phenotypic manifestations of different rare syndromes may be present. The presence of ceroid-like autofluorescent material in urinary sediment together with the histologic aspects and the autofluorescence of oral mucosa biopsy are consistent with a ceroid-like lipofuscin storage. HPS should be carefully tested for in suspected cases to prevent the severe visual impairment, rapidly progressive pulmonary fibrosis, and other complications associated with this disorder. PMID:12827064

  9. Familial Incidence of Cardiovascular Malformations in Hypoplastic Left Heart Syndrome.

    PubMed

    Kelle, Angela M; Qureshi, Muhammad Y; Olson, Timothy M; Eidem, Benjamin W; O'Leary, Patrick W

    2015-12-01

    Obstructive left-sided congenital heart lesions exhibit familial clustering, and familial echocardiographic screening for bicuspid aortic valve has become standard practice. Hypoplastic left heart syndrome (HLHS) is a severe left-sided obstructive lesion; however, familial screening is not universally recommended. The purpose of this study was to define the incidence of cardiovascular malformations (CVMs) in first-degree relatives of HLHS probands. First-degree relatives were screened for CVM by transthoracic echocardiography. Screening was completed in 152 family members (97 parents and 55 siblings) of 52 probands. Of these, 17 of 152 (11%) had CVM. Anomalies detected included: bicuspid aortic valve in 5 (3%), isolated dilated ascending aorta in 4 (3%), coarctation of the aorta in 1, partial anomalous pulmonary venous connection in 1, anomalous, intramural coronary artery in 1, bicuspid pulmonary valve in 1, and other anomalies in 4. Most were previously undiagnosed (11 of 17, 65%). Fourteen of 52 families (27%) had ≥1 relative with CVM. Overall, 7 of 55 siblings (13%), 5 of 46 fathers (11%) and 5 of 51 mothers (10%) had CVM. Although the incidence of CVM in first-degree relatives of HLHS probands was lower in this cohort than previously reported, it remained substantial, with at least one additional member having CVM in 27% of families. The frequent occurrence of undiagnosed CVM highlights the importance of routine familial screening in HLHS. In fact, even if screening was done in childhood, it may be appropriate to screen again in the third or fourth decade to exclude isolated enlargement of the ascending aorta. PMID:26433269

  10. Segregation and sporadic cases in families with Hunter's syndrome.

    PubMed Central

    Machill, G; Barbujani, G; Danieli, G A; Herrmann, F H

    1991-01-01

    Segregation analysis on five samples of families with Hunter's syndrome (158 cases overall) shows that the mutant allele segregates in agreement with Mendelian expectations for an X linked recessive disease, but the proportion of sporadic cases is significantly lower than expected under mutation-selection equilibrium. Heterogeneity among the samples is apparent, but it is caused entirely by a sample of Ashkenazi families, whose segregation pattern has previously been interpreted as supporting the hypothesis of prenatal selection in favour of the pathological allele. Conversely, our joint analysis of the five samples by a maximum likelihood approach does not suggest segregation distortion. Possible reasons for the apparent lack of sporadic cases include the effect of ascertainment bias. PMID:1908009

  11. Genetic heterogeneity of usher syndrome type 1 in French families

    SciTech Connect

    Larget-Piet, D.; Gerber, S.; Rozet, J.M. ); Bonneau, D. ); Marc, S.; Weissenbach, J. ); Ghazi, I.; Dufier, J.L. ); David, A. ); Bitoun, P. )

    1994-05-01

    Usher syndrome type 1 (US1) is an autosomal recessive disease characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa, and constant vestibular dysfunction. Three localizations have been described in US1: USH1A, 14q32; USH1B, 11q13.5; and USH1C, 11p15. Studying a series of 33 affected individuals belonging to 20 US1 pedigrees of French ancestry, the authors found that none of the three localizations accounted for all US1 families in the series. However, when the sample was split into two groups according to the geographic origin of the probands' grandparents, they were able to confirm the presence of a gene for US1 on chromosome 14q32 (USH1A) in 9 families originating from the Poitou region in Western France. Moreover, they refined the genetic mapping of USH1A by showing that the disease gene maps to the D14S13 locus, within the genetic interval defined by loci D14S78 and D14S250 (location score in log base 10 = 4.90). Consistent with this, nonsignificant lod score values for linkage to either USH1B or USH1C were found in this group. With regard to US1 families of other geographic origin (Normandy and Northern France, 11 families), nonsignificant lod scores for linkage to chromosome 11q13.5 were observed. However, the HOMOG test suggested that USH1B might account for the disease in 9/11 families in the series (families 10-19), the latter two families possibly being accounted for by USH1C (maximum likelihood for heterogeneity = 7.91 in lnL; heterogeneity versus homogeneity, P = 0.01; heterogeneity versus nonlinkage, P < 0.01). The present study supports the view that Usher syndrome type 1 is a genetically heterogeneous condition that is caused by at least three genes and possibly many more. 16 refs., 4 figs., 3 tabs.

  12. Johnson-McMillin Microtia Syndrome: New Additional Family.

    PubMed

    Abdel-Meguid, Nagwa; Gebril, Ola Hosny; Abdelraouf, Ehab Ragaa; Shafie, Mohammed Akmal; Bahgat, Mohammed

    2014-07-01

    Microtia is a congenital anomaly that is found with different prevalence among various populations. The exact etiology of ear anomalies is still unknown. We describe a new additional family with this rare disorder; Johnson-McMillin syndrome (JMS) where mother, son, and distant grandmother have multiple features of JMS in the form of microtia, facial asymmetry, ear malformation, hearing defect, and hypotrichosis. Variable presentations in this family could be referred to phenotype variation supporting an autosomal dominant pattern of inheritance. We observed that the mother was very sad and suffered from feelings of guilt. We found that she had isolated herself from family and community out of fear of being stigmatized and hurt. We concluded that the occurrence of microtia is of public health importance, adhering to traditional marriage customs in Egypt increases women's risk of giving birth to a disabled child, yet the mothers are blamed and shamed for their children's birth defects by their husbands, families, and communities, while the fathers are not stigmatized. PMID:25374870

  13. Familial Binswanger encephalopathy in the absence of hypertension; a new family with the CADASIL syndrome

    SciTech Connect

    Schanen, N.C.; Glusker, P.; Chung, M.

    1994-09-01

    Binswanger encephalopathy is a clinicopathologic entity characterized by deep white matter ischaemic lesions associated with hypertension and arteriosclerosis; but a rare inherited form, termed CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) has been recently described with earlier onset in the absence of hypertension. This syndrome has been linked to markers in chromosome band 19q12 in of two unrelated French families. We have identified a family of Central American heritage with a similar syndrome also demonstrating an autosomal dominant pattern of inheritance. Clinically, the onset of symptoms is between 19-53 years of age with variable progression in loss of neurologic function. Numerous lesions are visible on MRI involving the deep white matter including the corpus callosum as well as basal ganglia. None of the family members has had significant hypertension. Extensive evaluations of metabolic, infectious and inflammatory origin of disease have been noncontributory. In the two patients whose brains were examined pathologically, multiple cystic lesions, frequently centered around blood vessels, were present in the deep white matter and basal ganglia with diffuse loss of myelin and relative preservation of the neurons. The media of large and small parenchymal arteries shows hyaline and hydropic degeneration with replacement of the smooth muscle by a slate-grey amorphous substance on trichrome staining, corresponding to granular osmiophilic material on ultrastructural examination. There was no evidence of amyloid or atherosclerosis in the vessels. Phenotypically, this family appears to have the CADASIL syndrome. We are currently pursuing linkage analysis with chromosome 19 markers to investigate the genetic homogeneity of the disorder. Thirty-three individuals spanning three generations and including seven clinically affected patients are potentially available for study.

  14. Family Environment and Behavior Problems in Children, Adolescents, and Adults with Fragile X Syndrome

    ERIC Educational Resources Information Center

    Greenberg, Jan S.; Seltzer, Marsha Mailick; Baker, Jason K.; Smith, Leann E.; Warren, Steven F.; Brady, Nancy; Hong, Jinkuk

    2012-01-01

    We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth…

  15. Experiences of Supporting People with Down Syndrome and Alzheimer's Disease in Aged Care and Family Environments

    ERIC Educational Resources Information Center

    Carling-Jenkins, Rachel; Torr, Jennifer; Iacono, Teresa; Bigby, Christine

    2012-01-01

    Background: Research addressing the experiences of families of adults with Down syndrome and Alzheimer's disease in seeking diagnosis and gaining support is limited. The aim of this study was to gain a greater understanding of these processes by exploring the experiences of families and carers in supporting people with Down syndrome and…

  16. Familial gigantiform cementoma with Ehlers - Danlos syndrome: A report of 2 cases.

    PubMed

    Şakar, Olcay; Aren, Gamze; Mumcu, Zeynep; Ünalan, Fatma; Aksakallı, Nihan; Tolgay, Ceren Güney

    2015-04-01

    Ehlers-Danlos syndrome is an autosomal dominant hereditary disorder of connective tissue, while familial gigantiform cementoma is a condition that usually manifests as multiple radiopaque cementum-like masses throughout the jaws. This case report discusses the oral management and prosthetic rehabilitation of two patients presenting familial gigantiform cementoma with Ehlers-Danlos Syndrome. PMID:25932318

  17. Familial gigantiform cementoma with Ehlers - Danlos syndrome: A report of 2 cases

    PubMed Central

    2015-01-01

    Ehlers-Danlos syndrome is an autosomal dominant hereditary disorder of connective tissue, while familial gigantiform cementoma is a condition that usually manifests as multiple radiopaque cementum-like masses throughout the jaws. This case report discusses the oral management and prosthetic rehabilitation of two patients presenting familial gigantiform cementoma with Ehlers-Danlos Syndrome. PMID:25932318

  18. 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.

  19. Affected Kindred Analysis of Human X Chromosome Exomes to Identify Novel X-Linked Intellectual Disability Genes

    PubMed Central

    Niranjan, Tejasvi S.; Skinner, Cindy; May, Melanie; Turner, Tychele; Rose, Rebecca; Stevenson, Roger; Schwartz, Charles E.; Wang, Tao

    2015-01-01

    X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families (a single affected male from 30 families and two affected males from 26 families) using an Agilent SureSelect X-exome kit and the Illumina HiSeq 2000 platform. To enrich for disease-causing mutations, we first utilized variant filters based on dbSNP, the male-restricted portions of the 1000 Genomes Project, or the Exome Variant Server datasets. However, these databases present limitations as automatic filters for enrichment of XLID genes. We therefore developed and optimized a strategy that uses a cohort of affected male kindred pairs and an additional small cohort of affected unrelated males to enrich for potentially pathological variants and to remove neutral variants. This strategy, which we refer to as Affected Kindred/Cross-Cohort Analysis, achieves a substantial enrichment for potentially pathological variants in known XLID genes compared to variant filters from public reference databases, and it has identified novel XLID candidate genes. We conclude that Affected Kindred/Cross-Cohort Analysis can effectively enrich for disease-causing genes in rare, Mendelian disorders, and that public reference databases can be used effectively, but cautiously, as automatic filters for X-linked disorders. PMID:25679214

  20. Genetics of propionic acidemia in a Mennonite-Amish kindred.

    PubMed

    Kidd, J R; Wolf, B; Hsia, E; Kidd, K K

    1980-03-01

    A large Mennonite kindred was found to have propionic acidemia (complementation group pcc C) in at least four different sibships. Even within this kindred and this complementation group (where etiology may be assumed to be identical), there is a wide range of symptoms exhibited by homozygous pcc C-deficient individuals. The inbreeding coefficients (f) for the affected sibships ranged from 4.776 X 10(3) to 2.003 X 10(-2). Data from this study strongly support the single-locus autosomal recessive mode of inheritance. Three couples were found to be common in the ancestry (9--11 generations ago) of all eight parents of the four affected sibships. Relative likelihoods for a member of each of those couples to have been the early carrier of the defective allele were calculated at 1539, 278, and 1. Thus, one couple was designated the most likely earliest-known transmitter of the pcc-deficient allele. PMID:7386459

  1. Two Cases of Nevoid Basal Cell CarcinomaSyndrome in One Family

    PubMed Central

    Ryu, Dong Jin; Kwon, Yeon Sook; Roh, Mi Ryung

    2008-01-01

    The nevoid basal cell carcinoma syndrome, or Gorlin-Goltz syndrome, is an autosomal dominant multiple system disorder with high penetrance and variable expressions, although it can also arise spontaneously. The diagnostic criteria for nevoid basal cell carcinoma syndrome include multiple basal cell carcinomas, palmoplantar pits, multiple odontogenic keratocysts, skeletal anomalies, positive family history, ectopic calcification and neurological anomalies. We report a brother and sister who were both diagnosed with nevoid basal cell carcinoma syndrome. PMID:27303197

  2. 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. PMID:27034633

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

    PubMed

    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. PMID:27034633

  4. Familial pituitary adenomas.

    PubMed

    Vandeva, S; Vasilev, V; Vroonen, L; Naves, L; Jaffrain-Rea, M-L; Daly, A F; Zacharieva, S; Beckers, A

    2010-12-01

    Pituitary adenomas are benign intracranial neoplasms that present a major clinical concern because of hormonal overproduction or compression symptoms of adjacent structures. Most arise in a sporadic setting with a small percentage developing as a part of familial syndromes such as multiple endocrine neoplasia type 1 (MEN1), Carney complex (CNC), and the recently described familial isolated pituitary adenomas (FIPA) and MEN-4. While the genetic alterations responsible for the formation of sporadic adenomas remain largely unknown, considerable advances have been made in defining culprit genes in these familial syndromes. Mutations in MEN1 and PRKAR1A genes are found in the majority of MEN1 and CNC patients, respectively. About 15% of FIPA kindreds present with mutations of the aryl hydrocarbon receptor-interacting protein (AIP) gene. Mutations in the CDKN1B gene, encoding p27(Kip)¹ were identified in MEN4 cases. Familial tumours appear to differ from their sporadic counterparts not only in genetic basis but also in clinical characteristics. Evidence suggests that, especially in MEN1 and FIPA, they are more aggressive and affect patients at younger age, therefore justifying the importance of early diagnosis. In this review, we summarize the genetic and clinical characteristics of these familial pituitary adenomas. PMID:20961530

  5. Behaviour Problems, Maternal Internalising Symptoms and Family Relations in Families of Adolescents and Adults with Fragile X Syndrome

    ERIC Educational Resources Information Center

    Baker, J. K.; Seltzer, M. M.; Greenberg, J. S.

    2012-01-01

    Background: Studies have linked the behaviour problems of children with fragile X syndrome (FXS) to maternal well-being, but less is known about how behaviour problems relate to important family factors such as marital satisfaction and family cohesion. Methods: Married mothers of 115 adolescents and adults with FXS completed questionnaires and…

  6. Gestational, perinatal and family findings of patients with Patau syndrome

    PubMed Central

    Rosa, Rafael Fabiano M.; Sarmento, Melina Vaz; Polli, Janaina Borges; Groff, Daniela de Paoli; Petry, Patrícia; de Mattos, Vinícius Freitas; Rosa, Rosana Cardoso M.; Trevisan, Patrícia; Zen, Paulo Ricardo G.

    2013-01-01

    OBJECTIVE: To describe gestational, perinatal and family findings of patients with Patau syndrome (PS). METHODS: The study enrolled patients with PS consecutively evaluated during 38 years in a Clinical Genetics Service of a pediatric referral hospital in Southern Brazil. The clinical data and the results of cytogenetic analysis were collected from the medical records. For statistical analysis, the two-tailed Fisher's exact test and the chi-square test with Yates' correction were used, being significant p<0.05. RESULTS: The sample was composed of 27 patients, 63% were male, with a median age of nine days at the first evaluation. Full trisomy of chromosome 13 was the main cytogenetic finding (74%). Only six patients were submitted to obstetric ultrasound and none had prenatal diagnosis of PS. The patients' demographic characteristics, compared to born alive infants in the same Brazilian state showed a higher frequency of: mothers with 35 years old or more (37.5%); multiparous mothers (92.6%); vaginal delivery (77%); preterm birth (34.6%); birth weight <2500g (33.3%), and Apgar scores <7 in the 1st (75%) and in the 5th minute (42.9%). About half of them (53%) died during the first month of life. CONCLUSIONS: The understanding of the PS patients' gestational, perinatal and family findings has important implications, especially on the decision about the actions to be taken in relation to the management of these patients. PMID:24473950

  7. Characterisation of Familial Colorectal Cancer Type X, Lynch syndrome, and non-familial colorectal cancer

    PubMed Central

    Shiovitz, S; Copeland, W K; Passarelli, M N; Burnett-Hartman, A N; Grady, W M; Potter, J D; Gallinger, S; Buchanan, D D; Rosty, C; Win, A K; Jenkins, M; Thibodeau, S N; Haile, R; Baron, J A; Marchand, L L; Newcomb, P A; Lindor, N M

    2014-01-01

    Background: Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and ‘non-familial' (non-AC1) CRC cases. Methods: From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression. Results: Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage. Conclusions: FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX. PMID:24918813

  8. Hereditary multiple exostoses: report of a kindred.

    PubMed Central

    Gordon, S L; Buchanan, J R; Ladda, R L

    1981-01-01

    In a large family with 37 members with multiple exostoses, only one person has developed sarcomatous degeneration of a lesion. Our review of published reports revealed great variation in the incidence of malignancy in multiple exostoses (10 to 25%). Most studies had sampling errors leading to the apparent overstatement of risk. In large pedigrees with essentially complete ascertainment of affected subjects, the risk of malignancy is nearer 3% or less. This lower risk for malignancy may be more appropriate in counselling affected subjects. Images PMID:6977644

  9. Belief Systems of Families of Children with Autism Spectrum Disorders or Down Syndrome

    ERIC Educational Resources Information Center

    King, Gillian; Baxter, Donna; Rosenbaum, Peter; Zwaigenbaum, Lonnie; Bates, Anita

    2009-01-01

    Parents in 16 families of children with autism spectrum disorders or Down syndrome participated in a qualitative study examining family (i.e., all caregivers in the home) belief systems. All families had children who had recently entered elementary school or who were in the early years of high school. As a result of their experiences, families…

  10. IRF6 mutation screening in non-syndromic orofacial clefting: analysis of 1521 families.

    PubMed

    Leslie, E J; Koboldt, D C; Kang, C J; Ma, L; Hecht, J T; Wehby, G L; Christensen, K; Czeizel, A E; Deleyiannis, F W-B; Fulton, R S; Wilson, R K; Beaty, T H; Schutte, B C; Murray, J C; Marazita, M L

    2016-07-01

    Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission. PMID:26346622

  11. The Importance of Older Family Members in Providing Social Resources and Promoting Cancer Screening in Families with a Hereditary Cancer Syndrome

    ERIC Educational Resources Information Center

    Ashida, Sato; Hadley, Donald W.; Goergen, Andrea F.; Skapinsky, Kaley F.; Devlin, Hillary C.; Koehly, Laura M.

    2011-01-01

    Purpose: This study evaluates the role of older family members as providers of social resources within familial network systems affected by an inherited cancer susceptibility syndrome. Design and Methods: Respondents who previously participated in a study that involved genetic counseling and testing for Lynch syndrome and their family network…

  12. Two novel mutations identified in familial cases with Donohue syndrome

    PubMed Central

    Falik Zaccai, Tzipora C; Kalfon, Limor; Klar, Aharon; Elisha, Mordechai Ben; Hurvitz, Haggit; Weingarten, Galina; Chechik, Emelia; Fleisher Sheffer, Vered; Haj Yahya, Raid; Meidan, Gal; Gross-Kieselstein, Eva; Bauman, Dvora; Hershkovitz, Sylvia; Yaron, Yuval; Orr-Urtreger, Avi; Wertheimer, Efrat

    2014-01-01

    Donohue syndrome (DS) is a rare and lethal autosomal recessive disease caused by mutations in the insulin receptor (INSR) gene, manifesting marked insulin resistance, severe growth retardation, hypertrichosis, and characteristic dysmorphic features. We report the clinical, molecular, and biochemical characterization of three new patients with DS, and address genotype–phenotype issues playing a role in the pathophysiology of DS. A female infant born to first-degree cousins Muslim Arab parents and two brothers born to first-degree cousins Druze parents presented classical features of DS with hypertrophic cardiomyopathy and died in infancy. Each patient was found homozygous for one missense mutation within the extracellular domain of the INSR gene. Western blot analysis identified the proreceptor of INSR, but not its mature subunits alpha and beta. Of 95 healthy Muslims, no heterozygous was found and of 52 healthy Druze from the same village, one was heterozygous. This study presents two novel familial mutations in the alpha subunit of the INSR which appear to impair post-translational processing of the INSR, resulting loss of its function. Both mutations cause DS with hypertrophic cardiomyopathy and early death. Identification of the causative mutation enables prevention of this devastating disease. PMID:24498630

  13. Familial partial lipodystrophy: two types of an X linked dominant syndrome, lethal in the hemizygous state.

    PubMed Central

    Köbberling, J; Dunnigan, M G

    1986-01-01

    Familial lipodystrophy (referred to in publications as the Köbberling-Dunnigan syndrome) comprises at least two clinical phenotypes which are consistent within each pedigree. In type 1 familial lipodystrophy, loss of subcutaneous fat is confined to the limbs, sparing the face and trunk. In type 2 familial lipodystrophy, the trunk is also affected with the exception of the vulva, giving an appearance of labial hypertrophy. Diabetes mellitus, hyperlipoproteinaemia, and acanthosis nigricans are present to a variable degree in some but not all patients with familial lipodystrophy, and the abnormal distribution of subcutaneous fat is the essential hallmark of the syndrome. In addition to a survey of published reports, new cases with the syndrome are described. Both types of partial lipodystrophy, occurring either as familial disease or as sporadic cases, have only been observed in female patients. Study of the pedigrees of five families with familial lipodystrophy (two Scottish and three German) suggests an X linked dominant mode of transmission, lethal in the hemizygous (XY) state. The two clinical phenotypes with their variably expressive metabolic abnormalities are consistent either with different mutants of the same allele or with two genes on adjacent loci. Other clinical phenotypes of familial lipodystrophy may exist due to further mutations of the same allele or of genes on adjacent loci. The nature of the disorder in patients with familial lipodystrophy usually escapes recognition for many years and the syndrome is almost certainly much commoner than the few families described to date suggest. Images PMID:3712389

  14. Syndrome Specificity and Behavioural Disorders in Young Adults with Intellectual Disability: Cultural Differences in Family Impact

    ERIC Educational Resources Information Center

    Blacher, J.; McIntyre, L. L.

    2006-01-01

    Background: This study examined whether behaviour problems and adaptive behaviour of low functioning young adults, and well-being of their families, varied by diagnostic syndrome intellectual disability (ID) only, cerebral palsy, Down syndrome, autism, as well as by cultural group. Methods: Behaviour disorders in young adults with moderate to…

  15. Factors Predicting Mortality in Midlife Adults with and without Down Syndrome Living with Family

    ERIC Educational Resources Information Center

    Esbensen, A. J.; Seltzer, M. M.; Greenberg, J. S.

    2007-01-01

    Background: Little is known about the mortality of individuals with Down syndrome who have lived at home with their families throughout their lives. The current study evaluates the predictors, causes and patterns of mortality among co-residing individuals in midlife with Down syndrome as compared with co-residing individuals with ID owing to other…

  16. Phenotypic overlap between Blepharo-naso-facial syndrome and Nablus mask-like syndrome. Report from the first Indian family.

    PubMed

    Sachdev, Manav; Rastogi, Anju; Singh, Ankur; Kumar, Kamlesh; Kapoor, Seema; Bansal, Yuvika; Goel, Shilpa

    2013-01-01

    We describe two siblings with epiphora, telecanthus, expressionless face, thick facial skin, bulky nose and profound sensorineural hearing loss. Constellation of these features presented a phenotypic overlap with Blepharo-naso-facial syndrome (BNFS) and Nablus mask-like syndrome (NMLS). They in addition had posterior helical pits. The molecular basis of NMLS is known, while BNFS remains an elusive disorder. We report the first Indian family with features having significant overlap between the two but we attempt to summarize the frequency of reported features and bring out the most consistent features for these two syndromes for the treating clinician. PMID:22697357

  17. Multiple Endocrine Neoplasia: A Genetically Diverse Group of Familial Tumor Syndromes.

    PubMed

    Pacheco, M Cristina

    2016-06-01

    Multiple endocrine neoplasia (MEN) syndrome is a familial cancer syndrome characterized by neuroendocrine tumors. The syndrome encompasses four major subtypes: MEN1, MEN2A, MEN2B, and MEN4. MEN1 is caused by mutations in the MEN1 gene, MEN2A and MEN2B are caused by mutations in RET, and MEN4 is caused by mutations in CDKNB1. All are inherited in an autosomal dominant pattern, but de novo cases do arise. While all subtypes are associated with neuroendocrine tumors, each has characteristic organ involvement. Identifying patients with the syndrome can aid in proper screening and treatment. PMID:27617149

  18. Three cases of Troyer syndrome in two families of Filipino descent.

    PubMed

    Butler, Shauna; Helbig, Katherine L; Alcaraz, Wendy; Seaver, Laurie H; Hsieh, David T; Rohena, Luis

    2016-07-01

    Troyer syndrome is a complex hereditary spastic paraplegia (HSP) due to a mutation in SPG20 first reported in the Old Amish population. A genetic mutation in SPG20 is responsible for a loss of function of the protein spartin in this disease. Since its initial report, this syndrome has also been reported in Turkish and Omani families. Here we report the case of three patients of Filipino descent with Troyer syndrome. Whole exome sequencing (WES) identified a homozygous mutation c.364_365delAT which predicts p.Met122Valfs*2 in SPG20. This is the same mutation identified in affected patients from the Omani and Turkish families, and is the first report of this syndrome in the Filipino population. Although Troyer syndrome has characteristic phenotypic manifestations it is likely underdiagnosed due to its rarity and we expect that WES will lead to identifying this disease in other individuals. © 2016 Wiley Periodicals, Inc. PMID:27112432

  19. Family Environment and Behavior Problems in Children, Adolescents, and Adults with Fragile X Syndrome

    PubMed Central

    Greenberg, Jan S.; Seltzer, Marsha Mailick; Baker, Jason K.; Smith, Leann E.; Warren, Steven F.; Brady, Nancy; Hong, Jinkuk

    2012-01-01

    We examine how the family environment is associated with aspects of the Fragile X syndrome phenotype during childhood, adolescence, and adulthood. Mothers of children (n = 48), adolescents (n = 85), and adults (n = 34) with Fragile X syndrome participated in a multisite study. For children and adults with Fragile X syndrome, the presence of warmth and positivity and the absence of criticism were associated with fewer behavior problems. Although a higher level of criticism was significantly associated with greater behavior problems, there were only trend-level associations between levels of warmth and positivity and behavior problems during the adolescent years. The provision of family psychoeducation programs, which can reduce parental criticism, would likely benefit both the individual with Fragile X syndrome and the family. PMID:22809078

  20. Williams Syndrome: Daily Challenges and Positive Impact on the Family

    ERIC Educational Resources Information Center

    Scallan, Susan; Senior, Joyce; Reilly, Colin

    2011-01-01

    Background: Despite the distinctive physical, cognitive, personality and behavioural characteristics associated with Williams syndrome, few studies to date have examined parental experiences of raising a child with this genetic syndrome. Methods: This explorative pilot study employed predominantly qualitative methodologies via face-to-face…

  1. Family Influences on Adaptive Development in Young Children with Down Syndrome.

    ERIC Educational Resources Information Center

    Hauser-Cram, Penny; And Others

    1999-01-01

    Investigated the extent to which family environment predicted differences in trajectories of adaptive development in young children with Down syndrome. Found that growth in communication, daily living skills, and socialization domains were predicted by family cohesion and mother/child interaction beyond that predicted by maternal education. Bailey…

  2. Transient nephrotic syndrome after anaesthesia resulting from a familial cryofibrinogen precipitating at 35 degrees C.

    PubMed Central

    Lolin, Y; Razis, P A; O'Gorman, P; Hjelm, M; Wierzbicki, A S

    1989-01-01

    Transient nephrotic syndrome, haematuria, and cryofibrinogenuria in a child after anaesthesia were found in association with a plasma cryofibrinogen that precipitated at 35 degrees C. Investigation of the family showed this to be a familial trait probably with dominant inheritance. Images PMID:2585459

  3. Parents of Children with Asperger Syndrome or with Learning Disabilities: Family Environment and Social Support

    ERIC Educational Resources Information Center

    Heiman, Tali; Berger, Ornit

    2008-01-01

    The study examined the family environment and perceived social support of 33 parents with a child diagnosed with Asperger syndrome and 43 parents with a child with learning disability, which were compared to 45 parents of children without disabilities as a control group. Parents completed the Family Environment Scale and Social Support Scale…

  4. Tourniquet Syndrome: Interest of a Systematic Analysis of Families' Social Conditions to Detect Neglect Situations

    ERIC Educational Resources Information Center

    Claudet, Isabelle; Pasian, Nicolas; Debuisson, Cecile; Salanne, Sophie; Rekhroukh, Hocine

    2009-01-01

    Objective: Describe the correlates of tourniquet syndromes, analyze family social situation to detect neglectful behaviors and analyze the tracking of subsequent Pediatric Emergency Department (PED) admissions to identify at risk families. Material and methods: From January 1, 2003 to December 31, 2007 all patients admitted to the PED for…

  5. Use of Equipment and Respite Services and Caregiver Health among Australian Families Living with Rett Syndrome

    ERIC Educational Resources Information Center

    Urbanowicz, Anna; Downs, Jenny; Bebbington, Ami; Jacoby, Peter; Girdler, Sonya; Leonard, Helen

    2011-01-01

    This study assessed factors that could influence equipment and respite services use among Australian families caring for a girl/woman with Rett syndrome and examined relationships between use of these resources and the health of female caregivers. Data was sourced from questionnaires completed by families (n=170) contributing to the Australian…

  6. Report of a kindred with x-linked (or autosomal dominant sex-limited) 46, XY partial gonadal dysgenesis

    SciTech Connect

    Fechner, P.Y.; Marcantonio, S.M.; Ogata, T.; Rosales, T.O.; Smith, K.D.; Goodfellow, P.N.; Migeon, C.J.; Berkovitz, G.D. )

    1993-05-01

    The condition termed 46, XY complete gonadal dysgenesis is characterized by the lack of testicular determination with resulting streak gonads, normal Mullerian structures, and female external genitalia. In the partial form, there is incomplete testicular determination with a wide range in the degree of ambiguous genitalia and sexual duct development. The authors evaluated a kindred in which a partial form of 46, XY gonadal dysgenesis occurred in four subjects from two generations. Pedigree analysis indicated an X-linked or possibly an autosomal sex-limited mode of inheritance. All affected subjects were ascertained because of ambiguous genitalia with minimal virilization. At 10 days of age, the proband had a subnormal plasma level of testosterone, and at 4 months, there was no rise in plasma T after stimulation with hCG. At laparotomy, a dysgenetic gonad was found on the right side, but no gonad was found on the left side. A vas deferens was present on the right, indicating the presence of functional leydig cells early in fetal life. In the other affected subjects, gonadal tissue was also limited to one side of the abdomen and showed poorly developed seminiferous tubules. The sex-determining region Y gene, which encodes the testis-determining factor, was present and unaltered in the genomic DNA of all affected subjects. Duplication of the distal short arm of the X-chromosome has been associated with 46, XY complete gonadal dysgenesis in some patients. In the authors studies, Southern blot analysis revealed that sequences of the distal short arm of the X-chromosome were present in single copy, excluding a large duplication in this area of the X. Several kindreds with familial 46, XY complete gonadal dysgenesis have been reported; five of them had evidence of an X-linked mode of inheritance. The authors study of a kindred with 46, XY partial gonadal dysgenesis further supports the role of an X chromosome gene in testicular determination. 44 refs., 1 fig., 3 tabs.

  7. Gastric juice in congenital pernicious anemia contains no immunoreactive intrinsic factor molecule: study of three kindreds with variable ages at presentation, including a patient first diagnosed in adulthood.

    PubMed Central

    Carmel, R

    1983-01-01

    The mechanism responsible for the isolated intrinsic factor deficiency in congenital pernicious anemia is unknown. A new second-antibody radioimmunoassay capable of recognizing intrinsic factor independent of the molecule's ability to bind added cobalamin was used to study six patients from three kindreds with this disorder. One of the patients was first diagnosed at age 23 because of unusual circumstances in her case; yet the other patients also demonstrated great age variability at presentation of this presumably congenital disorder, even within the same kindred. The radioimmunoassay failed to detect immunoreactive intrinsic factor in any of the six patients, suggesting that elaboration of an abnormal molecule was not the pathogenetic mechanism. An unexpected incidental finding, contrasting with this observation in congenital pernicious anemia, was immunologic evidence that a previously described patient with familial R binder deficiency clearly elaborated an abnormal R binder molecule. PMID:6823973

  8. Familial spastic paraplegia with distal muscle wasting in the Old Order Amish; atypical Troyer syndrome or "new" syndrome.

    PubMed

    Neuhäuser, G; Wiffler, C; Opitz, J M

    1976-03-01

    The Troyer syndrome was found by Cross & McKusick (1967) in 20 members of 12 Old Order Amish families in Holmes County, Ohio; it is a form of hereditary spastic paraplegia combined with distal muscle wasting, i.e. signs of involvement of lower motor neurons. The condition usually begins at 1 to 2 years and progresses at variable rates. Further manifestations include growth retardation, delayed speech development with dysarthria and drooling, and cerebellar signs; mental functions are usually not affected but severe emotional lability is a common finding. Brothers in a Wisconsin Old Order Amish family are reported with spastic diplegia, mental retardation, behavioral disorder and shortness of stature; the condition apparently is not progressive, and may be a "new" syndrome but could also represent a variant of the Troyer syndrome. Autosomal recessive inheritance is most likely, although consanguinity of the parents could not be proven. Another child in this family suffers from focal scleroderma (morphea) which is not related to the neurological syndrome. PMID:1261070

  9. Cognitive structure from childhood to adulthood in kindreds densely affected by schizophrenia and bipolar disorder.

    PubMed

    Cellard, Caroline; Rouleau, Nancie; Moreau, Isabel; Gilbert, Elsa; Paccalet, Thomas; Roy, Marc-André; Jomphe, Valérie; Mérette, Chantal; Maziade, Michel

    2015-09-30

    The developmental aspects of cognitive structures from childhood until adulthood and across different levels of risk for psychopathology have been little studied. The aim of the current study was to explore the cognitive factorial structure in subsamples from highly familial and densely affected kindreds of schizophrenia and bipolar disorder - i.e. affected adult members, non-affected adult members and high-risk youth. The same neuropsychological battery was administered in a sample of 480 participants: schizophrenia and bipolar patients (n=51), young high-risk offspring (n=61), non-affected adult relatives of patients (n=96), and controls (n=272). Exploratory Factorial Analysis was performed in the control sample and yielded a 5-factor solution: verbal comprehension, processing speed/working memory, visual learning and memory, verbal learning and memory, reasoning and problem solving. Confirmatory factor analysis indicated that the hierarchical 5-factor solution was well suited for the young high-risk offspring, the non-affected adult relatives of patient and the patients. A hierarchical model with a "g" factor was a good fit for all subsamples. These results suggest that cognitive impairments may aggregate in highly familial individuals. PMID:26233828

  10. Exclusion of candidate loci and cholesterol biosynthetic abnormalities in familial Pallister-Hall syndrome.

    PubMed Central

    Biesecker, L G; Kang, S; Schäffer, A A; Abbott, M; Kelley, R I; Allen, J C; Clericuzio, C; Grebe, T; Olney, A; Graham, J M

    1996-01-01

    Pallister-Hall syndrome (PHS) was originally described in 1980 in six sporadic cases of children with structural anomalies including hypothalamic hamartoma, polydactyly, imperforate anus, and renal and pulmonary anomalies. In 1993, the first familial cases were reported, including affected sibs and vertical transmission. Three of these families are sufficiently large to allow initial evaluation by linkage studies to candidate genes or loci. We have evaluated candidate loci for PHS based on three clinical observations. The first is a patient with PHS-like malformations, including a hypothalamic hamartoma, and an unbalanced translocation involving 7q and 3p. The second is a family with familial PHS where the founder's father had an autosomal dominant hand malformation previously mapped to 17q. The third is the phenotypic overlap of PHS and Smith-Lemli-Opitz syndrome. In this report, we exclude these loci as candidates for linkage to the PHS phenotype on the basis of lod scores of less than-2.0. We conclude that hypothalamic hamartoma is not specific to PHS and that the dominant hand malformation in one of the families was a coincidence. To evaluate the relationship of PHS to Smith-Lemli-Opitz syndrome, we analysed levels of cholesterol and intermediate metabolites of the later stages of cholesterol biosynthesis. There is no evidence of a generalised disorder of cholesterol biosynthesis in patients with familial PHS. On genetic and biochemical grounds, we conclude that PHS and Smith-Lemli-Opitz syndrome are not allelic variants of a single locus. PMID:8950676

  11. Genetic analysis of a kindred with X-linked mental handicap and retinitis pigmentosa

    SciTech Connect

    Aldred, M.A.; Dry, K.L.; Hardwick, L.J.; Teague, P.W.; Lester, D.H.; Brown, J.; Spowart, G.; Carothers, A.D.; Wright, A.F.; Knight-Jones, E.B.

    1994-11-01

    A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5{prime}-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. 33 refs., 2 figs., 2 tabs.

  12. Genetic Analysis of a Kindred With X-linked Mental Handicap and Retinitis Pigmentosa

    PubMed Central

    Aldred, M. A.; Dry, K. L.; Knight-Jones, E. B.; Hardwick, L. J.; Teague, P. W.; Lester, D. H.; Brown, J.; Spowart, G.; Carothers, A. D.; Raeburn, J. A.; Bird, A. C.; Fielder, A. R.; Wright, A. F.

    1994-01-01

    A kindred is described in which X-linked nonspecific mental handicap segregates together with retinitis pigmentosa. Carrier females are mentally normal but may show signs of the X-linked retinitis pigmentosa carrier state and become symptomatic in their later years. Analysis of polymorphic DNA markers at nine loci on the short arm of the X chromosome shows that no crossing-over occurs between the disease and Xp11 markers DXS255, TIMP, DXS426, MAOA, and DXS228. The 90% confidence limits show that the locus is in the Xp21-q21 region. Haplotype analysis is consistent with the causal gene being located proximal to the Xp21 loci DXS538 and 5'-dystrophin on the short arm of the X chromosome. The posterior probability of linkage to the RP2 region of the X chromosome short arm (Xp11.4-p11.23) is .727, suggesting the possibility of a contiguous-gene-deletion syndrome. No cytogenetic abnormality has been identified. PMID:7977353

  13. Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome

    PubMed Central

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V.P.; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Liu, Xialin; Li, Yonghao; Ni, Yao; Chen, Jiangna; Lin, Zhuoling; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin; Liu, Yizhi

    2016-01-01

    Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak-like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best-corrected visual acuity, slit-lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811-812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of our knowledge, the

  14. [Cytogenetic study of a case of Fanconi's syndrome with a familial pericentric inversion].

    PubMed

    Crippa, L; Ferrier, S

    1975-03-01

    The cytogenetic study of a case of Fanconi syndrome in a 16-year-old boy revealed besides chromosomal breakages, quadriradials and dicentric chromosomes, a pericentric inversion of chromosome No. 1. An uncle and an aunt on the paternal side presented likewise this pericentric inversion, however without breakages or clinical signs of Fanconi syndrome. Another paternal aunt showed short thumbs, but without chromosomal anomalies. The authors point to possible genetic repercussions of this familial pericentric inversion. PMID:1165481

  15. Controversies in the surgery of patients with familial adenomatous polyposis and Lynch syndrome.

    PubMed

    Church, James M

    2016-07-01

    Dominantly inherited syndromes of colorectal cancer predisposition are characterized by multifocal neoplasia with an early age of onset. The risk of colorectal cancer is high in affected patients and care of the patients is based on the aims of cancer prevention and cancer cure. At the same time, quality of life should be disturbed as little as possible. Because patients are generally young, the stakes are high. Injudicious decision-making can have unfortunate effects on patients and families. In this article the controversial aspects of surgery in familial adenomatous polyposis and Lynch syndrome are discussed. Specifically the controversies in familial adenomatous polyposis include the timing and the type of surgery while for Lynch syndrome discussion revolves about prophylactic surgery, primary, secondary and tertiary. PMID:26869170

  16. Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists.

    PubMed

    Menko, Fred H; Aalfs, Cora M; Henneman, Lidewij; Stol, Yrrah; Wijdenes, Miranda; Otten, Ellen; Ploegmakers, Marleen M J; Legemaate, Johan; Smets, Ellen M A; de Wert, Guido M W R; Tibben, Aad

    2013-06-01

    The diagnosis of Lynch syndrome can lead to the prevention of colorectal cancer through periodic colonoscopies and removal of premalignant lesions in susceptible individuals. Therefore, predisposed individuals identified by mutation analysis are advised to inform their at-risk relatives about the options of predictive DNA testing and preventive measures. However, it has now been established that more than half of these relatives do not receive the necessary information. Barriers in conveying information include family communication problems and variable attitudes and practice among clinical geneticists. In this complex field, both medical, psychological, ethical and juridical aspects deserve consideration. Here we summarize the development of a revised guideline for clinical geneticists that allows a more active role of the geneticist, aimed at improving procedures to inform family members in Lynch syndrome and other hereditary and familial cancer syndromes. PMID:23535968

  17. Waardenburg syndrome with familial unilateral renal agenesis: a new syndrome variant?

    PubMed

    Webb, Katie M; Smith, Alisha J; Dansby, Linda M; Diskin, Charles J

    2015-06-01

    A 64-year-old man with Waardenburg syndrome presented with anuria and was subsequently discovered by renal ultrasound to have unilateral renal agenesis. The patient is one of three generations with incidental finding of renal agenesis also marked by the presence of Waardenburg syndrome. To our knowledge, there has been no mention elsewhere in the scientific literature of a variant of Waardenburg syndrome with associated renal agenesis. PMID:25402868

  18. Intrafamilial and interfamilial variability of phenotype in familial velo-cardio-facial syndrome

    SciTech Connect

    Hajianpour, M.J.; Covle, M.

    1994-09-01

    Two half-sisters and their mother from one family, and two full-brothers and their mother from another family presented with features of velo-cardio-facial syndrome (VCSF)/DiGeorge syndrome (DS) with intrafamilial and interfamilial variability of phenotypic expression. None of these patients had an apparent cleft palate. Cardiac anomaly, jejunal atresia and hypocalcemia were present only in the newborn patient. Fluorescence in situ hybridization for VCFS/DS with probe D22S75 showed a deletion in the 22q11.2 region in patients available for the study.

  19. Large mesenteric gastrointestinal stromal tumor in a patient with familial adenomatous polyposis syndrome.

    PubMed

    Moschos, John; Tzilves, Dimitrios; Paikos, Dimitrios; Tagarakis, Georgios; Pilpilidis, Ioannis; Antonopoulos, Zissis; Kadis, Savvas; Katsos, Ioannis; Tarpagos, Anestis

    2006-06-01

    We report a case of a 30-year-old man who presented with severe debilitation, anemia and diarrhea over two months. Colonoscopy revealed many (>100) polyps (familial adenomatous polyposis syndrome). Abdominal CT scan showed a large mass at the left upper abdomen in conjunction with the splenic flexure. Total colectomy with mesenteric mass and adjacent small bowel removal and ileoanal pouch was performed. Examination of the resected mesenteric mass showed a gastrointestinal stromal tumor (GIST) with scarce mitosis and infiltration of the adjacent small bowel. We describe for the first time in medical literature the coexistence of familial adenomatous polyposis syndrome and GIST in a 30-year-old man. PMID:16855925

  20. Dual Familial Roles: An Asperger's Syndrome Case Story

    ERIC Educational Resources Information Center

    Ivey, Julie K.; Ward, A. Kris

    2010-01-01

    Sibling interactions are challenges that all families face on a daily basis. These interactions are significantly more difficult when one child has autism. With the apparent increase in diagnoses of autism, there are more families each year who are dealing with issues of relationships. Children learn, as part of the growing up experience, how to…

  1. Down Syndrome, Birth to Adulthood: Giving Families an EDGE.

    ERIC Educational Resources Information Center

    Rynders, John E.; Horrobin, J. Margaret

    This updated book provides a collection of longitudinal perspectives on experiences of individuals with Down Syndrome, from birth to adulthood. The book is an outgrowth of a federally funded early intervention study called Project EDGE (Expanding Developmental Growth through Education). Contents cover the following topics: historical review of…

  2. A clinical study of a family with Cockayne's syndrome

    PubMed Central

    Proops, Rosalyn; Taylor, A M R; Insley, J

    1981-01-01

    Two sibs with Cockayne's syndrome are described. The recognised cellular sensitivity to ultraviolet light is confirmed. The clinical features in the two children are described and comparisons are made with some forms of xeroderma pigmentosum, a condition in which there is progressive neurological degeneration and cellular sensitivity to ultraviolet irradiation. Images PMID:7277423

  3. Fetal Alcohol Syndrome: A Guide for Families and Communities.

    ERIC Educational Resources Information Center

    Streissguth, Ann

    The 14 chapters of this book review the research and offer guidelines for intervention with infants and children having fetal alcohol syndrome or fetal alcohol effects (FAS/FAE). Chapters are grouped into five sections on the diseases of fetal alcohol, the science of FAS, a life-span approach to FAS, preparing people with FAS for life in the…

  4. Developing a Diary Program to Minimize Patient and Family Post-Intensive Care Syndrome.

    PubMed

    Locke, Meaghan; Eccleston, Sarah; Ryan, Claire N; Byrnes, Tiffany J; Mount, Cristin; McCarthy, Mary S

    2016-01-01

    A series of evidence-based interventions beginning with an intensive care unit diary and a patient/family educational pamphlet were implemented to address the long-term consequences of critical illness after discharge from the intensive care unit, bundled as post-intensive care syndrome and post-intensive care syndrome-family. An extensive literature review and nursing observations of the phenomenon highlighted the potential for this project to have a favorable impact on patients, their families, and the health care team. The goal of this article is to explain the education of all stakeholders; the introduction of the diary, video, and educational pamphlet; and the evaluation of the acceptance of these interventions. This process began with an informal evaluation of the educational products and overall perception of the usefulness of the diary by patients, family members, and staff. The efforts described contribute to the evidence base supporting diaries as an adjunct to intensive care. PMID:27153310

  5. Maternal Parenting Stress in Families with a Child with Angelman Syndrome or Prader-Willi Syndrome

    ERIC Educational Resources Information Center

    Wulffaert, Josette; Scholte, Evert M.; Van Berckelaer-Onnes, Ina A.

    2010-01-01

    Background: Parenting stress was investigated in mothers with a child with Angelman syndrome (AS) or Prader-Willi syndrome (PWS), which are genetically related. Method: Mothers of 24 children with AS and 23 children with PWS (2-12 years) completed the Nijmegen Parenting Stress Index-Short, Developmental Behaviour Checklist, and Vineland Screener…

  6. Trichohepatoenteric Syndrome or Syndromic Diarrhea—Report of Three Members in a Family, First Report from Iran

    PubMed Central

    Mahjoub, F. E.; Imanzadeh, F.; Mahdavi Izadi, S.; Nahali Moghaddam, A.

    2016-01-01

    Introduction. Intractable diarrhea of infancy (IDI) includes several types of early onset diarrhea; one of the rare etiologies is trichohepatoenteric (THE) syndrome, also known as syndromic diarrhea (SD) which was primarily described by Stankler et al. Hereby we report a family with several affected members which to our knowledge is the first case report from Iran. Report of Cases. A three-year-old boy referred with short stature, poor weight gain, and intermittent steatotic diarrhea to our center. He was born to healthy, relative parents (cousins). He did not gain any weight after four months of age and began having intermittent steatotic diarrhea, abdominal distension, and fever. He was hospitalized several times. Two other children in the family also showed somewhat similar symptoms. Two sweat tests were negative for cystic fibrosis. Workup for Celiac disease was performed several times which was negative; however, gluten-free diet was tried several times which was not effective. Workup for Hirschsprung's disease was performed but colon was ganglionic. Evidence of liver involvement was approved by elevated liver enzymes and coarse echo of liver on sonography. Discussion. Trichoenterohepatic syndrome should be put in mind in cases of intractable diarrhea presenting in a family with several affected members. Early diagnosis would save patients from unnecessary workups. PMID:26881168

  7. Van der Woude and Popliteal Pterygium Syndromes: Broad intrafamilial variability in a three generation family with mutation in IRF6.

    PubMed

    Busche, Andreas; Hehr, Ute; Sieg, Peter; Gillessen-Kaesbach, Gabriele

    2016-09-01

    Patients with Van der Woude syndrome typically present with cleft lip, cleft lip and palate, or with cleft palate only. In contrast to non-syndromic cleft lip and/or palate, Van der Woude syndrome typically is characterized by bilateral, paramedian lower-lip pits. Popliteal pterygium syndrome shares features with Van der Woude syndrome, but, in addition, is characterized by a popliteal pterygium, genital anomalies, cutaneous syndactyly of the fingers and the toes, and a characteristic pyramidal fold of skin overlying the nail of the hallux. In some patients oral synechiae or eyelid synechiae are present. Van der Woude Syndrome and Popliteal pterygium syndrome are autosomal dominantly inherited disorders caused by heterozygous mutations in IRF6. We present a three generation family with tremendous intrafamilial phenotypic variability. The newborn index patient had a diagnosis of Popliteal pterygium syndrome. The mother presented with a classic Van der Woude Syndrome, while the maternal grandfather had Van der Woude Syndrome as well as minor signs of Popliteal pterygium syndrome. In all three affecteds the known pathogenic mutation c.265A>G, p.Lys89Glu in IRF6 was identified. While inter- as well as intra-familial variability has been described in IRF6-related disorders, the occurrence of a typical Van der Woude Syndrome without any other anomalies as well as a diagnosis of Popliteal pterygium syndrome in the same family is rare. © 2016 Wiley Periodicals, Inc. PMID:27286731

  8. Adams Oliver syndrome: Description of a new phenotype with cerebellar abnormalities in a family

    PubMed Central

    D’Amico, Alessandra; Melis, Daniela; D’Arco, Felice; Di Paolo, Nilde; Carotenuto, Barbara; D’Anna, Gennaro; Russo, Carmela; Boemio, Pasquale; Brunetti, Arturo

    2013-01-01

    Summary Background To describe cerebellar abnormalities in a family composed by a father and two affected sibs with Adams Oliver syndrome (AOS) (OMIM 100300). Material/Methods Brain MRI and MR angiography were performed at 1.5T. Results The siblings presented cerebellar cortex dysplasia characterized by the presence of cysts. Conclusions Abnormalities of CNS are an unusual manifestation of AOS. To our knowledge, this is the first report of cerebellar cortical dysplasia in a family with AOS. PMID:24505229

  9. Unique family with Townes-Brocks syndrome, SALL1 mutation, and cardiac defects.

    PubMed

    Surka, W S; Kohlhase, J; Neunert, C E; Schneider, D S; Proud, V K

    2001-08-15

    Townes-Brocks syndrome (TBS) is a condition with imperforate anus, hand anomalies, and ear malformations with sensorineural hearing loss. Many cases are sporadic. Within and between families, the phenotype displays striking variability. Recently, the disease-causing gene for TBS was identified as SALL1, a zinc finger transcription factor. Here, we report a three-generation family with seven affected individuals who have a novel SALL1 mutation. Unique cardiac anomalies seen in this family include lethal truncus arteriosus in one patient and a lethal complicated defect, including pulmonary valve atresia, in a second patient. These severe cardiac anomalies have not previously been reported in a familial case of TBS. This family and a review of the literature indicate that cardiac evaluation is warranted in all individuals with this disorder. In addition, hypoplastic thumbs were seen in two individuals in this family and should, therefore, be considered a true feature of TBS. PMID:11484202

  10. Reduced Uptake of Family Screening in Genotype-Negative Versus Genotype-Positive Long QT Syndrome.

    PubMed

    Hanninen, Mikael; Klein, George J; Laksman, Zachary; Conacher, Susan S; Skanes, Allan C; Yee, Raymond; Gula, Lorne J; Leong-Sit, Peter; Manlucu, Jaimie; Krahn, Andrew D

    2015-08-01

    The acceptance and yield of family screening in genotype-negative long QT syndrome (LQTS) remains incompletely characterized. In this study of family screening for phenotype-definite Long QT Syndrome (LQTS, Schwartz score ≥3.5), probands at a regional Inherited Cardiac Arrhythmia clinic were reviewed. All LQTS patients were offered education by a qualified genetic counselor, along with materials for family screening including electronic and paper correspondence to provide to family members. Thirty-eight qualifying probands were identified and 20 of these had family members who participated in cascade screening. The acceptance of screening was found to be lower among families without a known pathogenic mutation (33 vs. 77 %, p = 0.02). A total of 52 relatives were screened; fewer relatives were screened per index case when the proband was genotype-negative (1.7 vs. 3.1, p = 0.02). The clinical yield of screening appeared to be similar irrespective of gene testing results (38 vs. 33 %, p = 0.69). Additional efforts to promote family screening among gene-negative long QT families may be warranted. PMID:25273952

  11. Family Health and Characteristics in Chronic Fatigue Syndrome, Juvenile Rheumatoid Arthritis, and Emotional Disorders of Childhood.

    ERIC Educational Resources Information Center

    Rangel, Luiza; Garralda, M. Elena; Jeffs, Jim; Rose, Gillian

    2005-01-01

    Objective: To compare family health and characteristics in children with chronic fatigue syndrome (CFS), in juvenile rheumatoid arthritis (JRA), and emotional disorders. Method: Parents of 28 children and adolescents aged 11 to 18 years with CFS, 30 with JRA, and 27 with emotional disorders (i.e., anxiety and/or depressive disorders) were…

  12. Microcephaly-lymphedema syndrome: report of a family with short stature as additional manifestation.

    PubMed

    Strenge, S; Froster, U G

    1998-12-28

    Patients with the rare autosomal dominant microcephaly-lymphedema syndrome have apparently normal intelligence. We report on a boy with microcephaly, lymphedema, and short stature as an additional manifestation. The family history of our patient suggests autosomal dominant inheritance with reduced penetrance and variable expressivity. However, X-linked inheritance cannot be excluded. PMID:9880217

  13. Neural deficits, intelligence, maladjustment and family response in children with the nephrotic syndrome.

    PubMed

    Naidoo, L R; Moodley, T Y; Coovadia, H M; Adhikari, M

    1987-01-10

    An intensive psychomedical study of a small number of children suffering from the nephrotic syndrome is reported. Significant organic and psychological sequelae exist in the nephrotic child. The patient's family also appears to need specialist psychological attention. The urgent need for well-organised liaison psychiatric services in non-psychiatric medical departments is emphasised. PMID:2432669

  14. Familial congenital anterior cervical hypertrichosis associated with peripheral sensory and motor neuropathy--a new syndrome?

    PubMed

    Trattner, A; Hodak, E; Sagie-Lerman, T; David, M; Nitzan, M; Garty, B Z

    1991-11-01

    We present three patients with familial congenital hypertrichosis localized to the anterior cervical region, associated with peripheral sensory and motor neuropathy. This association may represent a new neurocutaneous syndrome. The association of anterior midline cutaneous lesions with an underlying malformation is discussed. PMID:1666396

  15. The Adolescent with Down's Syndrome: Life for the Teenager and for the Family.

    ERIC Educational Resources Information Center

    Buckley, Sue; Sacks, Ben

    The book presents the results of a survey of the daily life and attitudes of 90 English families with an adolescent with Down Syndrome (DS). The first chapter reviews the typical development of DS children. Chapter 2 provides demographic data including schooling (94% attended schools for children with severe learning difficulties), residence (83%…

  16. Using an Epidemiological Approach to Examine Outcomes Affecting Young Children with Down Syndrome and Their Families

    ERIC Educational Resources Information Center

    Hodapp, Robert M.; Urbano, Richard C.; So, Stephanie A.

    2006-01-01

    In this paper, we utilise an approach drawn from the field of epidemiology to explore what is known and unknown about young children with Down syndrome and their families. After describing what we mean by an epidemiological approach, we review basic findings for children with intellectual disabilities, as well as challenges to performing such…

  17. Stress and Family Functioning in Parents of Girls with Rett Syndrome.

    ERIC Educational Resources Information Center

    Perry, Adrienne; And Others

    1992-01-01

    This survey of parents of 29 girls with Rett syndrome found that subjects reported more stress, lower marital satisfaction, and certain adaptations in family functioning compared to norms. However, most parents scored in the normal range. Scores were not related to socioeconomic status or characteristics of the affected child. (DB)

  18. Exploring the genetic basis of 3MC syndrome: Findings in 12 further families.

    PubMed

    Urquhart, Jill; Roberts, Rebecca; de Silva, Deepthi; Shalev, Stavit; Chervinsky, Elena; Nampoothiri, Sheela; Sznajer, Yves; Revencu, Nicole; Gunasekera, Romesh; Suri, Mohnish; Ellingford, Jamie; Williams, Simon; Bhaskar, Sanjeev; Clayton-Smith, Jill

    2016-05-01

    The 3MC syndromes are a group of rare autosomal recessive disorders where the main clinical features are cleft lip and palate, hypertelorism, highly arched eyebrows, caudal appendage, postnatal growth deficiency, and genitourinary tract anomalies. Ophthalmological abnormalities, most notably anterior chamber defects may also be seen. We describe the clinical and molecular findings in 13 individuals with suspected 3MC syndrome from 12 previously unreported families. The exclusion of the MASP1 and COLEC11 Loci in two individuals from different consanguineous families and the absence of mutations in four further individuals sequenced for both genes raises the possibility that that there is further genetic heterogeneity of 3MC syndrome. © 2016 Wiley Periodicals, Inc. PMID:26789649

  19. Muckle–Wells syndrome in an Indian family associated with NLRP3 mutation

    PubMed Central

    Abdulla, MC; Alungal, J; Hawkins, PN; Mohammed, S

    2015-01-01

    Muckle — Wells syndrome (MWS) is a rare autosomal dominant disease that belongs to a group of hereditary periodic fever syndromes. It is part of the wider spectrum of the cryopyrin-associated periodic syndrome (CAPS) which has only rarely been described in non-Caucasian individuals. It is characterized by recurrent self-limiting episodes of fever, urticaria, arthralgia, myalgia and conjunctivitis from childhood. Progressive sensorineural hearing loss and amyloidosis are two late complications. MWS is caused by gain of function mutations in the NLRP3 gene, which encodes cryopyrin, a protein involved in regulating the production of proinflammatory cytokines. We report two patients with MWS in an Indian family associated with the p.D303N mutation in the NLRP3 gene. These findings promote awareness of these hereditary periodic fever syndromes as a cause for recurrent fevers from childhood in the Indian population. PMID:25766347

  20. Irritable bowel syndrome. Strategy for the family physician.

    PubMed Central

    Thompson, W. G.

    1994-01-01

    Irritable bowel syndrome is one of the most common reasons for disability and health care seeking. A sensible strategy for management incorporates a confident diagnosis based upon history, physical examination, and pertinent tests. The physician can then reassure the patient, offer dietary and stress management advice, and recommend bran to relieve constipation and to evoke the placebo response. Patients who do not respond could require supportive psychotherapy or a drug for the dominant symptom. A few require careful referral, but overall responsibility should remain with the primary physician. Images Figures 1-2 PMID:8130678

  1. Immotile cilia syndrome: A recombinant family at HLA-linked gene locus

    SciTech Connect

    Gasparini, P.; Grifa, A.; Oggiano, N.; Fabbrizzi, E.; Giorgi, P.L.

    1994-02-15

    The immotile-cilia syndrome (ICS) is an autosomal recessive trait of congenital dismobility or even complete immobility of cilia in the ciliated epithelia (MIM 244400). Recurrent upper respiratory infections in early childhood are the most common clinical findings. Recently a disease locus was mapped by sib pair analysis in two unrelated families on 6p tightly linked to HLA class II loci, such as DR and DQ. In order to confirm this assignment and to test the presence of possible heterogeneity, the authors analyzed several ICS families utilizing DNA makers of HLA class II region. Here they report the identification of a recombinant family at this locus. 3 refs., 1 fig.

  2. Osteochondritis dissecans and Osgood Schlatter disease in a family with Stickler syndrome

    PubMed Central

    Al Kaissi, Ali; Klaushofer, Klaus; Grill, Franz

    2009-01-01

    Purpose Stickler syndrome is among the most common autosomal dominant connective tissue disorders but is often unrecognised and therefore not diagnosed by clinicians. Despite much speculation, the cause of osteochondrosis in general and osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) in particular remain unclear. Etiological understanding is essential. We describe a pair of family subjects presented with OCD and OSS as a symptom complex rather than a diagnosis. Methods Detailed clinical and radiographic examinations were undertaken with emphasis on the role of MRI imaging. Magnetic resonance imaging may allow early prediction of articular lesion healing potential in patients with Stickler syndrome. Results The phenotype of Stickler syndrome can be diverse and therefore misleading. The expectation that the full clinical criteria of any given genetic disorder such as Stickler syndrome will always be present can easily lead to an underestimation of these serious inheritable disorders. We report here two family subjects, a male proband and his aunt (paternal sister), both presented with the major features of Stickler syndrome. Tall stature with marfanoid habitus, astigmatism/congenital vitreous abnormality and submucus cleft palate/cleft uvula, and enlarged painful joints with early onset osteoarthritis. Osteochondritis dissecans (OCD) and Osgood Schlatter syndrome (OSS) were the predominating joint abnormalities. Conclusion We observed that the nature of the articular and physeal abnormalities was consistent with a localised manifestation of a more generalised epiphyseal dysplasia affecting the weight-bearing joints. In these two patients, OCD and OSS appeared to be the predominant pathologic musculoskeletal consequences of an underlying Stickler's syndrome. It is empirical to consider generalised epiphyseal dysplasia as a major underlying causation that might drastically affect the weight-bearing joints. PMID:19193224

  3. Familial renal cancer as an indicator of hereditary leiomyomatosis and renal cell cancer syndrome.

    PubMed

    Raymond, Victoria M; Herron, Casey M; Giordano, Thomas J; Gruber, Stephen B

    2012-03-01

    Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a hereditary condition which typically presents with cutaneous and uterine leiomyomata. Papillary type II renal cell carcinoma and other less common histologic subtypes of renal cancer have been reported in HLRCC. We describe the case of a 31-year-old man in which the pathology review of his renal carcinoma and a positive family history of renal carcinoma allowed for the identification of a pathogenic mutation in the FH gene (c.698G>A;p.R233H) confirming the diagnosis of HLRCC. Recognition of this syndrome allowed for appropriate surveillance as well as identification of at-risk family members. Pathology review is essential for accurate diagnosis of a hereditary cancer syndrome in the setting of familial renal cancer. PMID:22127509

  4. Prevalence of metabolic syndrome in the family members of women with polycystic ovary syndrome from North India

    PubMed Central

    Shabir, Iram; Ganie, Mohd Ashraf; Zargar, Mohd Afzal; Bhat, Dilafroz; Mir, Mohd Muzzafar; Jan, Aleem; Shah, Zaffar Amin; Jan, Vicar; Rasool, Riyaz; Naqati, Andleeb

    2014-01-01

    Background: Polycystic ovary syndrome (PCOS) is the most complex and common endocrine disorder of women in reproductive years. In addition to irregular menstrual cycles, chronic anovulation and hyperandrogenism, it has many metabolic manifestations such as obesity, hyperlipidemia, hyperinsulinemia, insulin resistance, dysglycemia, increased risk of cardiovascular disease or possibly endometrial cancer. Familial clustering of PCOS in consistence with the genetic susceptibility has been described. Materials and Methods: The present study assessed the clinical, biochemical and hormonal parameters including prevalence of metabolic syndrome by two different criteria in the first- degree relatives of patients with PCOS. Results: The average age of 37 index patients was 23 ± 3.6 years, with the mean age of menarche as 13.3 ± 1.2 years. The mean age and age of menarche in mothers (n = 22) was 48.8 ± 5.1 and 13 ± 1.3 years, respectively, whereas as it was 23.5 ± 4.7 and 13.3 ± 1.2 years in sisters (n = 22), respectively. Metabolic syndrome (MS) defined by International Diabetes Federation (IDF) criteria was present in 10 index patients, 1 brother, 4 sisters, 17 mothers and 15 fathers while as by Adult Treatment Panel III (ATP III) it was in 8 index patients, 5 sisters, 16 mothers and 11 fathers. Conclusion: The presence of MS or related metabolic derangements is high in the family members of women with PCOS. PMID:24944933

  5. A novel mutation in PAX3 associated with Waardenburg syndrome type I in a Chinese family.

    PubMed

    Xiao, Yun; Luo, Jianfen; Zhang, Fengguo; Li, Jianfeng; Han, Yuechen; Zhang, Daogong; Wang, Mingming; Ma, Yalin; Xu, Lei; Bai, Xiaohui; Wang, Haibo

    2016-05-01

    Conclusion The novel compound heterozygous mutation in PAX3 was the key genetic reason for WS1 in this family, which was useful to the molecular diagnosis of WS1. Purpose Screening the pathogenic mutations in a four generation Chinese family with Waardenburg syndrome type I (WS1). Methods WS1 was diagnosed in a 4-year-old boy according to the Waardenburg syndrome Consortium criteria. The detailed family history revealed four affected members in the family. Routine clinical, audiological examination, and ophthalmologic evaluation were performed on four affected and 10 healthy members in this family. The genetic analysis was conducted, including the targeted next-generation sequencing of 127 known deafness genes combined with Sanger sequencing, TA clone and bioinformatic analysis. Results A novel compound heterozygous mutation c.[169_170insC;172_174delAAG] (p.His57ProfsX55) was identified in PAX3, which was co-segregated with WS1 in the Chinese family. This mutation was absent in the unaffected family members and 200 ethnicity-matched controls. The phylogenetic analysis and three-dimensional (3D) modeling of Pax3 protein further confirmed that the novel compound heterozygous mutation was pathogenic. PMID:26824486

  6. Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome

    SciTech Connect

    Frebourg, T.; Barbier, N.; Yan, Yu-xin; Friend, S.H. |; Garber, J.E.; Dreyfus, M.; Li, F.P.; Fraumeni, J. Jr.

    1995-03-01

    Germ-line mutations of the tumor-suppressor gene p53 have been observed in some families with the Li-Fraumeni syndrome (LFS), a familial cancer syndrome in which affected relatives develop a diverse set of early-onset malignancies including breast carcinoma, sarcomas, and brain tumors. The analysis of the p53 gene in LFS families has been limited, in most studies to date, to the region between exon 5 and exon 9. In order to determine the frequency and distribution of germ-line p53 mutations in LFS, we sequenced the 10 coding exons of the p53 gene in lymphocytes and fibroblast cell lines derived from 14 families with the syndrome. Germ-line mutations were observed in eight families. Six mutations were missense mutations located between exons 5 and 8. One mutation was a nonsense mutation in exon 6, and one mutation was a splicing mutation in intron 4, generating aberrant shorter p53 RNA(s). In three families, a mutation of the p53 gene was observed in the fibroblast cell line derived from the proband. However, the mutation was not found in affected relatives in two families and in the blood from the one individual, indicating that the mutation probably occurred during cell culture in vitro. In four families, no mutation was observed. This study indicates that germ-line p53 mutations in LFS are mostly located between exons 5 and 8 and that {approximately}50% of patients with LFS have no germ-line mutations in the coding region of the p53 gene. The observation of p53 mutations occurring during primary cultures of human fibroblasts shows that analysis for germ-line p53 mutations must be performed on cells that have not been grown in vitro. 49 refs., 1 fig., 4 tabs.

  7. The gene responsible for X-linked cleft palate (CPX) in a British Columbia native kindred is localized between PGK1 and DXYS1.

    PubMed

    Gorski, S M; Adams, K J; Birch, P H; Friedman, J M; Goodfellow, P J

    1992-05-01

    Human craniofacial malformations are a class of common congenital anomalies in which the etiology is heterogeneous and often poorly understood. To better delineate the molecular basis of craniofacial development, we have undertaken a series of experiments directed toward the isolation of a gene involved in human secondary palate formation. DNA marker linkage studies have been performed in a large British Columbia (B.C.) Native family in which cleft palate segregates as an X-linked trait. We have examined 62 family members, including 15 affected males and 8 obligate carrier females. A previous clinical description of the clefting defect in this kindred included submucous cleft palate and bifid or absent uvula. Our recent reevaluation of the family has indicated that ankyloglossia (tongue-tie) is also a feature of X-linked cleft palate in some of the affected males and carrier females. Ankyloglossia has previously been associated with X-linked cleft palate in an Icelandic kindred in which a gene responsible for cleft palate (CPX) was assigned to the Xq21.3-q22 region between DXYS12 and DXS17. For the B.C. kindred reported here, we have mapped the gene responsible for cleft palate and/or ankyloglossia to a more proximal position on the X chromosome. No recombination was observed between B.C. CPX and the DNA marker DXS72 (peak lod score [Zmax] = 7.44 at recombination fraction [theta] = .0) localized to Xq21.1. Recombination was observed between CPX and PGK1 (Zmax = 7.35 at theta = .03) and between CPX and DXYS1 (Zmax = 5.59 at theta = .04). These recombination events localize B.C. CPX between PGK1 and DXYS1 in the Xq13-q21.31 region. PMID:1570839

  8. Quantitative and qualitative insights into the experiences of children with Rett syndrome and their families.

    PubMed

    Downs, Jenny; Leonard, Helen

    2016-09-01

    Rett syndrome is a rare neurodevelopmental disorder caused by a mutation in the MECP2 gene. It is associated with severe functional impairments and medical comorbidities such as scoliosis and poor growth. The population-based and longitudinal Australian Rett Syndrome Database was established in 1993 and has supported investigations of the natural history of Rett syndrome and effectiveness of treatments, as well as a suite of qualitative studies to identify deeper meanings. This paper describes the early presentation of Rett syndrome, including regression and challenges for families seeking a diagnosis. We discuss the importance of implementing strategies to enhance daily communication and movement, describe difficulties interpreting the presence of pain and discomfort, and argue for a stronger evidence base in relation to management. Finally, we outline a framework for understanding quality of life in Rett syndrome and suggest areas of life to which we can direct efforts in order to improve quality of life. Each of these descriptions is illustrated with vignettes of child and family experiences. Clinicians and researchers must continue to build this framework of knowledge and understanding with efforts committed to providing more effective treatments and supporting the best quality of life for those affected. PMID:27491552

  9. Imprinting mutations suggested by abnormal DNA methylation patterns in familial angelman and Prader-Willi syndromes

    SciTech Connect

    Reis, A. ); Dittrich, B.; Buiting, K.; Gillessen-Kaesbach, G.; Horsthemke, B. ); Greger, V.; Lalande, M. ); Anvret, M. )

    1994-05-01

    The D15S9 and D15S63 loci in the Prader-Willi/Angelman syndrome region on chromosome 15 are subject to parent-of-origin-specific DNA methylation. The authors have found two Prader-Willi syndrome families in which the patients carry a maternal methylation imprint on the paternal chromosome. In one of these families, the patients have a small deletion encompassing the gene for the small nuclear ribonucleoprotein polypeptide N, which maps 130 kb telomeric to D15S63. Furthermore, they have identified a pair of nondeletion Angelman syndrome sibs and two isolated Angelman syndrome patients who carry a paternal methylation imprint on the maternal chromosome. These Angelman and Prader-Willi syndrome patients may have a defect in the imprinting process in 15q11-13. The authors propose a model in which a cis-acting mutation prevents the resetting of the imprinting signal in the germ line and thus disturbs the expression of imprinted genes in this region. 39 refs., 4 figs., 1 tab.

  10. Autoimmune lymphoproliferative syndrome (ALPS). Case report and family history.

    PubMed

    Ries, F; Ferster, A; Rieux-Laucat, F; Biwer, A; Dicato, M

    2010-01-01

    Autoimmune lymphoproliferative syndrome (ALPS) is a rare disease caused by defective lymphocyte apoptosis and is characterized by non-malignant lymphoproliferation, hepatosplenomegaly, autoimmune manifestations and increased risk of both Hodgkin's and non-Hodgkin's lymphoma. Most forms of the disease are due to germ line mutations of the FAS gene and manifest during the first years of life with fluctuating lymphadenopathies, hemolysis, immune thrombocytopenia. During the second decade of life disease manifestations improve spontaneously but autoimmune problems still occur and there is an increased risk of lymphoproliferative malignancy. We describe a typical case of ALPS in a now 44 year old man, followed since the age of 2 for disease manifestations that were unclear at the beginning. PMID:20882745

  11. Infantile Pain Episodes Associated with Novel Nav1.9 Mutations in Familial Episodic Pain Syndrome in Japanese Families

    PubMed Central

    Kondo, Daiki; Harada, Kouji H.; Youssefian, Shohab; Shioi, Hirotomo; Kabata, Risako; Domon, Yuki; Kubota, Kazufumi; Kitano, Yutaka; Takayama, Yasunori; Hitomi, Toshiaki; Ohno, Kousaku; Saito, Yoshiaki; Asano, Takeshi; Tominaga, Makoto

    2016-01-01

    Painful peripheral neuropathy has been correlated with various voltage-gated sodium channel mutations in sensory neurons. Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. In this study, we performed a genetic study in six unrelated multigenerational Japanese families with episodic pain syndrome. Affected participants (n = 23) were characterized by infantile recurrent pain episodes with spontaneous mitigation around adolescence. This unique phenotype was inherited in an autosomal-dominant mode. Linkage analysis was performed for two families with 12 affected and nine unaffected members, and a single locus was identified on 3p22 (LOD score 4.32). Exome analysis (n = 14) was performed for affected and unaffected members in these two families and an additional family. Two missense variants were identified: R222H and R222S in SCN11A. Next, we generated a knock-in mouse model harboring one of the mutations (R222S). Behavioral tests (Hargreaves test and cold plate test) using R222S and wild-type C57BL/6 (WT) mice, young (8–9 weeks old; n = 10–12 for each group) and mature (36–38 weeks old; n = 5–6 for each group), showed that R222S mice were significantly (p < 0.05) more hypersensitive to hot and cold stimuli than WT mice. Electrophysiological studies using dorsal root ganglion neurons from 8–9-week-old mice showed no significant difference in resting membrane potential, but input impedance and firing frequency of evoked action potentials were significantly increased in R222S mice compared with WT mice. However, there was no significant difference among Nav1.9 (WT, R222S, and R222H)-overexpressing ND7/23 cell lines. These results suggest that our novel mutation is a gain-of-function mutation that causes infantile familial episodic pain. The mouse model developed here will be useful for drug screening for familial episodic pain syndrome associated with SCN11A mutations

  12. Molecular analysis of FGFR 2 and associated clinical observations in two Chinese families with Crouzon syndrome.

    PubMed

    Lin, Ying; Gao, Hongbin; Ai, Siming; Eswarakumar, Jacob V P; Li, Tao; Liu, Bingqian; Jiang, Hongye; Liu, Yuhua; Liu, Xialin; Li, Yonghao; Ni, Yao; Chen, Jiangna; Lin, Zhuoling; Liang, Xiaoling; Jin, Chenjin; Huang, Xinhua; Lu, Lin; Liu, Yizhi

    2016-09-01

    Crouzon syndrome, a dominantly inherited disorder and the most common type of craniosynostosis syndrome, is caused by mutations in the fibroblast growth factor receptor 2 (FGFR 2) gene, and characterized by craniosynostosis, shallow orbits, ocular proptosis, midface hypoplasia and a curved, beak‑like nose. The purpose of the present study was to investigate the fibroblast growth factor receptor 2 (FGFR 2) gene in two Chinese families with Crouzon syndrome and to characterize the associated clinical features. Two families underwent complete ophthalmic examination, and three patients in two families were diagnosed with Crouzon syndrome. Genomic DNA was extracted from leukocytes of peripheral blood samples, which were collected from the family members and 200 unrelated control subjects from the same population. Exons 8 and 10 of the FGFR 2 gene were amplified using polymerase chain reaction analysis and were directly sequenced. Ophthalmic examinations, including best‑corrected visual acuity, slit‑lamp examination, fundus examination and Computerized Tomography scans, and physical examinations were performed to exclude systemic diseases. These patients were affected with shallow orbits and ocular proptosis, accompanied by midface hypoplasia, craniosynostosis, strabismus or papilloedema, with clinically normal hands and feet. A heterozygous FGFR 2 missense mutation, c.811‑812insGAG (p.273insGlu) in exon 8 was identified in the affected individual, but not in the unaffected family members or the normal control individuals in family 1. In family 2, another heterozygous FGFR 2 missense mutation, c.842A>G (P.Tyr281Cys or Y281C), in exon 8 was identified in the affected boy and his mother, but not in the unaffected family members or the normal control individuals. Although FGFR 2 gene mutations and polymorphisms have been reported in various ethnic groups, particularly in the area of osteology, the present study reported for the first time, to the best of

  13. Employment Impact and Financial Burden for Families of Children with Fragile X Syndrome: Findings from the National Fragile X Survey

    ERIC Educational Resources Information Center

    Ouyang, L.; Grosse, S.; Raspa, M.; Bailey, D.

    2010-01-01

    Background: The employment impact and financial burden experienced by families of children with fragile X syndrome (FXS) has not been quantified in the USA. Method: Using a national fragile X family survey, we analysed data on 1019 families with at least one child who had a full FXS mutation. Out-of-pocket expenditures related to fragile X were…

  14. Waardenburg syndrome type I: Dental phenotypes and genetic analysis of an extended family

    PubMed Central

    de Aquino, Sibele-Nascimento; Paranaíba, Lívia-Maris-R.; Gomes, Andreia; dos-Santos-Neto, Pedro; Coletta, Ricardo-D.; Cardoso, Aline-Francoise; Frota, Ana-Cláudia; Martelli-Júnior, Hercílio

    2016-01-01

    Background The aim of this study was to describe the pattern of inheritance and the clinical features in a large family with Waardenburg syndrome type I (WS1), detailing the dental abnormalities and screening for PAX3 mutations. Material and Methods To characterize the pattern of inheritance and clinical features, 29 family members were evaluated by dermatologic, ophthalmologic, otorhinolaryngologic and orofacial examination. Molecular analysis of the PAX3 gene was performed. Results The pedigree of the family,including the last four generations, was constructed and revealed non-consanguineous marriages. Out of 29 descendants, 16 family members showed features of WS1, with 9 members showing two major criteria indicative of WS1. Five patients showed white forelock and iris hypopigmentation, and four showed dystopia canthorum and iris hypopigmentation. Two patients had hearing loss. Dental abnormalities were identified in three family members, including dental agenesis, conical teeth and taurodontism. Sequencing analysis failed to identify mutations in the PAX3 gene. Conclusions These results confirm that WS1 was transmitted in this family in an autosomal dominant pattern with variable expressivity and high penetrance. The presence of dental manifestations, especially tooth agenesis and conical teeth which resulted in considerable aesthetic impact on affected individuals was a major clinical feature. Clinical relevance: This article reveals the presence of well-defined dental changes associated with WS1 and tries to establish a possible association between these two entities showing a new spectrum of WS1. Key words:Waardenburg syndrome, hearing loss, oral manifestations, mutation. PMID:27031059

  15. Genetic and functional analysis of a Li Fraumeni syndrome family in China

    PubMed Central

    Hu, Huaying; Liu, Jingping; Liao, Xinbin; Zhang, Shuju; Li, Haibo; Lu, Renbin; Li, Xianfeng; Lin, Wei; Liu, Minji; Xia, Zanxian; Qing, Guoliang; Li, Jia-Da

    2016-01-01

    Li Fraumeni syndrome (LFS) is a rare familial cancer predisposition syndrome with autosomal-dominant inheritance, occurring as frequently as one in 5,000–20,000 individuals. However, no LFS case has been reported from mainland China although it constitutes one quarter of population on earth. In this study, we identified, to our best knowledge, the first Li Fraumeni syndrome family in China. Six family members were affected with various tumors. A TP53 mutation (c.730G > A; p.G244S) co-segregated with the tumor phenotype within this family. Functional analysis indicated that G244S mutation disrupted the transactivity, DNA-binding and cell growth inhibition activity of p53 protein. Two available tumor samples (medulloblastoma and choroid plexus papilloma) underwent large rearrangement in the chromosomes and loss of wild-type TP53. Our data warranted further studies on the prevalence of germline TP53 mutation in various tumor patients in China. PMID:26818906

  16. Novel Loci for Non-Syndromic Coarctation of the Aorta in Sporadic and Familial Cases

    PubMed Central

    Dittrich, Sven; Rüffer, André; Ekici, Arif B.; Toka, Okan

    2015-01-01

    Backround Coarctation of the aorta (CoA) accounts for 5-8% of all congenital heart defects. CoA can be detected in up to 20% of patients with Ullrich-Turner syndrome (UTS), in which a part or all of one of the X chromosomes is absent. The etiology of non-syndromic CoA is poorly understood. In the present work, we test the hypothesis that rare copy number variation (CNV) especially on the gonosomes, contribute to the etiology of non-syndromic CoA. Methods We performed high-resolution genome-wide CNV analysis using the Affymetrix SNP 6.0 microarray platform for 70 individuals with sporadic CoA, 3 families with inherited CoA (n=13) and 605 controls. Our analysis comprised genome wide association, CNV burden and linkage. CNV was validated by multiplex ligation-dependent probe amplification. Results We identified a significant abundance of large (>100 kb) CNVs on the X chromosome in males with CoA (p=0.005). 11 out of 51 (~ 22%) male cases had these large CNVs. Association analysis in the sporadic cohort revealed 14 novel loci for CoA. The locus on 21q22.3 in the sporadic CoA cohort overlapped with a gene locus identified in all familial cases of CoA (candidate gene TRPM2). We identified one CNV locus within a locus with high multipoint LOD score from a linkage analysis of the familial cases (SEPT9); another locus overlapped with a region implicated in Kabuki syndrome. In the familial cases, we identified a total of 7 CNV loci that were exclusively present in cases but not in unaffected family members. Conclusion Of all candidate loci identified, the TRPM2 locus was the most frequently implicated autosomal locus in sporadic and familial cases. However, the abundance of large CNVs on the X chromosome of affected males suggests that gonosomal aberrations are not only responsible for syndromic CoA but also involved in the development of sporadic and non-syndromic CoA and their male dominance. PMID:25984793

  17. Familial occurrence of the aniridia-Wilms tumor syndrome with deletion 11p13-14.1.

    PubMed

    Yunis, J J; Ramsay, N K

    1980-06-01

    A report of a family with two half-brothers and a maternal aunt affected with the aniridia-Wilms tumor syndrome is presented. The proband showed a deletion of most of band 11p13 and of subband 11p14.1 of one chromosome 11, and the proband's mother and an older brother, both phenotypically normal, showed a balanced chromosomal rearrangement. This family demonstrates that deletion of a small chromosome segment (11p13-14.1) is responsible for the aniridia-Wilms tumor syndrome and, that in some cases, the syndrome can be familial. PMID:6246230

  18. Netherton syndrome: mutation analysis of two Taiwanese families.

    PubMed

    Lin, Shuan-Pei; Huang, Shu-Yi; Tu, Mei-Eng; Wu, Yu-Hung; Lin, Cheng-Yueh; Lin, Hsiang-Yu; Lee-Chen, Guey-Jen

    2007-06-01

    Netherton syndrome (NS) is a severe autosomal recessive skin disorder characterized by congenital ichthyosiform erythroderma, hair shaft abnormalities, and atopic diathesis. Recently, pathogenic mutations were identified in serine protease inhibitor Kazal-type 5 (SPINK5), the gene that encodes lympho-epithelial Kazal-type related inhibitor (LEKTI), a type of serine protease inhibitor involved in the regulation of skin barrier formation and immunity. In the present report, we describe the mutation analysis of two Taiwanese patients with NS. Patient 1 has heterozygous mutations; the maternal allele has novel T808I (C-T transition in codon 808) and the paternal allele has recurrent R790X (C-T transition in codon 790). Patient 2 is homozygous for a novel polymorphism R267Q (G-A transition in codon 267). The change was not detected in the patient's father. Haplotype analysis revealed that the patient was homozygous for the 5 single nucleotide polymorphisms in the genomic sequence of SPINK5 as well as the flanking (GT)(17) and D5S413, in addition to the discrepancy of R267Q. Nevertheless real-time quantitative PCR analysis revealed no microdeletion in the genomic sequence of SPINK5. Thus uniparental disomy of maternal SPINK5 allele was indicated. PMID:17415575

  19. [Molecular genetics of familial tumour syndromes of the central nervous system].

    PubMed

    Murnyák, Balázs; Szepesi, Rita; Hortobágyi, Tibor

    2015-02-01

    Although most of the central nervous system tumours are sporadic, rarely they are associated with familial tumour syndromes. These disorders usually present with an autosomal dominant inheritance and neoplasia develops at younger age than in sporadic cases. Most of these tumours are bilateral, multiplex or multifocal. The causative mutations occur in genes involved in cell cycle regulation, cell growth, differentiation and DNA repair. Studying these hereditary cancer predisposition syndromes associated with nervous system tumours can facilitate the deeper understanding of the molecular background of sporadic tumours and the development of novel therapeutic agents. This review is an update on hereditary tumour syndromes with nervous system involvement with emphasis on molecular genetic characteristics and their clinical implications. PMID:25618858

  20. Protracted febrile myalgia syndrome in a kidney transplant recipient with familial Mediterranean fever.

    PubMed

    Abdel Halim, Medhat M; Al-Otaibi, Torki; Donia, Farouk; Gheith, Osama; Asif, Ponnambath; Nawas, Moideen; Rashad, Rashad H; Said, Tarek; Nair, Prasad; Nampoory, Narayanan

    2015-04-01

    Drug-induced toxic myopathy is a complication of familial Mediterranean fever in patients who receive colchicine, especially when combined with cyclosporine. Protracted febrile myalgia syndrome is a severe form of familial Mediterranean fever. A 34-year-old man who had familial Mediterranean fever for > 15 years developed kidney failure because of secondary amyloidosis. He received living-unrelated-donor kidney transplant that functioned normally. He was on colchicine prophylaxis that was continued after transplant, and he received immuno-suppression induction with antithymocyte globulin and maintenance with prednisolone, mycophenolate mofetil, and cyclosporine. After 2 months, he presented with severe myopathy and elevated creatine kinase. Muscle biopsy showed evidence of drug-induced toxic myopathy, most likely caused by cyclosporine in combination with colchicine. Cyclosporine was replaced with sirolimus and colchicine was stopped. Symptoms partially improved and creatine kinase decreased to normal. The prednisolone dosage was reduced gradually to 5 mg daily. At 8 months after transplant, he was readmitted because of severe arthralgia, prolonged fever, pleuritic chest pain, diffuse abdominal pain, purpuric rash, macroscopic hematuria, proteinuria, and diarrhea. The C-reactive protein and erythrocyte sedimentation rate were elevated. The clinical diagnosis was recurrent familial Mediterranean fever presenting as protracted febrile myalgia syndrome. Despite the history of toxic myopathy, he was restarted on colchicine (0.5 mg, twice daily), and colchicine was well tolerated. There was marked improvement of most symptoms within several days. Follow-up 5 years later showed normal kidney graft function and no familial Mediterranean fever activity on colchicine prophylaxis. In summary, familial Mediterranean fever reactivation and protracted febrile myalgia syndrome after kidney transplant may be treated with colchicine and modulation of immunosuppressive therapy

  1. Familial translocation resulting in Wolf-Hirschhorn syndrome in two related unbalanced individuals: Clinical evaluation of a 39-year-old man with Wolf-Hirschhorn syndrome

    SciTech Connect

    Wheeler, P.G.; Weaver, D.D.; Palmer, C.G.

    1995-02-13

    A chromosomal translocation between chromosomes 4 and 8 resulting in Wolf-Hirschhorn syndrome in 2 individuals has been traced through 4 generations of a family. Ascertainment of the family was through a newborn infant with evident Wolf-Hirschhorn syndrome who had an unbalanced chromosomal translocation (46,XY,-4,+der(4),t(4;8) (p15.32;p22)). Discussion with the family documented a paternal great-uncle who also had a similar phenotype and profound mental retardation. Subsequently this individual was found to have the same unbalanced chromosome constitution as the propositus. The 39-year-old great-uncle is the oldest reported individual with the Wolf-Hirschhorn syndrome. The importance of chromosome evaluation of older individuals with mental retardation syndromes is emphasized. 4 refs., 6 figs.

  2. The diagnosis of Liddle syndrome by identification of a mutation in the beta subunit of the epithelial sodium channel.

    PubMed Central

    Jackson, S N; Williams, B; Houtman, P; Trembath, R C

    1998-01-01

    Hypertension is a common multifactorial disorder associated with considerable morbidity and mortality. The kidney plays a major role in the long term regulation of blood pressure. Liddle syndrome (pseudo-hyperaldosteronism) is one of a number of monogenic disorders of salt and water transport. In a kindred with at least four affected members suffering from Liddle syndrome, we confirmed by direct DNA sequencing the identity of a novel heterozygous mutation in h betaENaC, the gene encoding the beta subunit of the amiloride sensitive epithelial sodium channel which is expressed in the distal nephron. Single stranded conformational polymorphism analysis showed cosegregation of the mutant allele within the kindred with the Liddle phenotype. An insertion of an additional cytosine into a string of six located between codons 593 and 595 results in a sequence frameshift and is predicted to produce a protein truncated by 34 amino acids. The availability of a molecular diagnostic tool has implications for the management of hypertension and genetic counselling in families with Liddle syndrome. Images PMID:9643296

  3. [Considerations on family dynamics and the malnutrition syndrome in Mexican children].

    PubMed

    Vásquez-Garibay, Edgar Manuel; González-Rico, José Luis; Romero-Velarde, Enrique; Sánchez-Talamantes, Eva; Navarro-Lozano, María Eugenia; Nápoles-Rodríguez, Francisco

    2015-01-01

    Since the early 1990s we noted that family dysfunction was more common in children with severe primary malnutrition than in children admitted to the hospital without malnutrition. Defects on feeding habits during the first year of life, especially early weaning and inadequate complementary feeding were more common in dysfunctional families. We also observed that chronic malnutrition in preschool children, and overweight and obesity in schoolchildren were more common in children from dysfunctional families. Once the association between dysfunctional family dynamics and obesity in schoolchildren was demonstrated, it was observed that low education of fathers and mothers increased twofold the possibility of family dysfunction: OR: 2.06; 95% CI: 1.37-3.10 and OR: 2.47; 95% CI: 1.57-3.89, respectively. In addition, the low-income and the lower purchasing power of foods were associated to family dysfunction (p<0.05). A remaining task is to explore how to assess family dysfunction in composite, extended, single-parent families where there exist other persons vulnerable to the different entities of malnutrition syndrome and indeed depend on adults for their care, food and nutrition. PMID:26581537

  4. [A case of a probable "cancer family syndrome" presenting four synchronous malignancies of the colon].

    PubMed

    Kawamura, O; Harigane, M; Ohara, H; Satoh, H; Oda, M; Kojima, M; Watanabe, H

    1988-06-01

    A 72-year-old male was admitted because of right lower quadrant pain, Barium enema and total colonoscopy disclosed multiple colon cancers and sequentially, a subtotal colectomy was performed. The resected specimen demonstrated 3 advanced carcinomas and an adenomatous cancer with additional multiple polyps. Investigation of his family history revealed that his mother and his elder sister had died of uterine cancer, and that his elder brother, his nephew, and his niece had been operated on for colorectal cancer. We thus supposed a case of "Cancer Family Syndrome" presenting multiple neoplasms of the colon. PMID:3294469

  5. Adaptive functioning in Williams syndrome and its relation to demographic variables and family environment.

    PubMed

    Brawn, Gabrielle; Porter, Melanie

    2014-12-01

    This study assessed adaptive functioning in children and adults with Williams syndrome. The aims were to: (1) profile adaptive functioning; (2) investigate the relationship between adaptive functions and gender, CA, and IQ; (3) investigate the relationship between levels of adaptive functioning and family environment characteristics. In line with predictions: (1) there was extensive variability in adaptive functions; (2) neither gender nor IQ were significantly related to adaptive skills, but Communication skills and Interpersonal Relationship skills failed to make appropriate gains relative to same aged peers and (3) adaptive functioning was significantly related to family environment. Practical and clinical implications are discussed. PMID:25310713

  6. Heterogeneity analysis in 40 X-linked retinitis pigmentosa families

    SciTech Connect

    Teague, P.W.; Aldred, M.A.; Dempster, M.; Harrison, C.; Carothers, A.D.; Hardwick, L.J.; Evans, H.J.; Wright, A.F.; Strain, L.; Brock, D.J.H. )

    1994-07-01

    Analysis of genetic heterogeneity in 40 kindreds with X-linked retinitis pigmentosa (XLRP), with 20 polymorphic markers, showed that significant heterogeneity is present (P=.001) and that 56% of kindreds are of RP3 type and that 26% are of RP2 type. The location of the RP3 locus was found to be 0.4 cM distal to OTC in the Xp21.1 region, and that of the RP2 locus was 6.5 cM proximal to DXS7 in Xp11.2-p11.3. Bayesian probabilities of linkage to RP2, RP3, or to neither locus were calculated. This showed that 20 of 40 kindreds could be assigned to one or the other locus, with a probability >.70 (14 kindreds with RP3 and 6 kindreds with RP2 disease). A further three kindreds were found to be unlinked to either locus, with a probability >.8. The remaining 17 kindreds could not be classified unambiguously. This highlights the difficulty of classifying families in the presence of genetic heterogeneity, where two loci are separated by an estimated 16 cM. 34 refs., 1 fig., 4 tabs.

  7. [Clinical heterogeneity of the autistic syndrome: a study of 60 families].

    PubMed

    Moreno, H; Borjas, L; Arrieta, A; Sáez, L; Prassad, A; Estévez, J; Bonilla, E

    1992-01-01

    Sixty families ascertained through a single proband, has helped to better define infantile autism as a heterogeneous group of disorders. Forty four patients showed a characteristic facio- auricular dysplasia. Twenty four of these, showed increased pyruvate and lactate and laboratory findings of metabolic acidosis i.e., anion gap above 18 mEq/L or serum bicarbonate below 21 mEq/L but only nine of these probands demonstrated reduction of plasma bicarbonate below 18 mEq/lt. Plasma amino acids in 17 probands and matched controls showed increased taurine with the rest of amino acids significantly (p less than 0.05) below the control level. Glutamate and aspartate were also significantly elevated (p less than 0.05; Student t-test). Segregation analysis in thirty four of these families which linked through at least one ancestral family name, suggested autosomal recessive inheritance (p = 0.20). Three out of eight probands who received megadoses of pyridoxine (Vitamin B6), subjectively gained in language abilities, affectivity and response to behavior modification therapy. Five autistic patients proved to have clinically defined syndromes: two with the Martin-Bell syndrome, and three girls affected respectively with the Rett syndrome, phenylketonuria and dicarboxylic aciduria. PMID:1391074

  8. Clinical and genetic investigation of families with type II Waardenburg syndrome.

    PubMed

    Chen, Yong; Yang, Fuwei; Zheng, Hexin; Zhou, Jianda; Zhu, Ganghua; Hu, Peng; Wu, Weijing

    2016-03-01

    The present study aimed to investigate the molecular pathology of Waardenburg syndrome type II in three families, in order to provide genetic diagnosis and hereditary counseling for family members. Relevant clinical examinations were conducted on the probands of the three pedigrees. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of paired box 3 (PAX3), microphthalmia‑associated transcription factor (MITF), sex‑determining region Y‑box 10 (SOX10) and snail family zinc finger 2 (SNAI2) were analyzed by polymerase chain reaction and DNA sequencing. The heterozygous mutation, c.649_651delAGA in exon 7 of the MITF gene was detected in the proband and all patients of pedigree 1; however, no pathological mutation of the relevant genes (MITF, SNAI2, SOX10 or PAX3) was detected in pedigrees 2 and 3. The heterozygous mutation c.649_651delAGA in exon 7 of the MITF gene is therefore considered the disease‑causing mutation in pedigree 1. However, there are novel disease‑causing genes in Waardenburg syndrome type II, which require further research. PMID:26781036

  9. Clinical and genetic investigation of families with type II Waardenburg syndrome

    PubMed Central

    CHEN, YONG; YANG, FUWEI; ZHENG, HEXIN; ZHOU, JIANDA; ZHU, GANGHUA; HU, PENG; WU, WEIJING

    2016-01-01

    The present study aimed to investigate the molecular pathology of Waardenburg syndrome type II in three families, in order to provide genetic diagnosis and hereditary counseling for family members. Relevant clinical examinations were conducted on the probands of the three pedigrees. Peripheral blood samples of the probands and related family members were collected and genomic DNA was extracted. The coding sequences of paired box 3 (PAX3), microphthalmia-associated transcription factor (MITF), sex-determining region Y-box 10 (SOX10) and snail family zinc finger 2 (SNAI2) were analyzed by polymerase chain reaction and DNA sequencing. The heterozygous mutation, c.649_651delAGA in exon 7 of the MITF gene was detected in the proband and all patients of pedigree 1; however, no pathological mutation of the relevant genes (MITF, SNAI2, SOX10 or PAX3) was detected in pedigrees 2 and 3. The heterozygous mutation c.649_651delAGA in exon 7 of the MITF gene is therefore considered the disease-causing mutation in pedigree 1. However, there are novel disease-causing genes in Waardenburg syndrome type II, which require further research. PMID:26781036

  10. Borderline cognitive level in a family with Bazex-Dupré-Christol syndrome.

    PubMed

    Gonfiantini, Michaela Veronika; Armando, Marco; Pucciarini, Maria Laura; Macchiaiolo, Marina; Buonuomo, Paola Sabrina; Diociaiuti, Andrea; Lepri, Francesca Romana; Sirleto, Pietro; Vicari, Stefano; Bartuli, Andrea

    2015-07-01

    Bazex-Dupré-Christol syndrome (BDCS) [OMIM 301845] is an X-linked dominant disorder of the hair follicle characterized by multiple basal cell carcinomas, follicular atrophoderma, congenital hypotrichosis, and hypohidrosis. Additional features include multiple milia, trichoepitheliomas, and axillary hidradenitis suppurativa as well as a variety of other symptoms. Some patients with a diagnosis of BDCS have had poor school performance. But no other associated psychopathological disorders have been described in the literature. We describe the neuropsychological characteristics and the co-occurring psychopathological disorders in an Italian family (brother and sister, and their mother) affected by BDCS. The BDCS phenotype in this family was characterized by hypotrichosis, atrophoderma follicularis, milia, and trichoepitheliomas. No basal cell carcinomas were documented. At neuropsychological assessment the three affected family members all had a borderline cognitive level. Other identified psychopathological disorders included attention deficit hyperactivity disorder, executive deficits, academic difficulties, deficits in lexical skills, and internalizing problems. The presence of cognitive impairment in the three family members affected by BDCS suggests that cognitive impairment may be associated with the syndrome. It may be useful to assess neuropsychological performance in patients with BDCS to identify possible associated neuropsychological disorders. PMID:25820919

  11. Mutational analysis of the androgen receptor gene in two Chinese families with complete androgen insensitivity syndrome

    PubMed Central

    WANG, SONG; XU, HAIKUN; AN, WEI; ZHU, DECHUN; LI, DEJUN

    2016-01-01

    Androgens are essential for normal male sex differentiation and are responsible for the normal development of male secondary sexual characteristics at puberty. The physiological effects of androgens are mediated by the androgen receptor (AR). Mutations in the AR gene are the most common cause of androgen insensitivity syndrome. The present study undertook a genetic analysis of the AR gene in two unrelated families affected by complete androgen insensitivity syndrome (CAIS) in China. In family 1, a previously reported nonsense mutation (G-to-A; p.W751X) was identified in exon 5 of the AR gene. In addition, a novel missense mutation was detected in exon 6 of the AR gene from family 2; this mutation resulted in a predicted amino acid change from phenylalanine to serine at codon 804 (T-to-C; p.F804S) in the ligand-binding domain (LBD) of AR. Computer simulation of the structural changes generated by the p.F804S substitution revealed marked conformational alterations in the hydrophobic core responsible for the stability and function of the AR-LBD. In conclusion, the present study identified two mutations from two unrelated Chinese families affected by CAIS. The novel mutation (p.F804S) may provide insights into the molecular mechanism underlying CAIS. Furthermore, it expands on the number of mutational hot spots in the international AR mutation database, which may be useful in the future for prenatal diagnosis and genetic counseling. PMID:27284311

  12. Analysis of Families with Lynch Syndrome Complicated by Advanced Serrated Neoplasia: The Importance of Pathology Review and Pedigree Analysis

    PubMed Central

    Walsh, Michael D; Buchanan, Daniel D; Walters, Rhiannon; Roberts, Aedan; Arnold, Sven; McKeone, Diane; Clendenning, Mark; Ruszkiewicz, Andrew R; Jenkins, Mark A; Hopper, John L; Goldblatt, Jack; George, Jillian; Suthers, Graeme K; Phillips, Kerry; Young, Graeme P; Macrae, Finlay; Drini, Musa; Woods, Michael O; Parry, Susan; Jass, Jeremy R; Young, Joanne P

    2009-01-01

    The identification of Lynch syndrome has been greatly assisted by the advent of tumour immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and by the recognition of the role of acquired somatic BRAF mutation in sporadic MMR-deficient colorectal cancer (CRC). However, somatic BRAF mutation may also be present in the tumours in families with a predisposition to develop serrated polyps in the colorectum. In a subgroup of affected members in these families, CRCs emerge which demonstrate clear evidence of MMR deficiency with absent MLH1 staining and high-level microsatellite instability (MSI). This may result in these families being erroneously classified as Lynch syndrome or, conversely, an individual is considered “sporadic” due to the presence of a somatic BRAF mutation in a tumour. In this report, we describe two Lynch syndrome families who demonstrated several such inconsistencies. In one family, IHC deficiency of both MSH2 and MLH1 was demonstrated in tumours from different affected family members, presenting a confusing diagnostic picture. In the second family, MLH1 loss was observed in the lesions of both MLH1 mutation carriers and those who showed normal MLH1 germline sequence. Both families had Lynch syndrome complicated by an independently segregating serrated neoplasia phenotype, suggesting that in families such as these, tumour and germline studies of several key members, rather than of a single proband, are indicated to clarify the spectrum of risk. PMID:19241144

  13. Magnetic resonance imaging of the endophenotype of a novel familial Möbius-like syndrome

    PubMed Central

    Dumars, Sean; Andrews, Caroline; Chan, Wai-Man; Engle, Elizabeth C.; Demer, Joseph L.

    2008-01-01

    Introduction Möbius’ syndrome typically presents as a sporadic trait with congenital facial palsy and abduction impairment. We used high resolution magnetic resonance imaging (MRI) and genetic analysis to examine a family with features of Möbius’ syndrome. Methods We examined three related family members having congenital complete opthalmoplegia with ptosis and facial diplegia. Orbits were imaged in quasi-coronal and sagittal planes 2 mm thick. Subarachnoid cranial nerves were imaged in planes 1 mm thick. Linkage and mutation analysis were performed to determine if the pedigree harbored mutations in four candidate genes. Results In affected subjects, MRI showed marked hypoplasia of extraocular muscles and intraorbital motor nerves. In the anterior orbit, rectus extraocular muscles were less hypoplastic but markedly curved toward insertion. Oblique extraocular muscles were hypoplastic and abnormally inserted. Posterior bony orbits were hypoplastic. Optic nerves were markedly straightened. Brainstems and cranial nerves III, VI, VII, and VIII were normal bilaterally. No pathogenic mutations were detected in affected individuals. Conclusions Previous MRI studies have demonstrated brainstem hypoplasia and cranial nerve aplasia in Möbius’ syndrome. The current family had normal brainstems and subarachnoid portions of motor cranial nerves innervating the orbit, but marked extraocular muscle hypoplasia. These clinical and MRI findings are atypical for Möbius’ syndrome and other congenital cranial dysinnervation disorders (CCDDs). Congenital facial weakness and complete ophthalmoplegia may occur despite MRI evidence of normal brainstem anatomy. The endophenotype appears to result from a genetic defect distinct from the CCDDs defined thus far, rather than a global brainstem insult. PMID:18455936

  14. Genotype-phenotype analysis of von Hippel-Lindau syndrome in fifteen Indian families.

    PubMed

    Vikkath, Narendranath; Valiyaveedan, Sindhu; Nampoothiri, Sheela; Radhakrishnan, Natasha; Pillai, Gopal S; Nair, Vasantha; Pooleri, Ginil Kumar; Mathew, Georgie; Menon, Krishnakumar N; Ariyannur, Prasanth S; Pillai, Ashok B

    2015-12-01

    The general prevalence of the familial multi-organ tumor disorder, von Hippel-Lindau syndrome (VHL), was estimated to be 1 in 25-40,000 in western studies two decades back. Few studies were done in Indian sub-continent, amidst a surge in clinical reports on VHL specific manifestations. The syndrome is correlated with mutations of the gene VHL (located in Chr 3p25.3). We aimed to conduct a prospective case series describing phenotypic and genotypic characteristics in Indian population. The VHL-specific clinical and radiological features were collected from patients and family members. Genotypic changes such as deletion/duplication or point mutation in the VHL locus were identified using sequencing and MLPA. Thirty-one subjects, from fifteen families with diagnosed VHL, were included in the study. Multicystic pancreas was found in 71% (22/31), CNS hemangioblastoma in 68% (21/31), renal cell carcinoma and retinal angiomas in 23% (7/31) each, pheochromocytoma in 9.7% (3/31) of the population and endolymphatic sac tumor in one subject. Four families (9 subjects) had full length deletion of VHL, three families (4 subjects) had a deletion of exon 3, eight families (18 subjects) had different exonic, splice-site and intronic point mutations and one subject had a de novo in-frame indel in exon 1. Multicystic pancreas and CNS hemangioblastomas were the most common manifestations in our population. The phenotypic expression patterns in terms of tumorigenesis, tissue tropism and penetrance in comparison to the genotypic features were found to be different from previous correlative studies. PMID:25952756

  15. Hereditary melanoma: Update on syndromes and management: Genetics of familial atypical multiple mole melanoma syndrome.

    PubMed

    Soura, Efthymia; Eliades, Philip J; Shannon, Kristen; Stratigos, Alexander J; Tsao, Hensin

    2016-03-01

    Malignant melanoma is considered the most lethal skin cancer if it is not detected and treated during its early stages. About 10% of melanoma patients report a family history of melanoma; however, individuals with features of true hereditary melanoma (ie, unilateral lineage, multigenerational, multiple primary lesions, and early onset of disease) are in fact quite rare. Although many new loci have been implicated in hereditary melanoma, CDKN2A mutations remain the most common. Familial melanoma in the presence of multiple atypical nevi should raise suspicion for a germline CDKN2A mutation. These patients have a high risk of developing multiple primary melanomas and internal organ malignancies, especially pancreatic cancer; therefore, a multidisciplinary approach is necessary in many cases. The value of dermoscopic examination and total body photography performed at regular intervals has been suggested by a number of studies, and should therefore be considered for these patients and their first-degree relatives. In addition, genetic counseling with the possibility of testing can be a valuable adjunct for familial melanoma patients. This must be performed with care, however, and only by qualified individuals trained in cancer risk analysis. PMID:26892650

  16. AMH gene mutations in two Egyptian families with persistent müllerian duct syndrome.

    PubMed

    Mazen, Inas; Abdel Hamid, M S; El-Gammal, M; Aref, A; Amr, K

    2011-01-01

    The anti-müllerian hormone (AMH) is responsible for regression of müllerian ducts during male sexual differentiation. Mutations in the AMH gene or its type II receptor gene AMHR2 lead to persistence of the uterus and fallopian tubes in male children, i.e. persistent müllerian duct syndrome (PMDS). Both conditions are transmitted according to an autosomal recessive pattern and are symptomatic only in males. We report on 2 unrelated Egyptian consanguineous families with PMDS. The first family comprised 3 affected prepubertal sibs complaining of undescended testes. Pelvic exploration and laparotomy revealed müllerian duct derivatives. The other family was presenting with an adolescent male with impalpable left testis, and pelvic exploration showed remnants of fallopian tubes and rudimentary uterus. AMH levels were very low and almost undetectable in all affected patients in both families. Direct sequencing of the coding region of the AMH gene identified 2 homozygous mutations in exon 1, R95X in the first family and V12G in the second family. These data confirmed the autosomal recessive type of PMDS. Molecular investigation of this rare disorder in a larger number of cases with undescended testes in Egypt is warranted for proper diagnosis and genetic counseling. PMID:22188863

  17. Partial KCNQ1OT1 hypomethylation: A disguised familial Beckwith-Wiedemann syndrome as a sporadic adrenocortical tumor.

    PubMed

    H'mida Ben-Brahim, Dorra; Hammami, Sabeur; Haddaji Mastouri, Marwa; Trabelsi, Saoussen; Chourabi, Maroua; Sassi, Sihem; Mougou, Soumaya; Gribaa, Moez; Zakhama, Abdelfattah; Guédiche, Mohamed Neji; Saad, Ali

    2015-03-01

    Beckwith-Wiedemann syndrome has a wide spectrum of complications such as embryonal tumors, namely adrenocortical tumor. Tumor predisposition is one of the most challenging manifestations of this syndrome. A 45-day old female with a family history of adrenocortical tumor presented with adrenocortical tumor. The case raised suspicion of a hereditary Beckwith-Wiedemann syndrome, therefore molecular analysis was undertaken. The results revealed partial KCNQ1OT1 hypomethylation in the infant's blood DNA which was associated with a complete loss of methylation in the infant's adrenocortical tumor tissue. It is unique for familial Beckwith-Wiedemann syndrome caused by KCNQ1OT1 partial hypomethylation to manifest solely through adrenocortical tumor. Incomplete penetrance and specific tissue mosaicism could provide explanations to this novel hereditary Beckwith-Wiedemann syndrome presentation. PMID:26937341

  18. [A lethal variant of Netherton syndrome in a large inbred family].

    PubMed

    Capri, Y; Vanlieferinghen, P; Boeuf, B; Dechelotte, P; Hovnanian, A; Lecomte, B

    2011-03-01

    Netherton syndrome is a rare autosomal recessive disorder characterized by the triad of ichthyosiform erythrodermia, typical hair dysplasia, and severe atopic features. The broad range of variable expression of this disease is well described and 20% of complications occur during the neonatal period such as hypernatremic dehydration, electrolyte imbalances, recurrent or severe infections, and failure to thrive. Mutation of the SPINK5 gene has been identified as disease-causing in Netherton syndrome, but the pathophysiology still remains unclear. Almost all SPINK5 mutations result in the absence of the serine-protease inhibitor LEKTI protein in both keratinocytes and lymphocytes. In this study, we report on a severe form of Netherton syndrome observed in three patients within a large inbred Rom family. All of them died in the first months of life despite early treatment. They were found to be homozygous for the c.1431-12G>A SPINK5 gene mutation, which has not been associated with a lethal form of the disease thus far. This family illustrates the extreme phenotype of Netherton disease of neonatal onset. Molecular diagnosis allowed further genetic counseling and prenatal testing during other pregnancies. PMID:21255986

  19. Exome analysis of a family with Wolff-Parkinson-White syndrome identifies a novel disease locus.

    PubMed

    Bowles, Neil E; Jou, Chuanchau J; Arrington, Cammon B; Kennedy, Brett J; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L; Etheridge, Susan P; Saarel, Elizabeth V; Bleyl, Steven B; Yost, H Joseph; Yandell, Mark; Leppert, Mark F; Tristani-Firouzi, Martin; Gruber, Peter J

    2015-12-01

    Wolff-Parkinson-White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5'-AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. PMID:26284702

  20. Exome Analysis of a Family with Wolff–Parkinson–White Syndrome Identifies a Novel Disease Locus

    PubMed Central

    Bowles, Neil E.; Jou, Chuanchau J.; Arrington, Cammon B.; Kennedy, Brett J.; Earl, Aubree; Matsunami, Norisada; Meyers, Lindsay L.; Etheridge, Susan P.; Saarel, Elizabeth V.; Bleyl, Steven B.; Yost, H. Joseph; Yandell, Mark; Leppert, Mark F.; Tristani-Firouzi, Martin; Gruber, Peter J.

    2016-01-01

    Wolff–Parkinson–White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5’ -AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene. PMID:26284702

  1. Brugada syndrome in a family with a high mortality rate: a case report

    PubMed Central

    2013-01-01

    Introduction Brugada syndrome is a hereditary arrhythmia characterized by a specific electrocardiographic pattern and an increased risk of sudden cardiac death, with an apparent absence of structural abnormalities or ischemic heart disease. To date, mutations in the sodium channel, voltage-gated, type V, alpha subunit gene and glycerol-3-phosphate dehydrogenase 1-like gene are estimated to account for approximately 28% of Brugada syndrome probands. Case presentation We report the case of a 32-year-old mixed-race Brazilian man who is sodium channel, voltage-gated, type V, alpha subunit gene and glycerol-3-phosphate dehydrogenase 1-like gene mutation-negative with a type 1 Brugada electrocardiographic pattern and a history of high family mortality, including five sudden deaths among relatives of whom four were first-degree relatives. Conclusion To the best of our knowledge, this is the first case of a patient who has Brugada syndrome and a history of sudden death in four first-degree family members. This case report reinforces the evidence that genetic studies are of limited use while determining risk but remain helpful for diagnosis, and that diagnosis via electrocardiography is of great importance in preventing adverse events and stratifying risk. Although there are several technologically advanced diagnostic tools, they might not be accessible in small towns and hospitals; however, a basic diagnostic tool like electrocardiography is easily accessible. PMID:23506330

  2. Keratitis–ichthyosis–deafness syndrome: first affected family reported in the Middle East

    PubMed Central

    Al Fahaad, Hamad

    2014-01-01

    Introduction Keratitis–ichthyosis–deafness (KID) syndrome is a rare congenital multisystem disorder affecting certain tissues of ectodermal origin such as epidermis, cochlea, and cornea, leading mainly to palmoplantar hyperkeratosis, ichthyosiform scaling, deafness, and blindness. The author reports for the first time in the Middle East three family members suffering from KID syndrome in the southwestern part of Saudi Arabia. Case presentation Three patients from one family (ages 26, 16, and 14 years) of apparently normal parents, with the two eldest being females and the youngest being male. All three patients were referred from a peripheral hospital to our dermatology clinic due to recurrent cutaneous fungal infections on their trunk, forearms, legs, and nails. On full assessment, they also found to have nearly similar cutaneous problems manifested by palmoplantar hyperkeratosis, generalized ichthyosiform scaling, subungual hyperkeratosis, and nail dystrophies. All patients suffered from total hearing loss in both ears since childhood as confirmed by pure tune audiometry. However, there was no blindness in any case; blepharitis with marked photophobia was the only ocular complaint. All these features are classically suggestive of KID syndrome. PMID:24741331

  3. Vanishing lung syndrome in one family: five cases with a 20-year follow-up.

    PubMed

    Gao, Xichun; Wang, Haiying; Gou, Kaihong; Huang, Baosheng; Xia, Dongzhou; Wu, Xiuli; Wei, Ming; Zheng, Shengxi; Ma, Shan; He, Juanxiang

    2015-01-01

    Vanishing lung syndrome, also known as idiopathic giant bullous emphysema, is a rare disease characterized by giant emphysematous bullae. The disease is diagnosed by radiological findings of giant bullae in one, or both, of the upper lobes of the lung, occupying at least one-third of the hemithorax. There have been several reports of vanishing lung syndrome, however it remains to be determined whether genetic inheritance is associated with the disease. In the present study, five patients within one family, with vanishing lung syndrome, were reported during a follow-up period of ~ 20 years. All of the patients were diagnosed by radiological findings, which showed diffuse bullae in the lungs, which were of varying size and asymmetrical distribution, and the occurrence of pneumothorax or emphysema. The Medical Ethics Committee of the People's Hospital of Zhangye Municipality (Zhangye, China) approved this study, and all subjects gave their informed consent During the follow-up period of 20 years, bullae in these patients were shown to progressively increase, and no other pulmonary diseases, including lung cancer, tuberculosis, pneumoconiosis and chronic bronchitis were observed. Autosomal dominant inheritance was observed in five cases, and autosomal recessive inheritance was observed in one case. The present study suggests that vanishing lung syndrome may be associated with autosomal dominant and recessive genetic inheritance. PMID:25322795

  4. Familial DiGeorge/velocardiofacial syndrome with deletions of chromosome area 22q11.2: Report of five families with a review of the literature

    SciTech Connect

    Leana-Cox, J.; Pangkanon, Suthipong; Eanet, K.R.

    1996-11-11

    The DiGeorge (DG), velocardiofacial (VCF), and conotruncal anomaly-face (CTAF) syndromes were originally described as distinct disorders, although overlapping phenotypes have been recognized. It is now clear that all three syndromes result from apparently similar or identical 22q11.2 deletions, suggesting that they represent phenotypic variability of a single genetic syndrome. We report on 12 individuals in five families with del(22)(q11.2) by fluorescent in situ hybridization, and define the frequency of phenotypic abnormalities in those cases and in 70 individuals from 27 del(22)(q11.2) families from the literature. Common manifestations include mental impairment (97%), abnormal face (93%), cardiac malformations (681%), thymic (64%) and parathyroid (63%) abnormalities, and cleft palate or velopharyngeal insufficiency (48%). Familial DG, VCF, and CTAF syndromes due to del(22)(q11.2) show significant inter- and intrafamilial clinical variability consistent with the hypothesis that a single gene or group of tightly linked genes is the common cause of these syndromes. Up to 25% of 22q deletions are inherited, indicating that parents of affected children warrant molecular cytogenetic evaluation. We propose use of the compound term {open_quotes}DiGeorge/velocardiofacial (DGNCF) syndrome{close_quotes} in referring to this condition, as it calls attention to the phenotypic spectrum using historically familiar names. 41 refs., 2 figs., 2 tabs.

  5. Targeted next-generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families.

    PubMed

    Talseth-Palmer, Bente A; Bauer, Denis C; Sjursen, Wenche; Evans, Tiffany J; McPhillips, Mary; Proietto, Anthony; Otton, Geoffrey; Spigelman, Allan D; Scott, Rodney J

    2016-05-01

    Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches. Next-generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single-nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant. PMID:26811195

  6. Identification of IRF6 gene variants in three families with Van der Woude syndrome.

    PubMed

    Tan, Ene-Choo; Lim, Eileen Chew-Ping; Yap, Shiao-Hui; Lee, Seng-Teik; Cheng, Joanne; Por, Yong-Chen; Yeow, Vincent

    2008-06-01

    Van der Woude syndrome is the most common cause of syndromic orofacial clefting. It is characterised by the presence of lip pits, cleft lip and/or cleft palate. It is transmitted in an autosomal dominant manner, with high penetrance and variable expressivity. Several mutations in the interferon regulatory factor 6 (IRF6) gene have been found in VWS families, suggesting that this gene is the primary locus. We screened for mutations in this gene in three families in our population. There was a recurrent nonsense mutation within exon 9 of the gene for a Malay family consisting of five affected members with different presentations. We also found a co-segregating rare polymorphism which would result in a non-synonymous change 23 bases downstream of the nonsense mutation. This polymorphism was present in <1% of the Malay subjects screened, but was not found among the Chinese and Indians in our population. For another family, a 396C-->T mutation (R45W in the DNA-binding domain) was found in the proband, although the possibility of a genetic defect elsewhere could not be excluded because his mother and twin sister (both unaffected) also had this variant. In the third case with complete absence of family history, a de novo deletion spanning the whole IRF6 gene was detected in the child with VWS. This case of haploinsufficiency caused disruption of orofacial development but not other organ systems as the child has no other medical or developmental abnormalities despite the deletion of at least five other genes. PMID:18506368

  7. Genetic heterogeneity in benign familial neonatal convulsions: Identification of a new locus on chromosome 8q

    SciTech Connect

    Lewis, T.B.; Leach, R.J.; O'Connell, P.; Ryan, S.G. ); Ward, K. )

    1993-09-01

    The syndrome of benign familial neonatal convulsions (BFNC) is a rare autosomal dominant disorder characterized by unprovoked seizures in the first weeks of life. One locus for BFNC has been mapped to chromosome 20 in several pedigrees, but the authors have excluded linkage to chromosome 20 in one large kindred. In order to identify this novel BFNC locus, dinucleotide repeat markers distributed throughout the genome were used to screen this family. Maximum pairwise LOD scores of 4.43 were obtained with markers D8S284 and D8S256 on chromosome 8q. Multipoint analysis placed the BFNC locus in the interval spanned by D8S198-D8S274. This study establishes the presence of a new BFNC locus and confirms genetic heterogeneity of this disorder. 26 refs., 3 figs., 1 tab.

  8. Molecular approach in the study of Alström syndrome: Analysis of ten Spanish families

    PubMed Central

    Piñeiro-Gallego, Teresa; Cortón, Marta; Ayuso, Carmen; Baiget, Montserrat

    2012-01-01

    Purpose To describe the clinical and genetic findings in 11 Spanish patients with confirmed (n=5) or suspected (n=6) Alström syndrome (AS). Methods Patients underwent clinical evaluation, and were screened for variations in Alström syndrome 1 gene (ALMS1) using a genotyping microarray from Asper Ophthalmics and by direct sequencing of coding exons 8, 10, and 16 of ALMS1. Furthermore, we analyzed the presence of the A229T variant of retinitis pigmentosa GTPase regulator-interacting protein 1-like gene (RPGRIP1L) with direct sequencing of coding exon 6. Results A great phenotypic variability was observed in our patients. Four mutations in ALMS1—two novel nonsense mutations in one family (p.Y1715X and p.S616X), one previously described mutation in homozygous state in another family (p.V3597Efs*4), and a likely pathogenic missense variation p.P1822L in a third family—were identified with direct sequencing. All patients were homozygous for 229A allele of RPGRIP1L, with the exception of a p.A229T heterozygous patient. Conclusions Our findings expand the spectrum of ALMS1 mutations causing Alström syndrome. The phenotypic differences between patients could be attributed to interactions with other genes inherited independently from the ALMS1 gene or with environmental factors. A clear understanding of the phenotypic spectrum in AS will be important to unravel the molecular mechanisms underlying this syndrome. PMID:22876109

  9. [Informing members of families affected by fragile X syndrome of this diagnosis].

    PubMed

    Carrasco, M

    2001-10-01

    Fragile X syndrome (FXS) is a genetic disorder that may seriously affect the development of patients. One of the hardest tasks for the professionals of medicine is to tell the parents that their child is suffering a serious illness that may cause some permanent handicap. This normally implies drastic changes in live projects and expectations for the parents. The knowledge of diagnosis and the supply of information to the parents give rise to an important emotional impact on both parents and the rest of the family. In general terms, the patient implies more than a single ill person--a genetic illness such as FXS, which causes serious cognitive and behavioural disturbances, implies three situations that the family has to face: on one hand, the family has to accept a new world that had never been known; a son or daughter with a genetic disorder unknown not only for them, but also for most of the professionals they have visited before having a diagnosis, and in many cases with special needs and serious behavioural disturbances. On the other hand, the family must accept that the diagnosis may not be restricted to the patient, because some other members of the family could be suffering from the same illness. Finally, they have to face the fact that one of the parents has transmitted the illness, that is, 'the genetic guilt' in the illness of their son or daughter. PMID:12447818

  10. A Brazilian family with Brown-Vialetto-van Laere syndrome with autosomal recessive inheritance.

    PubMed

    Malheiros, José Augusto; Camargos, Sarah Teixeira; Oliveira, José Teotonio de; Cardoso, Francisco E C

    2007-03-01

    We report the first Brazilian family with Brown-Vialetto-van Laere syndrome. The presence of consanguineous marriages and illness affecting three sisters and one niece support an autosomal recessive transmission. The age at onset of the illness ranged from 12 to 20 years old. The time interval between hearing loss and involvement of other cranial nerves varied from 3 to 12 years. MRI demonstrated bulbar atrophy and also high intensity signal at T2 weighted and fluid attenuated inversion recovery (FLAIR) sequences. PMID:17420823

  11. The first report of a Chinese family with McLeod syndrome

    PubMed Central

    Man, Bik Ling; Yuen, Yuet Ping; Fu, Yat Pang

    2014-01-01

    We report the first case of a Chinese family with McLeod syndrome (MLS). The two affected brothers show significant phenotypic heterogeneity. The index case has peripheral acanthocytosis, choreoathetosis of his feet, a slowly progressive neuropathy and myopathy, and an elevated serum creatine kinase (CK) level. His elder brother has more prominent chorea of the shoulders, epilepsy, a rapidly progressive neuropathy and normal serum CK. The diagnosis of MLS was confirmed by a genetic test which showed a hemizygous frameshift mutation in the XK gene. PMID:24895410

  12. Mapping the gene causing hereditary primary hyperparathyroidism in a Portuguese kindred to chromosome 1q22-q31.

    PubMed

    Williamson, C; Cavaco, B M; Jauch, A; Dixon, P H; Forbes, S; Harding, B; Holtgreve-Grez, H; Schoell, B; Pereira, M C; Font, A P; Loureiro, M M; Sobrinho, L G; Santos, M A; Thakker, R V; Jausch, A

    1999-02-01

    A Portuguese kindred with autosomal dominant isolated primary hyperparathyroidism (HPT) that was associated with parathyroid adenomas and carcinomas was investigated with the aim of determining the chromosomal location of this gene, designated HPTPort. Leukocyte DNA from 9 affected and 16 unaffected members and 7 parathyroid tumors from 4 patients was used in comparative genomic hybridization (CGH), tumor loss of heterozygosity (LOH), and family linkage studies. The CGH studies revealed abnormalities of chromosomes 1 and 13, and the results of LOH studies were consistent with the involvements of tumor suppressor genes from these regions. Family segregation studies mapped HPTPort to chromosome 1q22-q31 by establishing linkage with eight loci (D1S254, D1S222, D1S202, D1S238, D1S428, D1S2877, D1S422, and D1S412) (peak two-point LOD scores = 3. 46-5.14 at 0% recombination), and defined the location of HPT Port to a 21 cM region flanked centromerically by D1S215 and telomerically by D1S306. Thus, HPTPort has been mapped to chromosome 1q22-q31, and a characterization of this gene will help to elucidate further the mechanisms that are involved in the development of parathyroid tumors. PMID:9933477

  13. Lennox–Gastaut syndrome: impact on the caregivers and families of patients

    PubMed Central

    Gibson, Patricia A

    2014-01-01

    Lennox–Gastaut syndrome (LGS) has a major impact on the health-related quality of life (HRQL) of the affected children as well as their caregivers. The primary caregiver in the family is generally the mother, with support from the father and siblings. The burden of care and the effects of the disease on the child necessitate adjustments in virtually all aspects of the lives of their family. These adjustments inevitably affect the physical, emotional, social, and financial health of the whole family. Numerous sources of support for families can help to ease the burden of care. Improvements in the treatment of LGS, in addition to helping the child with LGS, would likely help improve the HRQL of the family members. This pilot parent survey was designed to explore the impact of epilepsy on caregiver HRQL. Parents of children with epilepsy who had contacted the Epilepsy Information Service at the Wake Forest University School of Medicine, Winston-Salem, NC, USA, were sent questionnaires comprising open- and closed-ended questions. A total of 200 surveys were distributed, with a return rate of 48%. The results revealed that 74% of the parents believed that having a child with epilepsy brought them and their partner closer together. However, when the parents were asked to explain the manner in which epilepsy affected their families, answers included continuous stress, major financial distress, and lack of time to spend with other children. Information and resources for the families of children with LGS could help improve the HRQL of both the patients and their relatives. PMID:25336963

  14. Genetic analysis of an Indian family with members affected with Waardenburg syndrome and Duchenne muscular dystrophy

    PubMed Central

    Kapoor, Saketh; Bindu, Parayil Sankaran; Taly, Arun B.; Sinha, Sanjib; Gayathri, Narayanappa; Rani, S. Vasantha; Chandak, Giriraj Ratan

    2012-01-01

    Purpose Waardenburg syndrome (WS) is characterized by sensorineural hearing loss and pigmentation defects of the eye, skin, and hair. It is caused by mutations in one of the following genes: PAX3 (paired box 3), MITF (microphthalmia-associated transcription factor), EDNRB (endothelin receptor type B), EDN3 (endothelin 3), SNAI2 (snail homolog 2, Drosophila) and SOX10 (SRY-box containing gene 10). Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the DMD gene. The purpose of this study was to identify the genetic causes of WS and DMD in an Indian family with two patients: one affected with WS and DMD, and another one affected with only WS. Methods Blood samples were collected from individuals for genomic DNA isolation. To determine the linkage of this family to the eight known WS loci, microsatellite markers were selected from the candidate regions and used to genotype the family. Exon-specific intronic primers for EDN3 were used to amplify and sequence DNA samples from affected individuals to detect mutations. A mutation in DMD was identified by multiplex PCR and multiplex ligation-dependent probe amplification method using exon-specific probes. Results Pedigree analysis suggested segregation of WS as an autosomal recessive trait in the family. Haplotype analysis suggested linkage of the family to the WS4B (EDN3) locus. DNA sequencing identified a novel missense mutation p.T98M in EDN3. A deletion mutation was identified in DMD. Conclusions This study reports a novel missense mutation in EDN3 and a deletion mutation in DMD in the same Indian family. The present study will be helpful in genetic diagnosis of this family and increases the mutation spectrum of EDN3. PMID:22876130

  15. Lennox-Gastaut syndrome: impact on the caregivers and families of patients.

    PubMed

    Gibson, Patricia A

    2014-01-01

    Lennox-Gastaut syndrome (LGS) has a major impact on the health-related quality of life (HRQL) of the affected children as well as their caregivers. The primary caregiver in the family is generally the mother, with support from the father and siblings. The burden of care and the effects of the disease on the child necessitate adjustments in virtually all aspects of the lives of their family. These adjustments inevitably affect the physical, emotional, social, and financial health of the whole family. Numerous sources of support for families can help to ease the burden of care. Improvements in the treatment of LGS, in addition to helping the child with LGS, would likely help improve the HRQL of the family members. This pilot parent survey was designed to explore the impact of epilepsy on caregiver HRQL. Parents of children with epilepsy who had contacted the Epilepsy Information Service at the Wake Forest University School of Medicine, Winston-Salem, NC, USA, were sent questionnaires comprising open- and closed-ended questions. A total of 200 surveys were distributed, with a return rate of 48%. The results revealed that 74% of the parents believed that having a child with epilepsy brought them and their partner closer together. However, when the parents were asked to explain the manner in which epilepsy affected their families, answers included continuous stress, major financial distress, and lack of time to spend with other children. Information and resources for the families of children with LGS could help improve the HRQL of both the patients and their relatives. PMID:25336963

  16. Familial cytomegalic adrenocortical hypoplasia: an X-linked syndrome of pubertal failure.

    PubMed Central

    Hay, I D; Smail, P J; Forsyth, C C

    1981-01-01

    Five boys with familial cytomegalic adrenocortical hypoplasia have been followed up for an average of 19 years. Despite treatment with replacement corticosteroids, all 5 failed to show a spontaneous onset of puberty and, when assessed at ages 13 to 19 years, all had both sexual infantilism and skeletal immaturity. Hypogonadism was confirmed by low levels of plasma testosterone, and pituitary reserve of gonadotrophin was shown to be inadequate by testing with gonadotrophin-releasing hormone. Two boys, both with adequate testosterone output on human chorionic gonadotrophin stimulation, were given gonadotrophin therapy, whereas the other 3 were treated with parenterally administered testosterone. With treatment, all 5 patients showed advances in pubertal staging. Although the mechanism of the hypogonadotropism remains unclear, the association of hypogonadotrophic hypogonadism with familial cytomegalic adrenocortical hypoplasia appears to be a constant one and may be considered as a treatable inherited syndrome of pubertal failure. PMID:7197507

  17. A Novel Mutation of SMAD3 Identified in a Chinese Family with Aneurysms-Osteoarthritis Syndrome

    PubMed Central

    Zhang, Wenwen; Zhou, Min; Liu, Cheng; Liu, Chen; Qiao, Tong; Huang, Dian; Ran, Feng; Wang, Wei; Liu, Changjian; Liu, Zhao

    2015-01-01

    Aneurysms-osteoarthritis syndrome (AOS) is a recently delineated autosomal dominant disorder characterized by aneurysms, dissections, and tortuosity throughout the arterial tree in association with early onset osteoarthritis, mild craniofacial features, and skeletal and cutaneous anomalies. Previous studies have demonstrated that mutations in SMAD3, a key regulator of TGF-β signal transduction, contribute to AOS. Here, we investigated a family of three generations affected by AOS. A novel SMAD3 mutation, c.266G>A (p.C89Y), was identified and cosegregated with the affected individuals in this family. Our finding expands the mutation spectrum of SMAD3 gene and further strengthens the connection between the presence of aneurysms-osteoarthritis phenotype and SMAD3 mutations, which facilitates the understanding of the genotype-phenotype correlation of AOS. PMID:26221609

  18. A new familial case of microdeletion syndrome 10p15.3.

    PubMed

    Eggert, Marlene; Müller, Stefan; Heinrich, Uwe; Mehraein, Yasmin

    2016-04-01

    In 2012 a small terminal deletion in the short arm of chromosome 10 in the region 10p15.3 was reported as a novel microdeletion syndrome. By now 21 patients, including a single familial case, have been reported. Characteristic findings comprise variable cognitive impairment or developmental delay, disorder of speech development, as well as various dysmorphic signs. We here report on a new patient, an eight year old girl, with a microdeletion syndrome 10p15.3. She is a foster child showing intellectual deficits, disorder of speech development, behavioral problems, congenital heart defect, and several dysmorphic signs. The same microdeletion was subsequently found in the six year old maternal half-sister, showing very similar developmental and cognitive issues, including major speech impairment. The mother has not obtained a school degree. She was described as being a dissocial person with severe alcohol abuse and showing minor cognitive disability. Thus inheritance of the microdeletion from a probably symptomatic mother can be assumed. The patients presented here add up to the as yet small number of reported cases of microdeletion 10p15.3 and thereby might help to establish a more comprehensive clinical spectrum of this rather newly discovered syndrome. PMID:26921531

  19. Galanin peptide family as a modulating target for contribution to metabolic syndrome.

    PubMed

    Fang, Penghua; Yu, Mei; Shi, Mingyi; Zhang, Zhenwen; Sui, Yumei; Guo, Lili; Bo, Ping

    2012-10-01

    Metabolic syndrome (MetS) is defined as abdominal central obesity, atherogenic dyslipidemia, insulin resistance, glucose intolerance and hypertension. The rapid increasing prevalence of MetS and the consequent diseases, such as type 2 diabetes mellitus and cardiovascular disorder, are becoming a global epidemic health problem. Despite considerable research into the etiology of this complex disease, the precise mechanism underlying MetS and the association of this complex disease with the development of type 2 diabetes mellitus and increased cardiovascular disease remains elusive. Therefore, researchers continue to actively search for new MetS treatments. Recent animal studies have indicated that the galanin peptide family of peptides may increase food intake, glucose intolerance, fat preference and the risk for obesity and dyslipidemia while decreasing insulin resistance and blood pressure, which diminishes the probability of type 2 diabetes mellitus and hypertension. To date, however, few papers have summarized the role of the galanin peptide family in modulating MetS. Through a summary of available papers and our recent studies, this study reviews the updated evidences of the effect that the galanin peptide family has on the clustering of MetS components, including obesity, dyslipidemia, insulin resistance and hypertension. This line of research will further deepen our understanding of the relationship between the galanin peptide family and the mechanisms underlying MetS, which will help develop new therapeutic strategies for this complex disease. PMID:22909974

  20. Linkage analysis in Usher syndrome type I (USH1) families from Spain.

    PubMed Central

    Espinós, C; Nájera, C; Millán, J M; Ayuso, C; Baiget, M; Pérez-Garrigues, H; Rodrigo, O; Vilela, C; Beneyto, M

    1998-01-01

    Usher syndrome (USH) is an autosomal recessive hereditary disorder characterised by congenital sensorineural hearing loss and gradual visual impairment secondary to retinitis pigmentosa (RP). The disorder is clinically and genetically heterogeneous. With regard to Usher type I (USH1), several subtypes have been described, the most frequent being USH1B located on chromosome 11q13.5. Of 18 USH1 families studied by linkage analysis, 12 (67%) showed significant lod score values for locus D11S527 (Zmax=14.032, theta=0.000) situated on chromosome 11q. Our findings suggest considerable genetic heterogeneity in the Spanish USH1 population. It is important to note that one of our families linked to the USH1B locus shows interesting intrafamilial clinical variability. As regards the remaining six USH1 families, the linkage analysis did not provide conclusive data, although two of them show slight linkage to markers located on chromosome 3q (Zmax=1.880, theta=0.000 for D3S1279), the same location that had previously been assigned to some USH3 families. Images PMID:9610802

  1. Recovery and outcomes after the acute respiratory distress syndrome (ARDS) in patients and their family caregivers.

    PubMed

    Herridge, Margaret S; Moss, Marc; Hough, Catherine L; Hopkins, Ramona O; Rice, Todd W; Bienvenu, O Joseph; Azoulay, Elie

    2016-05-01

    Outcomes after acute respiratory distress syndrome (ARDS) are similar to those of other survivors of critical illness and largely affect the nerve, muscle, and central nervous system but also include a constellation of varied physical devastations ranging from contractures and frozen joints to tooth loss and cosmesis. Compromised quality of life is related to a spectrum of impairment of physical, social, emotional, and neurocognitive function and to a much lesser extent discrete pulmonary disability. Intensive care unit-acquired weakness (ICUAW) is ubiquitous and includes contributions from both critical illness polyneuropathy and myopathy, and recovery from these lesions may be incomplete at 5 years after ICU discharge. Cognitive impairment in ARDS survivors ranges from 70 to 100 % at hospital discharge, 46 to 80 % at 1 year, and 20 % at 5 years, and mood disorders including depression and post-traumatic stress disorder (PTSD) are also sustained and prevalent. Robust multidisciplinary and longitudinal interventions that improve these outcomes are still uncertain and data in our literature are conflicting. Studies are needed in family members of ARDS survivors to better understand long-term outcomes of the post-ICU family syndrome and to evaluate how it affects patient recovery. PMID:27025938

  2. Familial Currarino syndrome associated with Hirschsprung disease: two cases of a mother and daughter.

    PubMed

    Ohno, Koichi; Nakamura, Tetsuro; Azuma, Takashi; Nakaoka, Tatsuo; Takama, Yuichi; Hayashi, Hiroaki; Horiike, Masaki; Zenitani, Masahiro; Higashio, Atsushi

    2013-01-01

    Currarino syndrome with Hirschsprung disease (CS-HD) is extremely rare. We present the first family with CS-HD. Case 1: A 28-year-old woman was admitted with severe abdominal distension and dyspnea. She was diagnosed with anal stenosis, hemisacrum, anterior sacral meningocele (ASM), tethered cord (TC), and short-segment aganglionosis. She underwent the modified Duhamel operation after meningocele repair and cord detethering. A bicornuate uterus, bilateral ovarian dermoid cysts, and small rectal duplication were also noted intraoperatively. Case 2: The daughter of case 1 was admitted for abdominal distension and anal stenosis at the age of 17 days. Studies revealed a hemisacrum, ASM, TC, presacral mass, atrial septal defect, polyp in the right nasal cavity, right vesicoureteral reflux, and short-segment aganglionosis. She underwent the modified Soave operation at the age of 1 year and 4 months after meningocele repair, cord detethering, and resection of the presacral mass (epidermoid cyst). In both cases, the aganglionic segments were confirmed by preoperative rectal suction biopsy and postoperative pathological examination on full-thickness rectal specimens. Some causal genes for Currarino syndrome (CS) and Hirschsprung disease (HD) are currently investigated. Thus far, 10 CS-HD cases have been reported, including 6 cases of familial CS. However, all the patients had sporadic HD. Recent reports suggest that anomalies of the enteric nerve system contribute to postoperative constipation in CS cases. PMID:23331821

  3. Exclusion of candidate genes in a family with arterial tortuosity syndrome.

    PubMed

    Gardella, Rita; Zoppi, Nicoletta; Assanelli, Deodato; Muiesan, Maria Lorenza; Barlati, Sergio; Colombi, Marina

    2004-04-30

    Arterial tortuosity syndrome (ATS) is a rare hereditary disorder with variable clinical presentation including tortuosity and elongation of the major arteries, often associated with pulmonary artery stenosis, pulmonary hypertension, and skin and joint laxity, suggestive of a connective tissue disorder. ATS is transmitted in an autosomal recessive mode, but the causal gene is unknown. We report an Italian pedigree with three inbred families in which five patients show signs of ATS. In particular, four adult patients present arterial tortuosity and elongation of the main arteries. Two of these patients, with the most severe degree of arterial tortuosity, also show severe peripheral stenosis of the main pulmonary artery. The fifth young patient shows a severe pulmonary valve stenosis in the absence of arterial tortuosity. All patients show signs of Ehlers-Danlos syndrome (EDS): soft skin with abundant subcutaneous tissue and joint laxity, hernias, and disorganization of the extracellular matrix (ECM) of fibronectin (FN) and of actin microfilaments in cultured skin fibroblasts. Linkage analysis of the genes involved in EDS and other connective tissue disorders, excluded COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL5A3, COL6A1, COL6A2, ADAMTS2, ELN, FN1, TNXA, and TNXB as candidate genes in the family under study, thus indicating that ATS is a distinct clinical and molecular entity. PMID:15054833

  4. Genetic analysis of Tunisian families with Usher syndrome type 1: toward improving early molecular diagnosis

    PubMed Central

    Ben-Rebeh, Imen; Bonnet, Crystel; Bouassida, Walid; Hadjamor, Imen; Ayadi, Hammadi; Ghorbel, Abdelmonem; Petit, Christine; Masmoudi, Saber

    2016-01-01

    Purpose Usher syndrome accounts for about 50% of all hereditary deaf-blindness cases. The most severe form of this syndrome, Usher syndrome type I (USH1), is characterized by profound congenital sensorineural deafness, vestibular dysfunction, and retinitis pigmentosa. Six USH1 genes have been identified, MYO7A, CDH23, PCDH15, USH1C, SANS, and CIB2, encoding myosin VIIA, cadherin-23, protocadherin-15, harmonin, scaffold protein containing ankyrin repeats and a sterile alpha motif (SAM) domain, and calcium- and integrin-binding member 2, respectively. Methods In the present study, we recruited four Tunisian families with a diagnosis of USH1, together with healthy unrelated controls. Affected members underwent detailed audiologic and ocular examinations. We used the North African Deafness (NADf) chip to search for known North African mutations associated with USH. Then, we selected microsatellite markers covering USH1 known loci to genotype the DNA samples. Finally, we performed DNA sequencing of three known USH1 genes: MYO7A, PCDH15, and USH1C. Results Four biallelic mutations, all single base changes, were found in the MYO7A, USH1C, and PCDH15 genes. These mutations consist of a previously reported splicing defect c.470+1G>A in MYO7A, three novel variants, including two nonsense (p.Arg3X and p.Arg134X) in USH1C and PCDH15, respectively, and one frameshift (p.Lys615Asnfs*6) in MYO7A. Conclusions We found a remarkable genetic heterogeneity in the studied families with USH1 with a variety of mutations, among which three were novel. These novel mutations will be included in the NADf mutation screening chip that will allow a higher diagnosis efficiency of this extremely genetically heterogeneous disease. Ultimately, efficient molecular diagnosis of USH in a patient’s early childhood is of utmost importance, allowing better educational and therapeutic management. PMID:27440999

  5. Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping.

    PubMed

    Pannain, S; Weiss, R E; Jackson, C E; Dian, D; Beck, J C; Sheffield, V C; Cox, N; Refetoff, S

    1999-03-01

    Approximately 10% of newborns with congenital hypothyroidism are unable to convert iodide into organic iodine. This iodide organification defect has a prevalence of 1 in 40,000 newborns and may be caused by defects in the thyroid peroxidase enzyme (TPO), the hydrogen peroxide-generating system, the TPO substrate thyroglobulin, or inhibitors of TPO. We identified a high incidence of severe hypothyroidism due to a complete iodide organification defect in the youngest generation of five nuclear families belonging to an inbred Amish kindred. Genealogical records permitted us to trace their origin to an ancestral couple 7-8 generations back and to identify an autosomal recessive pattern of inheritance. Initial studies of homozygosity by descent using two polymorphic markers within the TPO gene showed no linkage to the phenotype. In fact, 4 of 15 affected siblings from 2 of the nuclear families were heterozygous, resulting in homozygosity values of 73% and 53% in affected and unaffected family members, respectively. A genome-wide homozygosity screen using DNA pools from affected and unaffected family members localized the defect to a locus close to the TPO gene. Linkage analysis using 4 additional polymorphic markers within the TPO gene reduced the number of homozygous unaffected siblings to zero without altering the percent homozygosity initially found in the affected. Sequencing of the TPO gene revealed 2 missense mutations, E799K and R648Q. TPO 779K was found in both alleles of the 11 affected homozygotes, both mutations were present in each of the 3 affected compound heterozygotes, and there were no TPO mutations in 1 subject with hypothyroidism of different etiology. These results demonstrate the power of the DNA pooling strategy in the localization of a defective gene and the pitfalls of linkage analysis when 2 relatively rare mutations coexist in an inbred population. PMID:10084596

  6. Genome-wide sequencing to identify the cause of hereditary cancer syndromes: with examples from familial pancreatic cancer

    PubMed Central

    Roberts, Nicholas J.; Klein, Alison P.

    2013-01-01

    Advances in our understanding of the human genome and next-generation technologies have facilitated the use of genome-wide sequencing to decipher the genetic basis of Mendelian disease and hereditary cancer syndromes. The application of genome-wide sequencing in hereditary cancer syndromes has had mixed success, in part, due to complex nature of the underlying genetic architecture. In this review we discuss the use of genome-wide sequencing in both Mendelian diseases and hereditary cancer syndromes, highlighting the potential and challenges of this approach using familial pancreatic cancer as an example. PMID:23196058

  7. Linkage of morbid obesity with polymorphic microsatellite markers on chromosome 1q31 in a three-generation Canadian kindred

    SciTech Connect

    Murray, J.D.; Bulman, D.E.; Ebers, G.C. |

    1994-09-01

    Obesity is the most common nutritional disorder affecting Western societies. An estimated 3.7 million Canadians are considered to be overweight, a condition associated with hypertension, accelerated atherosclerosis, diabetes and a host of other medical problems. We have identified a 3 generation kindred in which morbid obesity appears to segregate in an autosomal dominant manner. All individuals were examined. Mass (kg) and heights (m) were measured in order to determine a body mass index (BMI) for each individual. Those individuals with BMI of greater than or equal to 30.0 were designated as affected. In the pedigree studied 25 individuals met this criteria and 12 of these were morbidly obese (BMI greater or equal to 40.0). A search of candidate genes proved unfruitful. A linkage study was initiated. All individuals in the pedigree were genotyped for microsatellite markers which were spaced every 20 centimorgans (cM). Positive evidence of linkage was detected with markers which map to 1q31-32 (lod score of 3.6 at {theta} = 0.05). Notably, strong effects for fatness in pigs have been found on pig chromosome 4 which has synteny with human chromosome 1q21-32. We are currently attempting to refine the position of this gene using linkage analysis with other microsatellite markers from this region of the genome. In addition we are screening other families in which obesity segregates for linkage to 1q31.

  8. Clinical and Genetic Description of a Family With a High Prevalence of Autosomal Dominant Restless Legs Syndrome

    PubMed Central

    Young, Jessica E.; Vilariño-Güell, Carles; Lin, Siong-Chi; Wszolek, Zbigniew K.; Farrer, Matthew J.

    2009-01-01

    OBJECTIVE: To conduct clinical and molecular genetic analyses of the members of an extended family in Central Indiana with a high prevalence of restless legs syndrome (RLS). PARTICIPANTS AND METHODS: From February 1, 2006, through August 31, 2008, we collected data from members of this family, which is of English descent. Genealogical methods were used to expand the family tree, and family members were screened with an RLS questionnaire. Telephone interviews and personal examinations were performed at Mayo Clinic and during a field trip to Central Indiana. Blood samples were collected for molecular genetic analysis. A follow-up telephone interview was conducted 1 year later. RESULTS: The family tree spans 7 generations with 88 living members, 30 of whom meet the criteria for diagnosis of RLS established by the International Restless Legs Syndrome Study Group. Three affected family members also have Parkinson disease or essential tremor. The mode of RLS inheritance is compatible with an autosomal dominant pattern. The affected family members do not exhibit linkage to the 5 known RLS loci or mutations in the RLS susceptibility genes MEIS1 and BTBD9. CONCLUSION: Of 88 members of this single extended family in Central Indiana, 30 were diagnosed as having RLS. Because our analysis shows that the disease is not linked to any of the known RLS loci or risk-associated genes, we postulate that members of this family may carry a gene mutation in a novel genetic locus. PMID:19181647

  9. [Increased incidence of multiple melanoma in sporadic and familial dysplastic nevus cell syndrome].

    PubMed

    Sigg, C; Pelloni, F; Schnyder, U W

    1989-09-01

    In 280 melanoma patients all data concerning familial and personal history, histology, and therapy were verified. All patients underwent total-body skin examination to check for the presence of dysplastic nevus syndrome (DNS). In 257/280 patients (91.8%) solitary melanomas were found, while in 23/280 patients (8.2%) multiple melanomas occurring simultaneously or consecutively were ascertained. Surprisingly, among the 12/280 patients (4.2%) with familial variants of melanoma, multiple melanomas were not found in a increased frequency. In patients with DNS (regardless of whether sporadic or familial) the frequency of multiple melanomas is higher: in patients with solitary melanomas DNS was found in 27/257 (10.5%), while in patients with multiple melanomas DNS was diagnosed in 11/23 (47.8%) (P less than 0.0005). In both groups (solitary and multiple melanomas) the mean age of patients with DNS was around 10 years lower. The frequency of additional primary malignancies in patients with cutaneous melanomas was 8.6%, and did not vary according as whether patients had solitary or multiple melanomas with or without DNS. PMID:2807914

  10. [Familial spastic paraplegia with severe amyotrophy of the hands. (Silver syndrome?)].

    PubMed

    Feki, I; Miladi, M I; Elleuch, N; Boukhris, A; Stévanin, G; Brice, A; Mhiri, C

    2007-04-01

    Familial spastic paraplegia (FSP) with severe muscular atrophy of hands and feet is exceptional. Autosomal dominant forms were initially described by Silver in 1966. We report two cases, from the same Tunisian family, presenting FSP with severe amyotrophy of the hands. A brother and his sister, aged respectively 37 and 36 years old, presented practically the same clinical picture. Their parents were cousins. The female patient was hospitalized. Both patients developed gait disorders around the age of three years. Muscular atrophy of the hands arose much later, around the age of 20 years. The neurological examination disclosed a spastic gait with distal amyotrophy, severe in the hands and moderate in the feet. Sensitivity was preserved and there was no fasciculation. The spinal cord and cerebral MRI was normal. Electromyography (EMG) showed a neurogenic pattern in the distal muscles. Stimulation of the median, ulnar and sciatica nerves was ineffective. The somatosensory evoked potentials (EP) were delayed (upper limb) or desynchronised (lower limb). The auditory and visual EP were normal. The cerebrospinal fluid contained 1 mononuclear cell/mm3 and 10 mg protein/100 ml. Abnormalities of the cranio-vertebral junction, Arnold-Chiari malformation, syringomyelia and familial juvenile amyotrophic lateral sclerosis (ALS) were excluded and the diagnosis of Silver's syndrome was evoked. PMID:17452950

  11. Detecting novel genetic mutations in Chinese Usher syndrome families using next-generation sequencing technology.

    PubMed

    Qu, Ling-Hui; Jin, Xin; Xu, Hai-Wei; Li, Shi-Ying; Yin, Zheng-Qin

    2015-02-01

    Usher syndrome (USH) is the most common cause of combined blindness and deafness inherited in an autosomal recessive mode. Molecular diagnosis is of great significance in revealing the molecular pathogenesis and aiding the clinical diagnosis of this disease. However, molecular diagnosis remains a challenge due to high phenotypic and genetic heterogeneity in USH. This study explored an approach for detecting disease-causing genetic mutations in candidate genes in five index cases from unrelated USH families based on targeted next-generation sequencing (NGS) technology. Through systematic data analysis using an established bioinformatics pipeline and segregation analysis, 10 pathogenic mutations in the USH disease genes were identified in the five USH families. Six of these mutations were novel: c.4398G > A and EX38-49del in MYO7A, c.988_989delAT in USH1C, c.15104_15105delCA and c.6875_6876insG in USH2A. All novel variations segregated with the disease phenotypes in their respective families and were absent from ethnically matched control individuals. This study expanded the mutation spectrum of USH and revealed the genotype-phenotype relationships of the novel USH mutations in Chinese patients. Moreover, this study proved that targeted NGS is an accurate and effective method for detecting genetic mutations related to USH. The identification of pathogenic mutations is of great significance for elucidating the underlying pathophysiology of USH. PMID:25252889

  12. Recommendations for the management of irritable bowel syndrome in family practice

    PubMed Central

    Paterson, W G; Thompson, W G; Vanner, S J; Faloon, T R; Rosser, W W; Birtwhistle, R W; Morse, J L; Touzel, T A

    1999-01-01

    To help family physicians manage patients with irritable bowel syndrome (IBS), a consensus conference was convened in June 1997 at which 5 internationally recognized experts in IBS presented position papers on selected topics previously circulated to the conference participants. Five working groups comprising family physicians, gastroenterologists and allied health care professionals from across Canada were then charged with developing recommendations for the diagnosis, patient education, psychosocial management, dietary advice and pharmacotherapy, respectively. An evidence-based approach was used where possible; otherwise, recommendations were made by consensus. The participants concluded that family physicians can make a positive diagnosis of IBS using symptom criteria. The pathophysiology is poorly understood, but motility and sensory disturbances appear to play a role. Neither psychological nor specific dietary factors cause IBS, but both can trigger symptoms. Drug therapy is not recommended for the routine treatment of IBS, but short-term trials of drug therapy may be targeted to predominant symptoms in selected patients. A step-wise, patient-centred approach to management is outlined. PMID:10439825

  13. A Novel TAZ Gene Mutation and Mosaicism in a Polish Family with Barth Syndrome

    PubMed Central

    Zapała, Barbara; Płatek, Teresa; Wybrańska, Iwona

    2015-01-01

    Barth syndrome (BTHS) is an X-linked recessive disease primarily affecting males. Clinically, the disease is characterized by hypertrophic or dilated cardiomyopathy, skeletal myopathy, chronic/cyclic neutropenia, 3-methylglutaconic aciduria, growth retardation and respiratory chain dysfunction. It is caused by mutations in the TAZ gene coding for the tafazzin protein which is responsible for cardiolipin remodeling. In this work, we present a novel pathogenic TAZ mutation c.83T>A, p.Val28Glu, found in mosaic form in almost all female members of a Polish family. Sanger sequencing of DNA from peripheral blood and from epithelial cells showed female mosaicism in three generations. This appears to be a new mechanism of inheritance and further research is required in order to understand the mechanism of this mosaicism. We conclude that BTHS genetic testing should include two or more tissues for women that appear to be noncarriers when blood DNA is initially tested. The results of our study should not only be applicable to BTHS families, but also to families with other X-linked diseases. PMID:25776009

  14. Reduced Penetrance of PRRT2 Mutation in a Chinese Family With Infantile Convulsion and Choreoathetosis Syndrome.

    PubMed

    Zhang, L M; An, Y; Pan, G; Ding, Y F; Zhou, Y F; Yao, Y H; Wu, B L; Zhou, S Z

    2015-09-01

    Paroxysmal kinesigenic dyskinesia is a rare episodic movement disorder that can be isolated or associated with benign infantile seizures as part of choreoathetosis syndrome. Mutations in the PRRT2 gene have been recently identified as a cause of paroxysmal kinesigenic dyskinesia and infantile convulsion and choreoathetosis (ICCA). We reported a PRRT2 heterozygous mutation (c.604-607delTCAC, p.S202Hfs*25) in a 3-generation Chinese family with infantile convulsion and choreoathetosis and paroxysmal kinesigenic dyskinesia. The mutation was present in 5 family members, of which 4 were clinically affected and 1 was an obligate carrier with reduced penetrance of PRRT2. The affected carriers of this mutation presented with a similar type of infantile convulsion during early childhood and developed additional paroxysmal kinesigenic dyskinesia symptoms later in life. In addition, they all had a dramatic clinical response to oxcarbazepine/phenytoin therapy. Reduced penetrance of the PRRT2 mutation in this family could warrant genetic counseling. PMID:25403460

  15. A novel TAZ gene mutation and mosaicism in a Polish family with Barth syndrome.

    PubMed

    Zapała, Barbara; Płatek, Teresa; Wybrańska, Iwona

    2015-05-01

    Barth syndrome (BTHS) is an X-linked recessive disease primarily affecting males. Clinically, the disease is characterized by hypertrophic or dilated cardiomyopathy, skeletal myopathy, chronic/cyclic neutropenia, 3-methylglutaconic aciduria, growth retardation and respiratory chain dysfunction. It is caused by mutations in the TAZ gene coding for the tafazzin protein which is responsible for cardiolipin remodeling. In this work, we present a novel pathogenic TAZ mutation c.83T>A, p.Val28Glu, found in mosaic form in almost all female members of a Polish family. Sanger sequencing of DNA from peripheral blood and from epithelial cells showed female mosaicism in three generations. This appears to be a new mechanism of inheritance and further research is required in order to understand the mechanism of this mosaicism. We conclude that BTHS genetic testing should include two or more tissues for women that appear to be noncarriers when blood DNA is initially tested. The results of our study should not only be applicable to BTHS families, but also to families with other X-linked diseases. PMID:25776009

  16. Molecular characterization of Blau syndrome: Genetic linkage to chromosome 16

    SciTech Connect

    Tromp, G.; Duivaniemi, H.; Christiano, A.

    1994-09-01

    The Blau syndrome is an autosomal, dominantly-inherited disease characterized by multi-organ, tissue-specific inflammation. Its clinical phenotype includes granulomatous uveitis, arthritis and skin rash. The syndrome is unique in that it is the sole human model for a variety of multi-system inflammatory diseases that afflict a significant percentage of the population. Karyotypic analysis of the large, three generation kindred whose disease originally characterized the syndrome was unremarkable. Following exclusion of a number of extracellular matrix candidates genes, a genome-wide search was undertaken of the Blau susceptibility locus. Fifty-seven members of the family were genotyped for about 200 highly polymorphic dinucleotide repeat markers. Linkage analysis was performed using the LINKAGE package of programs under a model of dominant inheritance with reduced penetrance. Five liability classes were used to specify penetrances and phenocopy rates for those affected the arthritis, uveitis, skin rash and combinations thererof. In addition, five age-dependent penetrance classes were used for unaffected individuals. The marker D16S298 gave a maximum lod score of 3.6 at {theta} = 0.05 with two-point analysis. Lod scores for flanking markers were consistent. These data provide convincing evidence that the Blau susceptibility locus is situated within the 16p12-q21 interval. Fine mapping of the candidate interval with additional families exhibiting the Blau phenotype, as well as with more polymorphic markers, is underway.

  17. DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions

    PubMed Central

    Yang, Jiandong; Doros, Leslie; Williams, Gretchen M.; Harris, Anne; Stewart, Douglas R.; Messinger, Yoav; Field, Amanda; Dehner, Louis P.; Hill, D Ashley

    2014-01-01

    Germline mutations in DICER1 are associated with increased risk for a wide variety of neoplastic conditions, including pleuropulmonary blastoma (PPB), cystic nephroma, nasal chondromesenchymal hamartoma, ovarian Sertoli-Leydig cell tumors, botryoid embryonal rhabdomyosarcoma of the uterine cervix, ciliary body medulloepithelioma, pineoblastoma, pituitary blastoma and nodular thyroid hyperplasia or thyroid carcinoma. These tumors may be seen in isolation or in constellation with other characteristic tumor types in individuals or family members. Here we describe the medical history of a child with a heterozygous, loss of function germline DICER1 mutation and multiple tumors associated with the syndrome.. Although germline mutations in DICER1 are rare, tumors of these types will be seen by practicing pathologists and should prompt consideration of an underlying DICER1 mutation. PMID:25356068

  18. Pleuropulmonary Blastoma: Evolution of an Entity as an Entry into a Familial Tumor Predisposition Syndrome.

    PubMed

    Dehner, Louis P; Messinger, Yoav H; Schultz, Kris Ann P; Williams, Gretchen M; Wikenheiser-Brokamp, Kathryn; Hill, D Ashley

    2015-01-01

    Pleuropulmonary blastoma (PPB) is the most common primary malignant neoplasm of the lung in children. Like other solid dysontogenic neoplasms, this tumor typically presents before 7 years of age. The earliest manifestation is the presence of a lung cyst(s), which is usually recognized in the first year of life and is difficult to differentiate on the basis of imaging studies from non-neoplastic cysts of early childhood. From a multilocular cyst, PPB has the potential to progress to a high-grade multipatterned primitive sarcoma. More than 65% of all affected children have a heterozygous germline mutation in DICER1. The DICER1 PPB familial tumor predisposition syndrome is initially recognized in most cases on the basis of PPB alone but also by several other unique and characteristic extrapulmonary tumors, including pediatric cystic nephroma, nasal chondromesenchymal hamartoma, nodular lesions of the thyroid, embryonal rhabdomyosarcoma of the cervix, and ciliary body medulloepithelioma. PMID:26698637

  19. Japanese familial case of myoclonus-dystonia syndrome with a splicing mutation in SGCE.

    PubMed

    Wada, Takahito; Takano, Kyoko; Tsurusaki, Yoshinori; Miyake, Noriko; Nakashima, Mitsuko; Saitsu, Hirotomo; Matsumoto, Naomichi; Osaka, Hitoshi

    2015-04-01

    Myoclonus-dystonia syndrome (MDS) is a rare autosomal-dominant movement disorder characterized by brief, frequently alcohol-responsive myoclonic jerks that begin in childhood or early adolescence, caused by mutations in the ε-sarcoglycan gene (SGCE). The patient was a 6-year-old boy. At 2 years 8 months, he had abnormal movement when he ran due to dystonia of his left leg. At 3 years 5 months, he exhibited dystonia and myoclonic movement of his arms when eating. Myoclonus was likely to develop when he felt anxiety or exhaustion. Genomic DNA showed a heterozygous mutation in SGCE (c.109 + 1 G > T). His father and uncle with the same mutation also experienced milder dystonia or myoclonic movements. SGCE mutation can cause a broad range of clinical symptoms between and within families. We should consider MDS as a differential diagnosis for patients with paroxysmal walking abnormalities and/or myoclonic movements. PMID:25868953

  20. A novel CHSY1 gene mutation underlies Temtamy preaxial brachydactyly syndrome in a Pakistani family.

    PubMed

    Sher, Gulab; Naeem, Muhammad

    2014-01-01

    Temtamy preaxial brachydactyly syndrome (TPBS) is an autosomal recessive rare disorder characterized by hyperphalangism of digits, facial dysmorphism, dental anomalies, sensorineural hearing loss, delayed motor and mental development, and growth retardation. Loss of function mutations have been recently reported in the CHSY1 gene to cause the TPBS. Here, we report a novel missense mutation (c.1897 G > A) in the CHSY1 gene in two TPBS patients from a consanguineous Pakistani family. The mutation predicted substitution of a highly conserved aspartate amino acid residue to asparagine at position 633 in the protein (D633N). Polyphen analysis supported the pathogenicity of D36N mutation. Our finding extends the body of recent evidence that supports the role of CHSY1 as a potential mediator of BMP signaling. PMID:24269551

  1. Atypical "benign" partial epilepsy of childhood or pseudo-lennox syndrome. Part II: family study.

    PubMed

    Doose, H; Hahn, A; Neubauer, B A; Pistohl, J; Stephani, U

    2001-02-01

    Atypical benign partial epilepsy of childhood (ABPE = Pseudo-Lennox syndrome) shows semiologic parallels to Lennox-Gastaut syndrome, however--besides the lack of tonic seizures--it has an entirely different etiology and prognosis. Recently Hahn et al [17] investigated the long-term evolution of 43 cases with ABPE. Symptomatology, EEG findings, and course were found to overlap with Rolandic epilepsy, Landau-Kleffner syndrome and ESES. The incidence of seizures in relatives was determined in the whole series investigated by Hahn et al [17]. Five of 56 siblings suffered from seizures (3 Rolandic seizures; one febrile convulsions; one unclassified). Three fathers reported grand mal. In 29 families of the series of Hahn et al EEG recordings were performed: 22 brothers, 19 sisters and 16 pairs of parents. In 29% of the siblings a sharp wave focus was demonstrable. The rate rose to 40% when only siblings investigated at the age of maximum expression (3 to 10 years) were considered. Sharp wave foci were mostly multifocal and indistinguishable from those observed in siblings of children with Rolandic epilepsy. Photoparoxysmal response and generalized spikes and waves during rest and hyperventilation were also found to be significantly elevated (26% and 13% respectively). We conclude that ABPE is a subgroup of idiopathic partial epilepsy of childhood (representing a less benign part of a spectrum) that has to be ranked in a continuum with Rolandic epilepsy. The different clinical phenotype might be caused by a higher expressivity of the identical genetic trait, possibly facilitated by other genetic or acquired factors. Genetic heterogeneity represents another possibility. PMID:11315204

  2. Metabolic Syndrome in Korean Cancer Survivors and Family Members: A Study in a Health Promotion Center.

    PubMed

    Shin, Jin Young; Choi, Yoon Ho; Song, Yun Mi

    2015-01-01

    This cross-sectional study evaluated the risk of metabolic syndrome (MetS) in cancer survivors and family members. Subjects were 48,934 adults (24,786 men, 24,148 women) aged ≥40yr who receive a routine health examination at 1 hospital from January 2010 to December 2012. There were 2468 cancer survivors, 18,211 with cancer patients in the family, and 28,255 noncancer subjects, who never experienced cancer and whose family members either. Associations between MetS and cancer experience were assessed using multiple logistic regression analysis. The odds ratio (OR) of MetS in female cancer survivors was significantly higher than noncancer subjects after adjusting for age, smoking, physical activity, and alcohol intake (OR = 1.22, 95% confidence intervals: 1.02-1.47]. However, the OR of MetS for male survivors did not differ from that of noncancer subjects. Gastric cancer survivors had a lower OR of MetS than noncancer subjects (0.37, 0.27-0.50). ORs of breast cancer (1.49, 1.00-2.23) and prostate cancer survivors (1.46, 1.07-1.99) were higher than the OR of MetS for noncancer subjects. There was no difference in the OR of MetS between the family members of cancer patients and non-cancer subjects. These findings suggest that the odds of MetS for cancer survivors may differ by cancer type and by sex. PMID:26317444

  3. A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome.

    PubMed

    Ni, Cheng; Yan, Ming; Zhang, Jia; Cheng, Ruhong; Liang, Jianying; Deng, Dan; Wang, Zhen; Li, Ming; Yao, Zhirong

    2016-01-01

    Olmsted syndrome (OS) is a rare keratinization disorder, typically characterized by two primary diagnostic hallmarks--mutilating palmoplanter and periorificial keratoderma. However, there's a growing body of literature reporting on the phenotypic diversity of OS, including the absence of aforementioned hallmarks and the presence of some unusual clinical features. Here we presented an atypical familial case of OS that could be confused with Huriez syndrome due to the presence of a scleodactyly-like appearance and tapered fingers in the proband. We ruled out this possibility and made a definitive diagnosis of OS based on clinical features and a genetic assay. Recently, mutations in TRPV3 associated with autosomal dominant or recessive OS continued to be reported, thus conducing to clarifying the underlying relationship between the genotype and phenotype of OS. So we further explored the genotype-phenotype correlation by integrating functionl assays with in silico predictions. Our research not only redefined the phenotypic spectrum of OS, but also provided concrete molecular insights into how mutations in a single gene can lead to significant differences in the severity of this rare disease. PMID:26902751

  4. A novel mutation in TRPV3 gene causes atypical familial Olmsted syndrome

    PubMed Central

    Ni, Cheng; Yan, Ming; Zhang, Jia; Cheng, Ruhong; Liang, Jianying; Deng, Dan; Wang, Zhen; Li, Ming; Yao, Zhirong

    2016-01-01

    Olmsted syndrome (OS) is a rare keratinization disorder, typically characterized by two primary diagnostic hallmarks—mutilating palmoplanter and periorificial keratoderma. However, there’s a growing body of literature reporting on the phenotypic diversity of OS, including the absence of aforementioned hallmarks and the presence of some unusual clinical features. Here we presented an atypical familial case of OS that could be confused with Huriez syndrome due to the presence of a scleodactyly-like appearance and tapered fingers in the proband. We ruled out this possibility and made a definitive diagnosis of OS based on clinical features and a genetic assay. Recently, mutations in TRPV3 associated with autosomal dominant or recessive OS continued to be reported, thus conducing to clarifying the underlying relationship between the genotype and phenotype of OS. So we further explored the genotype-phenotype correlation by integrating functionl assays with in silico predictions. Our research not only redefined the phenotypic spectrum of OS, but also provided concrete molecular insights into how mutations in a single gene can lead to significant differences in the severity of this rare disease. PMID:26902751

  5. Fahr's Syndrome

    MedlinePlus

    ... Awards Enhancing Diversity Find People About NINDS NINDS Fahr's Syndrome Information Page Synonym(s): Familial Idiopathic Basal Ganglia ... is being done? Clinical Trials Organizations What is Fahr's Syndrome? Fahr's Syndrome is a rare, genetically dominant, ...

  6. Psychological Well-Being of Mothers and Siblings in Families of Girls and Women with Rett Syndrome

    ERIC Educational Resources Information Center

    Cianfaglione, Rina; Hastings, Richard P.; Felce, David; Clarke, Angus; Kerr, Michael P.

    2015-01-01

    Few published studies have reported on the psychological well-being of family members of individuals with Rett syndrome (RTT). Eighty-seven mothers of girls and women with RTT completed a questionnaire survey about their daughters' behavioral phenotype, current health, and behavior problems, and their own and a sibling's well-being. Mothers…

  7. The Impact of Tourette's Syndrome in the School and the Family: Perspectives from Three Stakeholder Groups

    ERIC Educational Resources Information Center

    Rivera-Navarro, Jesús; Cubo, Esther; Almazán, Javier

    2014-01-01

    This article analyzes the perceptions of Spanish health professionals, children with Tourette's Syndrome (TS) and their parents about social, school and family problems related to the disorder. A qualitative research methodology was used involving Focus Groups (FGs) made up of children with TS (× 2 FGs), parents/caregivers of persons with TS…

  8. Adjustment in Mothers of Children with Asperger Syndrome: An Application of the Double ABCX Model of Family Adjustment

    ERIC Educational Resources Information Center

    Pakenham, Kenneth I.; Samios, Christina; Sofronoff, Kate

    2005-01-01

    The present study examined the applicability of the double ABCX model of family adjustment in explaining maternal adjustment to caring for a child diagnosed with Asperger syndrome. Forty-seven mothers completed questionnaires at a university clinic while their children were participating in an anxiety intervention. The children were aged between…

  9. Woodhouse-Sakati Syndrome: Report of the First Tunisian Family with the C2orf37 Gene Mutation

    PubMed Central

    Hdiji, Olfa; Turki, Emna; Bouzidi, Nouha; Bouchhima, Imen; Damak, Mariem; Bohlega, Saeed; Mhiri, Chokri

    2016-01-01

    Woodhouse-Sakati syndrome (WSS) is an infrequent autosomal recessive condition characterized by progressive extrapyramidal signs, mental retardation, hypogonadism, alopecia, and diabetes mellitus. This syndrome belongs to a heterogeneous group of inherited neurodegenerative disorders characterized iron accumulation in the brain, and it is caused by mutations of the C2orf37 gene. We report the first Tunisian family with two affected sisters presenting with a phenotype suggestive of WSS. We examined the index patient presenting with movement disorders and mental retardation and then searched for similar cases in her family, which identified a sister with similar signs. We performed a genetic study that confirmed the diagnosis and revealed a c.436delC mutation of the C2orf37 gene. Therefore, WSS is an important consideration in patients presenting with movement disorders and intellectual disability. A high consanguinity contributes to the clustering of such rare autosomal recessive syndromes. PMID:27240811

  10. Familial clustering strongly suggests that the phenotypic variation of the 8344 A>G lys mitochondrial tRNA mutation is encoded in cis.

    PubMed

    Kazakos, Kyriakos; Kotsa, Kalliopi; Yavropoulou, Maria; Dionyssopoulos, Alexander; Grabs, Rosemary; Yovos, John; Polychronakos, Constantin

    2012-07-01

    The maternally inherited 8344 A>G mutation in the mitochondrial Lys tRNA is classically associated with the myoclonic epilepsy, ragged-red muscle fiber (MERRF) syndrome. Multiple lipomatosis (Madelung's disease) is occasionally described. Here we report a large kindred with a statistically significant clustering of very unusual clinical manifestations. We have studied a Greek family that includes seven symptomatic cases of 8344 A>G. Clinical features, glucose tolerance and heteroplasmy in fat, muscle and blood were analyzed. The patients, aged 34-76 at the time of assessment, all suffer from progressive proximal limb-girdle myopathy and extensive lipomatosis. Four of the seven have either impaired glucose tolerance or diabetes but none has had epilepsy, a cardinal feature of MERRF. Heteroplasmy was not higher in adipose tissue than that found in the literature. Compared to literature reports, the familial clustering of this unusual combination of manifestations (lipomatosis in all, epilepsy in none) is statistically significant. The clustering of unusual manifestations in this large kindred strongly suggests that much of the phenotypic variability of 8344 A>G is determined by mitochondrially encoded modifiers in cis. PMID:22681518

  11. Morquio syndrome

    MedlinePlus

    ... to have children and who have a family history of Morquio syndrome. Counseling is also recommended for families who have a child with Morquio syndrome to help them understand the condition and possible treatments. Prenatal testing is available.

  12. p63 Gene Mutations in EEC Syndrome, Limb-Mammary Syndrome, and Isolated Split Hand–Split Foot Malformation Suggest a Genotype-Phenotype Correlation

    PubMed Central

    van Bokhoven, Hans; Hamel, Ben C. J.; Bamshad, Mike; Sangiorgi, Eugenio; Gurrieri, Fiorella; Duijf, Pascal H. G.; Vanmolkot, Kaate R. J.; van Beusekom, Ellen; van Beersum, Sylvia E. C.; Celli, Jacopo; Merkx, Gerard F. M.; Tenconi, Romano; Fryns, Jean Pierre; Verloes, Alain; Newbury-Ecob, Ruth A.; Raas-Rotschild, Annick; Majewski, Frank; Beemer, Frits A.; Janecke, Andreas; Chitayat, David; Crisponi, Giangiorgio; Kayserili, Hülya; Yates, John R. W.; Neri, Giovanni; Brunner, Han G.

    2001-01-01

    p63 mutations have been associated with EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate), as well as with nonsyndromic split hand–split foot malformation (SHFM). We performed p63 mutation analysis in a sample of 43 individuals and families affected with EEC syndrome, in 35 individuals affected with SHFM, and in three families with the EEC-like condition limb-mammary syndrome (LMS), which is characterized by ectrodactyly, cleft palate, and mammary-gland abnormalities. The results differed for these three conditions. p63 gene mutations were detected in almost all (40/43) individuals affected with EEC syndrome. Apart from a frameshift mutation in exon 13, all other EEC mutations were missense, predominantly involving codons 204, 227, 279, 280, and 304. In contrast, p63 mutations were detected in only a small proportion (4/35) of patients with isolated SHFM. p63 mutations in SHFM included three novel mutations: a missense mutation (K193E), a nonsense mutation (Q634X), and a mutation in the 3′ splice site for exon 5. The fourth SHFM mutation (R280H) in this series was also found in a patient with classical EEC syndrome, suggesting partial overlap between the EEC and SHFM mutational spectra. The original family with LMS (van Bokhoven et al. 1999) had no detectable p63 mutation, although it clearly localizes to the p63 locus in 3q27. In two other small kindreds affected with LMS, frameshift mutations were detected in exons 13 and 14, respectively. The combined data show that p63 is the major gene for EEC syndrome, and that it makes a modest contribution to SHFM. There appears to be a genotype-phenotype correlation, in that there is a specific pattern of missense mutations in EEC syndrome that are not generally found in SHFM or LMS. PMID:11462173

  13. A kindred with MYH-associated polyposis and pilomatricomas.

    PubMed

    Baglioni, Silvana; Melean, German; Gensini, Francesca; Santucci, Marco; Scatizzi, Marco; Papi, Laura; Genuardi, Maurizio

    2005-04-15

    MYH-associated polyposis (MAP) is a recently described autosomal recessive form of familial adenomatous polyposis (FAP) associated with susceptibility to colorectal carcinoma (CRC). MAP is caused by biallelic inactivating mutations of the MYH gene, a component of the base excision repair (BER) machinery, whose dysfunction leads to an increase in the rate of G > T transversions following DNA oxidative damage. MAP patients can present with either classic or attenuated polyposis. However, the MAP colonic and extracolonic phenotype has yet to be defined. We report on two siblings, born from consanguineous parents, who were found to be homozygotes for an MYH frameshift mutation. The propositus presented with a low number of colonic lesions and an early-onset CRC. Both siblings had a history of pilomatricomas, benign tumors derived from hair follicles, in childhood. The findings presented provide further evidence of phenotypic variability in MAP, and suggest that multiple pilomatricomas may be a useful cutaneous marker of MAP. PMID:15690400

  14. A novel mutation of the adrenocorticotropin receptor (ACTH-R) gene in a family with the syndrome of isolated glucocorticoid deficiency, but no ACTH-R abnormalities in two families with the triple A syndrome

    SciTech Connect

    Tsigos, C.; Arai, K.; Latronico, A.C. ||

    1995-07-01

    Isolated glucocorticoid deficiency (IGD) is an autosomal recessive disorder characterized by primary adrenocortical insufficiency, usually without mineralocorticoid deficiency. Occasionally, the disorder is associated with alacrima and achalasia of the esophagus (triple A syndrome), suggesting potential heterogeneity in its etiology. Mutations in the ACTH receptor gene have been reported in several families with IGD. We have amplified and directly sequenced the entire intronless ACTH receptor gene in 1 other family with IGD and 2 famlies with triple A syndrome. The proband with IGD was a homozygote for an A {r_arrow}G substitution, changing tyrosine 254 to cysteine in the third extracellular loop of the receptor protein, probably interfering with ligand binding. Both of her parents were heterozygotes for this mutation, which was not detected in 100 normal alleles. No mutations were identified in the entire coding area of the ACTH receptor in the 2 families with triple A syndrome, supporting the idea of a developmental or postreceptor defect in this syndrome. 19 refs., 1 fig.

  15. Maternal Well-Being and Child Behavior in Families with Fragile X Syndrome

    PubMed Central

    Hauser, Claire T.; Kover, Sara T.; Abbeduto, Leonard

    2014-01-01

    The purpose of this study was to examine the bidirectional relationshipsnetres behavioral functioning of children with fragile X syndrome (FXS), the leading cause of inherited intellectual disability. Children with FXS commonly demonstrate challenging behavior related to anxiety, attention, and aggression, whereas mothers of children with FXS have been identified as susceptible to mental health disorders due to their status as genetic carriers of the FXS premutation, as well as the environmental stressors of raising children with special needs. The longitudinal design of this study builds upon prior work that established a concurrent relationship among these factors in families of children with other intellectual disorders. Findings indicated that maternal mental health status was not significantly related to changes in levels of child challenging behavior, child challenging behavior was related to changes in maternal depression over time, and heightened levels of child challenging behavior was related to increased feelings of maternal closeness toward the child over time. The unexpected nature of the result regarding maternal closeness provides new and more complex hypotheses about how mothers of special needs children demonstrate adaptation and resilience. The findings have implications for maternal and familial mental health treatment as well as future research. PMID:24984053

  16. Cytogenetic and Clinical Assessment of a Family with Treacher Collins Syndrome

    PubMed Central

    Kumar, Manoj; Kumar, Rakesh; Tanwar, Mukesh; Ghose, Supriyo; Kaur, Jasbir; Dada, Rima

    2011-01-01

    Treacher Collins syndrome (TCS) is a rare autosomal dominant disorder characterized by craniofacial deformities. It is the most common type of mandibulofacial dysostosis (MFD). The objective of this study is to do cytogenetic analysis of a TCS family. Physical examination and all available medical records were reviewed. 50 GTG-banded metaphases were analysed to detect any structural or numerical chromosomal abnormality. Downward slanting of palpebral fissures, hypoplasia of zygomatic arch complex, and hypoplasia of mandible were present in all. Cytogenetic findings show interstitial deletion in chromosomes 5(q32-q33) and 3(q23–q25). We report four members of three generations of a family having TCS in a unique way that the deletion has been found in 3q and 5q which has not been reported. Mosaicism of deletion on 5q was detected in all affected members whereas 3q deletion was found only in one member (II.2). This finding may represent a more severe manifestation of the TCS. Thus the evaluation and counselling of the TCS patients should be undertaken with caution. PMID:21765846

  17. Non-syndromic multiple supernumerary teeth in a family unit with a normal karyotype: case report.

    PubMed

    Inchingolo, Francesco; Tatullo, Marco; Abenavoli, Fabio M; Marrelli, Massimo; Inchingolo, Alessio D; Gentile, Mattia; Inchingolo, Angelo M; Dipalma, Gianna

    2010-01-01

    Introduction. Hyperdontia is an odontostomatologic anomaly characterized by an excess in tooth number. It seems to occur more often in patients with hereditary factors concerning this anomaly: this case represents a rare form of hyperdontia, with bilateral multiple supernumerary teeth, with evident penetrance of the phenotype in the family unit engaged in the present study. The karyotype determination excludes a pathogenesis on chromosomal basis.Case report. A 30 years old patient came to our observation with five impacted teeth (1.8, 2.8, 3.8, 4.7 and 4.8), as well as with the presence of an impacted supernumerary tooth (distomolar 4.9). The patient was suggested to allow us to perform a radiologic screening to his two sisters aged 17 and 13 years.The X-ray photography showed that the elder sister had nine impacted teeth; these were 1.8 - 1.9 - 2.8 - 2.9 - 2.10 - 3.8 - 3.9 - 4.8 - 4.9; while the youngest sister had four impacted teeth, that is 1.8 - 1.9 - 2.8 - 2.9.Conclusions. The value of the present case report can be used as a paradigm for the assessment of the hereditary factors predisposing the onset of hyperdontia, and for the consequent management by oral surgeon of family units in which the odontostomatologic anomaly was detected without any syndromic forms. PMID:21060725

  18. Dermal ultrastructure in low Beighton score members of 17 families with hypermobile-type Ehlers-Danlos syndrome.

    PubMed

    Hermanns-Lê, Trinh; Reginster, Marie-Annick; Piérard-Franchimont, Claudine; Delvenne, Philippe; Piérard, Gérald E; Manicourt, Daniel

    2012-01-01

    The distinction between the Ehlers-Danlos syndrome hypermobile type (EDSH) and the benign joint hypermobility syndrome (BJHS) is unclear. The aim of the present study was to compare skin ultrastructural abnormalities of EDSH and BJHS among different families. Skin of 23 EDSH, 27 BJHS, and 41 asymptomatic subjects from 17 families was examined using transmission electron microscopy. Similar ultrastructural abnormalities were found irrespective of the Beighton score. Flower-like collagen fibrils represented the key change and elastic fibers were altered as well. Beighton score is a clinical parameter rating joint mobility that appeared unrelated to quantitative and qualitative collagen ultrastructural alterations in the skin. Some EDSH family members fit with BJHS diagnosis. BJHS possibly represents a mild variant of EDSH. PMID:23091361

  19. Analysis of four families with the Stickler syndrome by linkage studies. Identification of a new premature stop codon in the COL2A1 gene in a family

    SciTech Connect

    Bonaventure, J.; Lasselin, C.; Toutain, A.

    1994-09-01

    The Stickler syndrome is an arthro-ophthalmopathy which associates progressive myopia with vitreal degeneration and retinal detachment. Cleft palate, cranio-facial abnormalities, deafness and osteoarthritis are often associated symptoms. Genetic heterogeneity of this autosomal dominant disease was consistent with its large clinical variability. Linkage studies have provided evidence for cosegregation of the disease with COL2A1, the gene coding for type II collagen, in about 50% of the families. Four additional families are reported here. Linkage analyses by using a VNTR located in the 3{prime} region of the gene were achieved. In three families, positive lod scores were obtained with a cumulative maximal value of 3.5 at a recombination fraction of 0. In one of these families, single strand conformation analysis of 25 exons disclosed a new mutation in exon 42. Codon for glutamic acid at position a1-803 was converted into a stop codon. The mutation was detected in DNA samples from all the affected members of the family but not in the unaffected. This result confirms that most of the Stickler syndromes linked to COL2A1 are due to premature stop codons. In a second family, an abnormal SSCP pattern of exon 34 was detected in all the affected individuals. The mutation is likely to correspond to a splicing defect in the acceptor site of intron 33. In one family the disease did not segregate with the COL2A1 locus. Further linkage studies with intragenic dimorphic sites in the COL10A1 gene and highly polymorphic markers close to the COL9A1 locus indicated that this disorder did not result from defects in these two genes.

  20. Characterizations of 9p21 candidate genes in familial melanoma

    SciTech Connect

    Walker, G.J.; Flores, J.F.; Glendening, J.M.

    1994-09-01

    We have previously collected and characterized 16 melanoma families for the inheritance of a familial melanoma predisposition gene on 9p21. Clear evidence for genetic linkage has been detected in 8 of these families with the 9p21 markers D9S126 and 1FNA, while linkage of the remaining families to this region is less certain. A candidate for the 9p21 familial melanoma gene, the cyclin kinase inhibitor gene p16 (also known as the multiple tumor suppressor 1 (MTS1) gene), has been recently indentified. Notably, a nonsense mutation within the p16 gene has been detected in the lymphoblastoid cell line DNA from a dysplastic nevus syndrome (DNS), or familial melanoma, patient. The p16 gene is also known to be frequently deleted or mutated in a variety of tumor cell lines (including melanoma) and resides within a region that has been defined as harboring the 9p21 melanoma predisposition locus. This region is delineated on the distal side by the marker D9S736 (which resides just distal to the p16 gene) and extends in a proximal direction to the marker D9S171. Overall, the entire distance between these two loci is estimated at 3-5Mb. Preliminary analysis of our two largest 9p21-linked melanoma kindreds (by direct sequencing of PCR products) has not yet revealed mutations within the coding region of the p16 gene. Others have reported that 8/11 unrelated 9p21-linked melanoma families do not appear to carry p16 mutations; thus the possibility exists that p16 is not a melanoma susceptibility gene per se, although it appears to play some role in melanoma tumor progression. Our melanoma kindred DNAs are currently being analyzed by SSCP using primers that amplify exons of other candidate genes from the 9p21 region implicated in familial melanoma. These novel genes reside within a distinct critical region of homozygous loss in melanoma which is located >2 Mb from the p16 gene on 9p21.

  1. Whole-exome sequencing in familial atrial fibrillation

    PubMed Central

    Weeke, Peter; Muhammad, Raafia; Delaney, Jessica T.; Shaffer, Christian; Mosley, Jonathan D.; Blair, Marcia; Short, Laura; Stubblefield, Tanya; Roden, Dan M.; Darbar, Dawood

    2014-01-01

    Aims Positional cloning and candidate gene approaches have shown that atrial fibrillation (AF) is a complex disease with familial aggregation. Here, we employed whole-exome sequencing (WES) in AF kindreds to identify variants associated with familial AF. Methods and results WES was performed on 18 individuals in six modestly sized familial AF kindreds. After filtering very rare variants by multiple metrics, we identified 39 very rare and potentially pathogenic variants [minor allele frequency (MAF) ≤0.04%] in genes not previously associated with AF. Despite stringent filtering >1 very rare variants in the 5/6 of the kindreds were identified, whereas no plausible variants contributing to familial AF were found in 1/6 of the kindreds. Two candidate AF variants in the calcium channel subunit genes (CACNB2 and CACNA2D4) were identified in two separate families using expression data and predicted function. Conclusion By coupling family data with exome sequencing, we identified multiple very rare potentially pathogenic variants in five of six families, suggestive of a complex disease mechanism, whereas none were identified in the remaining AF pedigree. This study highlights some important limitations and challenges associated with performing WES in AF including the importance of having large well-curated multi-generational pedigrees, the issue of potential AF misclassification, and limitations of WES technology when applied to a complex disease. PMID:24727801

  2. Genetic Information-Seeking Behaviors and Knowledge among Family Members and Patients with Inherited Bone Marrow Failure Syndromes.

    PubMed

    Hamilton, Jada G; Hutson, Sadie P; Frohnmayer, Amy E; Han, Paul K J; Peters, June A; Carr, Ann G; Alter, Blanche P

    2015-10-01

    Inherited bone marrow failure syndromes (IBMFS) including Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome are rare genetic disorders characterized by hematologic complications and increased risk of cancer. Patients and their families likely experience obstacles in obtaining sufficient health information given their disorders' rarity. To investigate this possibility, we examined information-seeking behaviors and levels of general and disorder-specific genetic knowledge among 315 members of 174 families with an IBMFS, and how information-seeking behaviors and socio-demographic factors may be associated with their genetic knowledge. Cross-sectional survey data indicated that participants were most likely to have ever used the Internet or healthcare providers for genetic information. On average, participants correctly answered 57 % of items assessing general genetic knowledge and 49-59 % of disorder-specific knowledge items. Greater knowledge was associated with greater education and ever experiencing genetic counseling, attending a scientific meeting, and seeking information from the Internet and scientific literature. Among families with Fanconi anemia (whose family support organization has the longest history of providing information), greater disorder-specific genetic knowledge was also associated with seeking information from support groups and other affected families. Results suggest that families with IBMFS have uncertainty regarding genetic aspects of their disorder, and highlight potential channels for delivering educational resources. PMID:25540896

  3. A Missense Mutation in CASK Causes FG Syndrome in an Italian Family

    PubMed Central

    Piluso, Giulio; D'Amico, Francesca; Saccone, Valentina; Bismuto, Ettore; Rotundo, Ida Luisa; Di Domenico, Marina; Aurino, Stefania; Schwartz, Charles E.; Neri, Giovanni; Nigro, Vincenzo

    2009-01-01

    First described in 1974, FG syndrome (FGS) is an X-linked multiple congenital anomaly/mental retardation (MCA/MR) disorder, characterized by high clinical variability and genetic heterogeneity. Five loci (FGS1-5) have so far been linked to this phenotype on the X chromosome, but only one gene, MED12, has been identified to date. Mutations in this gene account for a restricted number of FGS patients with a more distinctive phenotype, referred to as the Opitz-Kaveggia phenotype. We report here that a p.R28L (c.83G→T) missense mutation in CASK causes FGS phenotype in an Italian family previously mapped to Xp11.4-p11.3 (FGS4). The identified missense mutation cosegregates with the phenotype in this family and is absent in 1000 control X chromosomes of the same ethnic origin. An extensive analysis of CASK protein functions as well as structural and dynamic studies performed by molecular dynamics (MD) simulation did not reveal significant alterations induced by the p.R28L substitution. However, we observed a partial skipping of the exon 2 of CASK, presumably a consequence of improper recognition of exonic splicing enhancers (ESEs) induced by the c.83G→T transversion. CASK is a multidomain scaffold protein highly expressed in the central nervous system (CNS) with specific localization to the synapses, where it forms large signaling complexes regulating neurotransmission. We suggest that the observed phenotype is most likely a consequence of an altered CASK expression profile during embryogenesis, brain development, and differentiation. PMID:19200522

  4. Juvenile paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation.

    PubMed

    Saki, Forough; Karamizadeh, Zohreh; Nasirabadi, Shiva; Mumm, Steven; McAlister, William H; Whyte, Michael P

    2013-06-01

    Juvenile Paget's disease (JPD) is a rare heritable osteopathy characterized biochemically by markedly increased serum alkaline phosphatase (ALP) activity emanating from generalized acceleration of skeletal turnover. Affected infants and children typically suffer bone pain and fractures and deformities, become deaf, and have macrocranium. Some who survive to young adult life develop blindness from retinopathy engendered by vascular microcalcification. Most cases of JPD are caused by osteoprotegerin (OPG) deficiency due to homozygous loss-of-function mutations within the TNFRSF11B gene that encodes OPG. We report a 3-year-old Iranian girl with JPD and craniosynostosis who had vitamin D deficiency in infancy. She presented with fractures during the first year-of-life followed by bone deformities, delayed development, failure-to-thrive, and pneumonias. At 1 year-of-age, biochemical studies of serum revealed marked hyperphosphatasemia together with low-normal calcium and low inorganic phosphate and 25-hydroxyvitamin D levels. Several family members in previous generations of this consanguineous kindred may also have had JPD and vitamin D deficiency. Mutation analysis showed homozygosity for a unique missense change (c.130T>C, p.Cys44Arg) in TNFRSF11B that would compromise the cysteine-rich domain of OPG that binds receptor activator of NF-κB ligand (RANKL). Both parents were heterozygous for this mutation. The patient's serum OPG level was extremely low and RANKL level markedly elevated. She responded well to rapid oral vitamin D repletion followed by pamidronate treatment given intravenously. Our patient is the first Iranian reported with JPD. Her novel mutation in TNFRSF11B plus vitamin D deficiency in infancy was associated with severe JPD uniquely complicated by craniosynostosis. Pamidronate treatment with vitamin D sufficiency can be effective therapy for the skeletal disease caused by the OPG deficiency form of JPD. PMID:23322328

  5. Middle East Respiratory Syndrome Coronavirus Transmission in Extended Family, Saudi Arabia, 2014

    PubMed Central

    Arwady, M. Allison; Alraddadi, Basem; Basler, Colin; Azhar, Esam I.; Abuelzein, Eltayb; Sindy, Abdulfattah I.; Sadiq, Bakr M. Bin; Althaqafi, Abdulhakeem O.; Shabouni, Omaima; Banjar, Ayman; Haynes, Lia M.; Gerber, Susan I.; Feikin, Daniel R.

    2016-01-01

    Risk factors for human-to-human transmission of Middle East respiratory syndrome coronavirus (MERS-CoV) are largely unknown. After MERS-CoV infections occurred in an extended family in Saudi Arabia in 2014, relatives were tested by using real-time reverse transcription PCR (rRT-PCR) and serologic methods. Among 79 relatives, 19 (24%) were MERS-CoV positive; 11 were hospitalized, and 2 died. Eleven (58%) tested positive by rRT-PCR; 8 (42%) tested negative by rRT-PCR but positive by serology. Compared with MERS-CoV–negative adult relatives, MERS-CoV–positive adult relatives were older and more likely to be male and to have chronic medical conditions. Risk factors for household transmission included sleeping in an index patient’s room and touching respiratory secretions from an index patient. Casual contact and simple proximity were not associated with transmission. Serology was more sensitive than standard rRT-PCR for identifying infected relatives, highlighting the value of including serology in future investigations. PMID:27191038

  6. Clinical, biochemical and molecular analysis of two infants with familial chylomicronemia syndrome.

    PubMed

    Zhang, Yonghong; Zhou, Jing; Zheng, Wenxin; Lan, Zhangzhang; Huang, Zhiwei; Yang, Qingnan; Liu, Chengbo; Gao, Rui; Zhang, Yongjun

    2016-01-01

    Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disease due mainly to inherited deficiencies in the proteins or enzymes involved in the clearance of triglycerides from circulation. It usually happens in late childhood and adolescence, which can have serious consequences if misdiagnosed or untreated. In the present study, we investigated two Chinese male babies (A and B), 30d and 48d in age, respectively, who have milky plasma. Clinical, biochemical, and radiological assessments were performed, while samples from the patients were referred for molecular diagnosis, including genetic testing and subsequent analysis of related genes. The fasting serum lipids of the two patients showed extreme lipid abnormalities. Through a low-lipid formula diet including skimmed milk and dietary advice, their plasma lipid levels were significantly lower and more stable at the time of hospital discharge. The genetic testing revealed compound heterozygote mutations in the lipoprotein lipase (LPL) gene for patient A and two known compound heterozygote LPL gene mutations for the patient B. FCS is the most dramatic example of severe hypertriglyceridemia. Early diagnosis and timely dietary intervention is very important for affected children. PMID:27153815

  7. Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome.

    PubMed

    Hulle, Severine Van; Craen, Margarita; Callewaert, Bert; Joustra, Sjoerd; Oostdijk, Wilma; Losekoot, Monique; Wit, Jan Maarten; Turgeon, Marc Olivier; Bernard, Daniel J; Schepper, Jean De

    2016-03-01

    Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro-orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency. PMID:26757742

  8. A novel nonsense GPSM2 mutation in a Yemeni family underlying Chudley-McCullough syndrome.

    PubMed

    Hamzeh, Abdul Rezzak; Nair, Pratibha; Mohamed, Madiha; Saif, Fatima; Tawfiq, Nafisa; Al-Ali, Mahmoud Taleb; Bastaki, Fatma

    2016-06-01

    Mutations in the G Protein Signaling Modulator 2 (GPSM2) cause the autosomal recessive disorder Chudley-McCullough syndrome (CMS), which is characterized by profound congenital sensorineural hearing loss with various abnormalities in the brain. This phenotypic combination is attributed to the role played by GPSM2 in the establishment of planar polarity and spindle orientation during asymmetric cell divisions. Here we present two brothers from a Yemeni family who were diagnosed clinically with CMS then tested for GPSM2 mutations using Sanger sequencing. Consequent to sequencing, in silico tools (such as CADD) were utilized to assess functional consequences. Molecular analysis revealed a previously unreported homozygous mutation in GPSM2 in both brothers (c.1055C > A) leading to a truncating protein change; (p.Ser352*). This mutation is predicted to abolish all four GoLoco domains in GPSM2 and this explains the bioinformatic prediction for this mutation to be functionally damaging. Full clinical and molecular accounts of the novel mutation are provided in this paper. PMID:27180139

  9. Dubin-Johnson syndrome with multiple liver cavernous hemangiomas: report of a familial case

    PubMed Central

    Li, Peifeng; Wang, Yingmei; Zhang, Jinmei; Geng, Ming; Li, Zengshan

    2013-01-01

    Dubin-Johnson syndrome (DJS) is a rare autosomal recessive inheritance disorder of bilirubin metabolism. Herein we reported a complicated but interesting case which is readily resulted in misdiagnosis or an indefinite diagnosis, and this is the first reported familial case of DJS with multiple liver cavernous hemangiomas. A 49-year-old man was referred to our hospital for jaundice and multiple low-density liver masses. Extensive laboratory investigations showed conjugated hyperbilirubinaemia and positive urine bilirubin. Microscopically, lesions were composed of blood-filled vascular channels of various sizes lined by a single layer of flat endothelial cells supported by fibrous tissue. Coarse brown granules presented in the hepatocytes of the liver lobules locating beside the tumor, particularly in the centrilobular hepatocytes, and the granules showed blue-green with Schmorl’s reaction lipofuscin staining. Interestingly, one of the patient’s six siblings (female) shared the same condition with him. The relationship between DJS and hemangiomas remains unclear, and it might be contributed to some hereditary factors, or probably occurred simultaneously by chance. It was certified that the true reason for the long-term unclear jaundice was DJS, which was presumed clinically to be caused by bile excretion obstacles associated with the hemangiomas. Liver biopsy and histochemical stain may be helpful to identify the reason of jaundice and avoid misdiagnosis or an indefinite diagnosis. PMID:24228133

  10. Family-based analysis of eight susceptibility loci in polycystic ovary syndrome

    PubMed Central

    Zhao, Shigang; Tian, Ye; Gao, Xuan; Zhang, Xiuqing; Liu, Hongbin; You, Li; Cao, Yongzhi; Su, Shizhen; Chan, Wai-Yee; Sun, Yun; Zhao, Han; Chen, Zi-Jiang

    2015-01-01

    Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that is proposed to have a genetic basis. A recent genome-wide association study (GWAS) identified eight new risk loci that are independently associated with PCOS. To further validate the findings, a total of 321 case-parent trios (963 participants) who had a proband affected with PCOS were recruited for the family-based study. The transmission disequilibrium test (TDT) was used to analyze associations between PCOS and ten single nucleotide polymorphisms (SNPs) mapped to eight new susceptibility loci. Significant differences in transmission were observed for the SNPs rs2349415 (located in the FSHR gene, P = 0.0001) and rs3802457 (located in the C9orf3 gene, P = 0.0001), even after correction for multiple testing bias. The present data provides further evidence for an association between two susceptibility loci, 2p16.3 and 9q22.32, and PCOS. Follow-up functional studies on the FSHR and C9orf3 genes are required to understand their roles in PCOS development. PMID:26220222

  11. Delayed Adrenarche may be an Additional Feature of Immunoglobulin Super Family Member 1 Deficiency Syndrome

    PubMed Central

    Hulle, Severine Van; Craen, Margarita; Callewaert, Bert; Joustra, Sjoerd; Oostdijk, Wilma; Losekoot, Monique; Wit, Jan Maarten; Turgeon, Marc Olivier; Bernard, Daniel J.; Schepper, Jean De

    2016-01-01

    Immunoglobulin super family member 1 (IGSF1) deficiency syndrome is characterized by central hypothyroidism, delayed surge in testosterone during puberty, macro-orchidism, and in some cases, hypoprolactinemia and/or transient growth hormone (GH) deficiency. Our patient was a 19-year-old male adolescent who had been treated since the age of 9 years with GH and thyroxine for an idiopathic combined GH, thyroid-stimulating hormone (TSH), and prolactin (PRL) deficiency. His GH deficiency proved to be transient, but deficiencies of TSH and PRL persisted, and he had developed macro-orchidism since the end of puberty. Brain magnetic resonance imaging and PROP1 and POU1F1 sequencing were normal. A disharmonious puberty (delayed genital and pubic hair development, bone maturation, and pubertal growth spurt, despite normal testicular growth) was observed as well as a delayed adrenarche, as reflected by very low dehydroepiandrosterone sulfate and delayed pubarche. Direct sequencing of the IGSF1 gene revealed a novel hemizygous mutation, c.3127T>C, p.Cys1043Arg. Pathogenicity of the mutation was demonstrated in vitro. Male children with an idiopathic combined GH, PRL, and TSH deficiency, showing persistent central hypothyroidism but transient GH deficiency upon retesting at adult height, should be screened for mutations in the IGSF1 gene, especially when macro-orchidism and/or hypoprolactinemia are present. We suspect that delayed adrenarche, as a consequence of PRL deficiency, might be part of the clinical phenotype of patients with IGSF1 deficiency. PMID:26757742

  12. Unified Modeling of Familial Mediterranean Fever and Cryopyrin Associated Periodic Syndromes.

    PubMed

    Bozkurt, Yasemin; Demir, Alper; Erman, Burak; Gül, Ahmet

    2015-01-01

    Familial mediterranean fever (FMF) and Cryopyrin associated periodic syndromes (CAPS) are two prototypical hereditary autoinflammatory diseases, characterized by recurrent episodes of fever and inflammation as a result of mutations in MEFV and NLRP3 genes encoding Pyrin and Cryopyrin proteins, respectively. Pyrin and Cryopyrin play key roles in the multiprotein inflammasome complex assembly, which regulates activity of an enzyme, Caspase 1, and its target cytokine, IL-1β. Overproduction of IL-1β by Caspase 1 is the main cause of episodic fever and inflammatory findings in FMF and CAPS. We present a unifying dynamical model for FMF and CAPS in the form of coupled nonlinear ordinary differential equations. The model is composed of two subsystems, which capture the interactions and dynamics of the key molecular players and the insults on the immune system. One of the subsystems, which contains a coupled positive-negative feedback motif, captures the dynamics of inflammation formation and regulation. We perform a comprehensive bifurcation analysis of the model and show that it exhibits three modes, capturing the Healthy, FMF, and CAPS cases. The mutations in Pyrin and Cryopyrin are reflected in the values of three parameters in the model. We present extensive simulation results for the model that match clinical observations. PMID:26161132

  13. Brown-Vialetto-Van Laere syndrome in a large inbred Lebanese family: confirmation of autosomal recessive inheritance?

    PubMed

    Mégarbané, A; Desguerres, I; Rizkallah, E; Delague, V; Nabbout, R; Barois, A; Urtizberea, A

    2000-05-15

    Brown-Vialetto-Van Laere syndrome or pontobulbar palsy with deafness is a rare disorder characterized by bilateral nerve deafness, a variety of cranial nerve disorders usually involving the motor components of the 7th and 9th to 12th cranial nerves, and less commonly an involvement of spinal motor nerves and upper motor neurons. Familial and sporadic cases have been reported. Based on particular evidence, autosomal recessive, autosomal dominant, and X-linked inheritance, as well as autoimmune origin have been considered. We report on a large inbred Lebanese family with four patients of both sexes, strongly suggesting autosomal recessive inheritance. PMID:10797435

  14. Complete androgen insensitivity syndrome associated with male gender identity or female precocious puberty in the same family.

    PubMed

    Bermúdez de la Vega, José A; Fernández-Cancio, Mónica; Bernal, Susana; Audí, Laura

    2015-01-01

    In 4 complete androgen insensitivity syndrome (CAIS) members of one family, 2 presented extreme and unusual clinical features: male gender identity disorder (case 1) and female precocious central puberty (case 2). The AR gene carried the mutation c.1752C>G, p.Phe584Leu. Gender dysphoria in CAIS may be considered as a true transgender and has been described in 3 other cases. Central precocious puberty has only been described in 1 case; Müllerian ducts in case 2 permitted menarche. Despite the common CAIS phenotype, there was a familial disparity for gender identity adequacy and timing and type of puberty. PMID:25633053

  15. Characterization of seven novel mutations of the c-erbA beta gene in unrelated kindreds with generalized thyroid hormone resistance. Evidence for two "hot spot" regions of the ligand binding domain.

    PubMed Central

    Parrilla, R; Mixson, A J; McPherson, J A; McClaskey, J H; Weintraub, B D

    1991-01-01

    Genetic analysis in our laboratory of families with generalized thyroid hormone resistance (GTHR) has demonstrated tight linkage with a locus, c-erbA beta, encoding a nuclear T3 receptor. Three point mutations and two deletions in this locus have previously been reported in affected individuals in unrelated families as potential molecular bases for this disorder. In the present study, we have used direct sequencing of polymerase chain reaction-amplified exons of the c-erbA beta gene to rapidly identify novel point mutations from seven previously uncharacterized kindreds with GTHR. Six single base substitutions and one single base insertion were identified and found to be clustered in two regions of exons 9 and 10 in the ligand binding domain of the receptor: in the distal ligand-binding subdomain L2 and across the juncture of the taui and dimerization subdomains. Reduction of T3-binding affinity in each of four mutations tested as well as segregation of all mutations to clinically affected individuals strongly supports the hypothesis that these changes are the cause of GTHR in these kindreds. In view of the diversity of clinical phenotypes manifested, the distinct topographic clustering of the mutations provides an invaluable genetic tool for the molecular dissection of thyroid receptor function. Images PMID:1661299

  16. Changes in Occupational Employment in the Food and Kindred Products Industry, 1977-1980. Technical Note No. 1.

    ERIC Educational Resources Information Center

    Lewis, Gary

    The extent to which occupational staffing patterns change over time was examined in a study focusing on the Food and Kindred Products industry--Standard Industrial Classification (SIC) 20. Data were taken from the 1977 and 1980 Occupational Employment Statistics program coordinated by the United States Department of Labor Statistics. Actual 1980…

  17. PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib.

    PubMed

    Arts, F A; Chand, D; Pecquet, C; Velghe, A I; Constantinescu, S; Hallberg, B; Demoulin, J-B

    2016-06-23

    Recently, germline and somatic heterozygous mutations in the platelet-derived growth factor receptor β (PDGFRB) have been associated with familial infantile myofibromatosis (IM), which is characterized by soft tissue tumors, and overgrowth syndrome, a disease that predisposes to cancer. These mutations have not been functionally characterized. In the present study, the activity of three PDGFRB mutants associated with familial IM (R561C, P660T and N666K) and one PDGFRB mutant found in patients with overgrowth syndrome (P584R) was tested in various models. The P660T mutant showed no difference with the wild-type receptor, suggesting that it might represent a polymorphic variant unrelated to the disease. By contrast, the three other mutants were constitutively active and able to transform NIH3T3 and Ba/F3 cells to different extents. In particular, the germline mutant identified in overgrowth syndrome, P584R, was a stronger oncogene than the germline R561C mutant associated with myofibromatosis. The distinct phenotypes associated with these two mutations could be related to this difference of potency. Importantly, all activated mutants were sensitive to tyrosine kinase inhibitors such as imatinib, nilotinib and ponatinib. In conclusion, the PDGFRB mutations previously identified in familial IM and overgrowth syndrome activate the receptor in the absence of ligand, supporting the hypothesis that these mutations cause the diseases. Moreover, imatinib seems to be a promising treatment for patients carrying these mutations. To our knowledge, these are the first confirmed gain-of-function point mutations of PDGFRB in human cancer. PMID:26455322

  18. Obesity and its association with generalised epilepsy, idiopathic syndrome, and family history of epilepsy.

    PubMed

    Ladino, Lady D; Hernández-Ronquillo, Lizbeth; Téllez-Zenteno, José F

    2014-09-01

    Aim. Previous studies support the concept that obesity is a common comorbid condition in patients with epilepsy (PWE). In this study, we present the body mass index (BMI) and data from a survey to assess physical activity in a sample of PWE from an epilepsy clinic. Methods. Between June of 2011 and January of 2013, 100 PWE from an adult epilepsy clinic were included. We obtained BMI, waist circumference, and information regarding physical activity using a standardised questionnaire. Clinical, demographic, electrographic, and imaging parameters were collected from charts. Results. Mean age of patients was 40 ± 14 (18-77) years. The BMI distribution was as follows: 2 patients (2%) underweight, 26 (26%) normal weight, 34 (34%) overweight, 25 (25%) obese, and 13 (13%) with morbid obesity. In our study, obesity was defined as having a BMI ≥ 30. We found 38 (38%) patients in this range. There was no difference in the rate of drug-resistant epilepsy between obese and non-obese patients (55 vs. 55%; p=0.05). Leisure time habit was reported in 82% of obese patients and 79% of patients without obesity. Overall, the most frequent activity was walking (70%). Factors associated with obesity were generalised epilepsy (OR: 2.7, 1.1-6.6; p=0.012), idiopathic syndrome (OR: 2.7, 1.04-7; p=0.018), and family history of epilepsy (OR: 6.1, 1.5-24.2; p=0.002). Conclusion. Our study suggests an association between obesity, idiopathic generalised epilepsy, and family history of epilepsy. Our study shows that PWE are physically active and there is no clear relation between exercise and obesity. We could not identify any association between drug-resistant epilepsy and obesity. Absence of direct comparison with a control non-epileptic population; a cross-sectional design not allowing evaluation of a causal association among variables; and reliance on self-reported physical activity are to be considered as limitations of the present study. PMID:25179745

  19. Genetic analysis, in silico prediction, and family segregation in long QT syndrome.

    PubMed

    Riuró, Helena; Campuzano, Oscar; Berne, Paola; Arbelo, Elena; Iglesias, Anna; Pérez-Serra, Alexandra; Coll-Vidal, Mònica; Partemi, Sara; Mademont-Soler, Irene; Picó, Ferran; Allegue, Catarina; Oliva, Antonio; Gerstenfeld, Edward; Sarquella-Brugada, Georgia; Castro-Urda, Víctor; Fernández-Lozano, Ignacio; Mont, Lluís; Brugada, Josep; Scornik, Fabiana S; Brugada, Ramon

    2015-01-01

    The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality. PMID:24667783

  20. Genetic analysis, in silico prediction, and family segregation in long QT syndrome

    PubMed Central

    Riuró, Helena; Campuzano, Oscar; Berne, Paola; Arbelo, Elena; Iglesias, Anna; Pérez-Serra, Alexandra; Coll-Vidal, Mònica; Partemi, Sara; Mademont-Soler, Irene; Picó, Ferran; Allegue, Catarina; Oliva, Antonio; Gerstenfeld, Edward; Sarquella-Brugada, Georgia; Castro-Urda, Víctor; Fernández-Lozano, Ignacio; Mont, Lluís; Brugada, Josep; Scornik, Fabiana S; Brugada, Ramon

    2015-01-01

    The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality. PMID:24667783

  1. Two familial cases of Olmsted-like syndrome with a G573V mutation of the TRPV3 gene.

    PubMed

    Zhi, Y P; Liu, J; Han, J W; Huang, Y P; Gao, Z Q; Yang, Y; Wu, R N

    2016-07-01

    Olmsted syndrome (OS) is a rare disease, characterized by symmetrical, sharply defined, hyperkeratotic, mutilating plaques on the palms and soles, which are associated with periorificial keratotic plaques. Other clinical manifestations of OS include diffuse alopecia, leucokeratosis of the oral mucosa, onychodystrophy, hyperkeratotic linear streaks, follicular hyperkeratosis and constriction of the digits. A recent study identified de novo mutations in the gene for transient receptor potential vanilloid 3 (TRPV3), causing constitutive activation of the TRPV3 channel, as a cause of OS. We report familial inheritance of OS in a family from Mongolia, which was caused by a previously undescribed G573V point mutation in TRPV3. To date, mutations in the G573 residue of TRPV3 have been reported in seven cases of OS: G573S in five cases, and G573C and G573A mutations in one case each. We present a Mongolian familial case of G573V point mutation in TRPV3. PMID:27273692

  2. A novel deletion in ZBTB24 in a Lebanese family with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2.

    PubMed

    Chouery, E; Abou-Ghoch, J; Corbani, S; El Ali, N; Korban, R; Salem, N; Castro, C; Klayme, S; Azoury-Abou Rjeily, M; Khoury-Matar, R; Debo, G; Germanos-Haddad, M; Delague, V; Lefranc, G; Mégarbané, A

    2012-11-01

    The immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a rare autosomal recessive disease characterized by targeted chromosome breakage, directly related to a genomic methylation defect. It manifests with phenotypic and clinical variability, with the most consistent features being developmental delay, facial anomalies, cytogenetic defects and immunodeficiency with a reduction in serum immunoglobulin levels. From the molecular point of view, ICF syndrome was always divided into ICF type I (ICF1) and ICF type 2 (ICF2). Mutations in DNMT3B gene are responsible for ICF1, while mutations in ZBTB24 have been reported to be responsible for ICF2. In this study, we describe a Lebanese family with three ICF2 affected brothers. Sanger sequencing of the coding sequence of ZBTB24 gene was conducted and revealed a novel deletion: c.396_397delTA (p.His132Glnfs*19), resulting in a loss-of-function of the corresponding protein. ZBTB24 belongs to a large family of transcriptional factors and may be involved in DNA methylation of juxtacentromeric DNA. Detailed molecular and functional studies of the ZBTB24 and DNMT3B genes are needed to understand the pathophysiology of ICF syndrome. PMID:21906047

  3. Loss-of-Function FERMT1 Mutations in Kindler Syndrome Implicate a Role for Fermitin Family Homolog-1 in Integrin Activation

    PubMed Central

    Lai-Cheong, Joey E.; Parsons, Maddy; Tanaka, Akio; Ussar, Siegfried; South, Andrew P.; Gomathy, Sethuraman; Mee, John B.; Barbaroux, Jean-Baptiste; Techanukul, Tanasit; Almaani, Noor; Clements, Suzanne E.; Hart, Ian R.; McGrath, John A.

    2009-01-01

    Kindler syndrome is an autosomal recessive disorder characterized by skin atrophy and blistering. It results from loss-of-function mutations in the FERMT1 gene encoding the focal adhesion protein, fermitin family homolog-1. How and why deficiency of fermitin family homolog-1 results in skin atrophy and blistering are unclear. In this study, we investigated the epidermal basement membrane and keratinocyte biology abnormalities in Kindler syndrome. We identified altered distribution of several basement membrane proteins, including types IV, VII, and XVII collagens and laminin-332 in Kindler syndrome skin. In addition, reduced immunolabeling intensity of epidermal cell markers such as β1 and α6 integrins and cytokeratin 15 was noted. At the cellular level, there was loss of β4 integrin immunolocalization and random distribution of laminin-332 in Kindler syndrome keratinocytes. Of note, active β1 integrin was reduced but overexpression of fermitin family homolog-1 restored integrin activation and partially rescued the Kindler syndrome cellular phenotype. This study provides evidence that fermitin family homolog-1 is implicated in integrin activation and demonstrates that lack of this protein leads to pathological changes beyond focal adhesions, with disruption of several hemidesmosomal components and reduced expression of keratinocyte stem cell markers. These findings collectively provide novel data on the role of fermitin family homolog-1 in skin and further insight into the pathophysiology of Kindler syndrome. PMID:19762710

  4. Partial deletion of TCF4 in three generation family with non-syndromic intellectual disability, without features of Pitt-Hopkins syndrome.

    PubMed

    Kharbanda, Mira; Kannike, Kaja; Lampe, Anne; Berg, Jonathan; Timmusk, Tõnis; Sepp, Mari

    2016-06-01

    Mutations in TCF4 (basic helix-loop-helix transcription factor 4), a gene with complex organization and multiple transcription initiation sites, are usually associated with Pitt-Hopkins syndrome (PTHS). However, a translocation encompassing the 5' end of TCF4 and several point mutations have been linked to non-syndromic intellectual disability (NSID). Here we describe a family with autosomal dominantly inherited NSID in seven relatives with a partial deletion of TCF4, disrupting the 5' end of the gene, predicted to result in the reduction of the number of mRNAs that can be produced by alternative transcription initiation. Functional studies indicate that it leads to reduced levels of transcripts coding for TCF4 protein isoforms with a nuclear localization signal, which may be relevant to the phenotype. The findings in our family support the notion that the position of the mutation in TCF4 is relevant to the phenotype, with those mutations in the 5' region, cassette exons and regions not affecting the important functional domains being linked to NSID rather than PTHS. We suggest that screening for mutations in TCF4 could be considered in the investigation of NSID. PMID:27132474

  5. Translocations involving 4p16.3 in three families: deletion causing the Pitt-Rogers-Danks syndrome and duplication resulting in a new overgrowth syndrome.

    PubMed Central

    Partington, M W; Fagan, K; Soubjaki, V; Turner, G

    1997-01-01

    Three families are reported who have a translocation involving 4p16.3. Nine subjects are described with the clinical features of the Pitt-Rogers-Danks (PRD) syndrome confirming pre- and postnatal growth failure, microcephaly, severe mental retardation, seizures, and a distinctive facial appearance; a deletion of 4p16.3 was seen in all eight patients studied with fluorescence in situ hybridisation (FISH). Eleven subjects had a new syndrome with physical overgrowth, heavy facial features, and mild to moderate mental handicap; a duplication of the chromosome region 4p16.3 was found in the four subjects studied. It is suggested that the growth abnormalities in these two families may be explained by a dosage effect of the fibroblast growth factor receptor gene 3 (FGFR3), which is located at 4p16.3, that is, a single dose leads to growth failure and a triple dose to physical overgrowth. We describe the molecular mapping of the translocation breakpoint and define it to within locus D4S43. Images PMID:9321756

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

    PubMed

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

    2016-07-01

    Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive disorder, which is characterized by congenital cataracts, cerebellar ataxia, progressive muscle weakness, and delayed psychomotor development. SIL1, which is located at 5q31.2, is the only gene known to cause MSS. Dandy-Walker syndrome (DWS) is defined by hypoplasia, upward rotation of the cerebellar vermis, and cystic dilation of the fourth ventricle; however, its genetic pathogeny remains unclear. Here, we report a Chinese consanguineous family with MSS and DWS. Whole exome sequencing identified a novel nonstop mutation in SIL1. Sanger sequencing revealed that the mutation was segregated in this family according to a recessive mode of inheritance. We found that the mutation changed a stop codon (TGA) to an arginine codon (CGA), and no in-frame termination codon in the 3' untranslated region (UTR) of SIL1 could be found. The mRNA levels of SIL1 were decreased by 56.6% and 37.5% in immortalized lymphoblasts of the patients respectively; the protein levels of SIL1 were substantially decreased. This case study is the first report on Chinese MSS patients, MSS complicated by DWS, and a nonstop mutation in SIL1. Our findings imply the pathogenetic association between DWS and MSS. PMID:27106665

  7. Progress in a genome scan for linkage in schizophrenia in a large Swedish kindred

    SciTech Connect

    Barr, C.L.; Kennedy, J.L.; Pakstis, A.J.

    1994-03-15

    Genetic linkage studies of a kindred from Sweden segregating for schizophrenia have been performed using a genetic model (autosomal dominant, f - 0.72, q - 0.02, phenocopies=0.001) as described in Kennedy et al., 1988. Analyses of the restriction fragment length polymorphism (RFLP), allele-specific oligonucleotides (ASO), and short tandem repeat (STR also called microsatellite) data for 180 polymorphisms (individual probe-enzyme, ASO, or STR systems) at 155 loci have been completed using the MLINK and LIPED programs. Linkage to schizophrenia was excluded, under the given model, at 47 loci; indeterminate lod scores occurred at 108 loci. The total exclusion region across 20 chromosomes is estimated at 330 cM; 211 cM excluded by pairwise analyses and 119 cM previously excluded by multipoint analyses. 37 refs., 2 tabs.

  8. 100th anniversary of Perusini's second case: patient RM and his kindred.

    PubMed

    Braun, Birgit; Stadlober-Degwerth, Marion; Hajak, Göran; Klünemann, Hans-Hermann

    2010-05-01

    The first 4 cases of Alzheimer's disease published by Alois Alzheimer's laboratory were authored by the young Italian physician Gaetano Perusini. In his discourse, ''Uber klinisch und histologisch eigenartige Erkrankungen des späteren Lebensalters'' Perusini describes 4 cases of histological and clinical findings of peculiar psychiatric diseases of older age. With regard to case number II, Perusini remarks ''since 1899 RM has psychically changed.'' As RM is said to be 45 years of age on admission, this would imply the obvious onset of disease at the early age of 37. A detailed analysis of archival material revealed that RM was actually 10 years older. Perusini's hint that ''one of the patient's brothers does not seem to be normal'' initiated our search for this individual to rule out an autosomal dominant inheritance in this kindred. We initiated genealogical studies over 8 generations to get more detailed information about this early case of psychiatric history. PMID:20392861

  9. Outcome in Adult Life for People with Williams Syndrome Results from a Survey of 239 Families

    ERIC Educational Resources Information Center

    Howlin, P.; Udwin, O.

    2006-01-01

    BACKGROUND: Although there has been considerable research into the genotype and phenotype of Williams syndrome, there have been relatively few studies of long-term prognosis. As a preliminary to a more detailed investigation of adults with Williams syndrome, a parental questionnaire was distributed to members of the UK Williams Syndrome…

  10. Living with Lowe's Syndrome. A Guide for Families, Friends, and Professionals.

    ERIC Educational Resources Information Center

    Lowe's Syndrome Association, Inc., West Lafayette, IN.

    The document describes Lowe's syndrome, a hereditary condition that affects only males and is typically diagnosed during the first year of life. Effects of Lowe's syndrome on the eyes (cataracts, glaucoma, corneal degeneration, and strabismus) are discussed, as well as related problems with the central nervous system, muscles, kidneys, bones, and…

  11. Tourette Syndrome: A Collaborative Approach Focused on Empowering Students, Families and Teachers

    ERIC Educational Resources Information Center

    Christner, Beth; Dieker, Lisa A.

    2008-01-01

    Tourette syndrome (TS) is a neurobiological disorder marked by a wide range of involuntary motor and vocal movements and sounds called "tics" (American Psychiatric Association, APA, 2000). This syndrome is frequently misunderstood and difficult to diagnose (Chamberlain, 2003). Recent television shows featuring the topic of TS such as "The Oprah…

  12. Stress, Locus of Control, and Family Cohesion and Adaptability in Parents of Children with Down, Williams, Fragile X, and Prader-Willi Syndromes

    ERIC Educational Resources Information Center

    Lanfranchi, Silvia; Vianello, Renzo

    2012-01-01

    The present study analyzes differences in parental stress in families of children with Down, Williams, Fragile X, and Prader-Willi syndromes, exploring factors that influence parental stress, such as child's characteristics, parental locus of control, and family cohesion and adaptability. Differences between mothers and fathers are also…

  13. Identification of a Novel Mutation in Solute Carrier Family 29, Member 3 in a Chinese Patient with H Syndrome

    PubMed Central

    Liu, Jia-Wei; Si, Nuo; Wang, Lian-Qing; Shen, Ti; Zeng, Xue-Jun; Zhang, Xue; Ma, Dong-Lai

    2015-01-01

    Background: H syndrome (OMIM 612391) is a recently described autosomal recessive genodermatosis characterized by indurated hyperpigmented and hypertrichotic skin, as well as other systemic manifestations. Most of the cases occurred in the Middle East areas or nearby countries such as Spain or India. The syndrome is caused by mutations in solute carrier family 29, member 3 (SLC29A3), the gene encoding equilibrative nucleoside transporter 3. The aim of this study was to identify pathogenic SLC29A3 mutations in a Chinese patient clinically diagnosed with H syndrome. Methods: Peripheral blood samples were collected from the patient and his parents. Genomic DNA was isolated by the standard method. All six SLC29A3 exons and their flanking intronic sequences were polymerase chain reaction (PCR)-amplified and the PCR products were subjected to direct sequencing. Results: The patient, an 18-year-old man born to a nonconsanguineous Chinese couple, had more extensive cutaneous lesions, involving both buttocks and knee. In his genomic DNA, we identified a novel homozygous insertion-deletion, c. 1269_1270delinsA, in SLC29A3. Both of his parents were carriers of the mutation. Conclusions: We have identified a pathogenic mutation in a Chinese patient with H syndrome. PMID:25963354

  14. X-exome sequencing in Finnish families with Intellectual Disability - four novel mutations and two novel syndromic phenotypes

    PubMed Central

    2014-01-01

    Background X-linked intellectual disability (XLID) is a group of genetically heterogeneous disorders characterized by substantial impairment in cognitive abilities, social and behavioral adaptive skills. Next generation sequencing technologies have become a powerful approach for identifying molecular gene mutations relevant for diagnosis. Methods & objectives Enrichment of X-chromosome specific exons and massively parallel sequencing was performed for identifying the causative mutations in 14 Finnish families, each of them having several males affected with intellectual disability of unknown cause. Results We found four novel mutations in known XLID genes. Two mutations; one previously reported missense mutation (c.1111C > T), and one novel frameshift mutation (c. 990_991insGCTGC) were identified in SLC16A2, a gene that has been linked to Allan-Herndon-Dudley syndrome (AHDS). One novel missense mutation (c.1888G > C) was found in GRIA3 and two novel splice donor site mutations (c.357 + 1G > C and c.985 + 1G > C) were identified in the DLG3 gene. One missense mutation (c.1321C > T) was identified in the candidate gene ZMYM3 in three affected males with a previously unrecognized syndrome characterized by unique facial features, aortic stenosis and hypospadia was detected. All of the identified mutations segregated in the corresponding families and were absent in > 100 Finnish controls and in the publicly available databases. In addition, a previously reported benign variant (c.877G > A) in SYP was identified in a large family with nine affected males in three generations, who have a syndromic phenotype. Conclusions All of the mutations found in this study are being reported for the first time in Finnish families with several affected male patients whose etiological diagnoses have remained unknown to us, in some families, for more than 30 years. This study illustrates the impact of X-exome sequencing to identify rare gene mutations

  15. The localization of a gene causing X-linked cleft palate and ankyloglossia (CPX) in an Icelandic kindred is between DXS326 and DXYS1X

    SciTech Connect

    Stainer, P.; Forbes, S.A.; Moore, G. ); Arnason, A.; Sveinbjornsdottir, E. ); Bjornsson, A. ); Williamson, R. )

    1993-09-01

    The locus responsible for X-linked, nonsyndromic cleft palate and/or ankyloglossia (CPX) has previously been mapped to the proximal long arm of the human X chromosome between Xq21.31 and q21.33 in an Icelandic kindred. The authors have extended these studies by analyzing an additional 14 informative markers in the family as well as including several newly investigated family members. Recombination analysis indicates that the CPX locus is more proximal than previously thought, within the interval Xq21.1-q21.31. Two recombinants place DXYS1X as the distal flanking marker, while one recombinant defines DXS326 as the proximal flanking marker, an interval of less than 5 cM. Each of the flanking markers recombines with the CPX locus, giving 2-point lod scores of Z[sub max] = 4.16 at [theta] = 0.08 (DXS326) and Z[sub max] = 5.80 at [theta] = 0.06 (DXYS1X). 35 refs., 3 figs., 2 tabs.

  16. Common ancestry of three Ashkenazi-American families with Alport syndrome and COL4A5 R1677Q.

    PubMed

    Barker, D F; Denison, J C; Atkin, C L; Gregory, M C

    1997-05-01

    Mutations in the basement membrane collagen gene COL4A5 cause the progressive renal glomerular nephropathy and typical hearing loss that occur in X-linked Alport syndrome. Nearly all cases involve distinct mutations, as expected for an X-linked disease that significantly reduces the fitness of affected males. A few exceptional COL4A5 mutations appear to be associated with a reduced disease severity and may account for a significant proportion of late-onset Alport syndrome in populations where a founder effect has occurred. The novel mutation reported here, COL4A5 arg1677gln, has been detected in three independently ascertained Ashkenazi-American families, causes a relatively mild form of nephritis with typical onset in the fourth or fifth decade, and may be involved in the etiology of a large proportion of adult-onset hereditary nephritis in Ashkenazi Jews. PMID:9150741

  17. Super-Transactivation TP53 Variant in the Germline of a Family with Li-Fraumeni Syndrome.

    PubMed

    Id Said, Badr; Kim, Han; Tran, James; Novokmet, Ana; Malkin, David

    2016-09-01

    Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant familial cancer syndrome, characterized by multiple malignancies and frequent germline alterations in TP53. In this study, we highlight four unclassified exonic TP53 variants detected in patients with a suspected diagnosis of LFS. Most intriguing was the discovery of a "super-transactivation" variant within Exon 10 of TP53 (c.1079G>T/p.G360V). Functional analysis of this novel variant revealed a paradoxical "super-transactivation" effect on tp53 response elements and a corresponding tumor suppressive effect on colony formation and apoptosis. While unlikely to be disease-causing, we propose that this variant may represent a novel tp53 polymorphism and potential phenotypic modifier in LFS. In the future, the enhanced transactivation effects of p.G360V-tp53 may also prove useful in designing more efficacious tp53-based gene therapies. PMID:27297285

  18. Identical by descent L1CAM mutation in two apparently unrelated families with intellectual disability without L1 syndrome.

    PubMed

    Shaw, Marie; Yap, Tzu Ying; Henden, Lyndal; Bahlo, Melanie; Gardner, Alison; Kalscheuer, Vera M; Haan, Eric; Christie, Louise; Hackett, Anna; Gecz, Jozef

    2015-01-01

    Mutations in the L1 Cell Adhesion Molecule (L1CAM) gene (MIM#308840) cause a variety of X-linked recessive neurological disorders collectively called L1 syndrome. Using massively parallel sequencing (MPS) of the X-chromosome exome, we identified a novel missense variant in L1CAM in two Caucasian families with mild-moderate intellectual disability without obvious L1 syndrome features. These families were not known to be related. SNP data extracted from MPS identified a 5.6 cM tract of identity by descent (IBD), encompassing the L1CAM gene, between the DNA of the two probands. This cannot be explained by chance alone and strongly implies that the two families are related. It also suggests that the L1CAM (NM_000425.3, c.604G > A, p.D202N) variant is pathogenic. This report also demonstrates the usefulness of additional information, which can be extracted from exome sequencing data. PMID:25934484

  19. Fryns Syndrome Associated with Recessive Mutations in PIGN in two Separate Families.

    PubMed

    McInerney-Leo, Aideen M; Harris, Jessica E; Gattas, Michael; Peach, Elizabeth E; Sinnott, Stephen; Dudding-Byth, Tracy; Rajagopalan, Sulekha; Barnett, Christopher P; Anderson, Lisa K; Wheeler, Lawrie; Brown, Matthew A; Leo, Paul J; Wicking, Carol; Duncan, Emma L

    2016-07-01

    Fryns syndrome is an autosomal recessive condition characterized by congenital diaphragmatic hernia (CDH), dysmorphic facial features, distal digital hypoplasia, and other associated malformations, and is the most common syndromic form of CDH. No gene has been associated with this condition. Whole-exome sequence data from two siblings and three unrelated individuals with Fryns syndrome were filtered for rare, good quality, coding mutations fitting a recessive inheritance model. Compound heterozygous mutations in PIGN were identified in the siblings, with appropriate parental segregation: a novel STOP mutation (c.1966C>T: p.Glu656X) and a rare (minor allele frequency <0.001) donor splice site mutation (c.1674+1G>C) causing skipping of exon 18 and utilization of a cryptic acceptor site in exon 19. A further novel homozygous STOP mutation in PIGN (c.694A>T: p.Lys232X) was detected in one unrelated case. All three variants affected highly conserved bases. The two remaining cases were negative for PIGN mutations. Mutations in PIGN have been reported in cases with multiple congenital anomalies, including one case with syndromic CDH. Fryns syndrome can be caused by recessive mutations in PIGN. Whether PIGN affects other syndromic and non-syndromic forms of CDH warrants investigation. PMID:27038415

  20. [Arduous navigation: the life story of a family raising a young child with Prader-Willi syndrome].

    PubMed

    Chen, I-Ju; Chou, Chih-Huey

    2007-06-01

    The purpose of this narrative research was to explore the life experience of a family with a son suffering from congenital Prader-Willi syndrome (PWS). Difficulties associated with raising a PWS child led the mother to leave the family with her afflicted son. The author analyzed the story of this family and applied metaphors to describe the course of the family's life in terms of a "navigational map of life". This map included the six components of: 1. Leaving port (sailing toward an unknown future); 2. Facing a tsunami (undergoing a trial from God); 3. Striking a reef (a fragile boat in a vast ocean); 4. Isolated on an island (the interdependent relationship between mother and child); 5. Transformation (adjustment and starting over); and 6. Hoisting the sails (staying to the course of making dreams come true). In this study, the researcher served as the nu rse case manager and interacted with family members to provide health care, consultation and support as needed. The mother of this young PWS child has empowered herself, overcome her suffering and prepared herself well to face the challenges of the future. PMID:17554668

  1. Family-based association study of the restless legs syndrome loci 2 and 3 in a European population.

    PubMed

    Kemlink, David; Polo, Olli; Montagna, Pasquale; Provini, Federica; Stiasny-Kolster, Karin; Oertel, Wolfgang; de Weerd, Al; Nevsimalova, Sona; Sonka, Karel; Högl, Birgit; Frauscher, Birgit; Poewe, Werner; Trenkwalder, Claudia; Pramstaller, Peter P; Ferini-Strambi, Luigi; Zucconi, Marco; Konofal, Eric; Arnulf, Isabelle; Hadjigeorgiou, Georgios M; Happe, Svenja; Klein, Christine; Hiller, Anja; Lichtner, Peter; Meitinger, Thomas; Müller-Myshok, Betram; Winkelmann, Juliane

    2007-01-15

    Three loci for the restless legs syndrome (RLS) on chromosomes 12q, 14q, and 9p (RLS1, RLS2, and RLS3) have been mapped, but no gene has been identified as yet. RLS1 has been confirmed in families from three different populations. We conducted a family-based association study of 159 European RLS trios. The subjects were genotyped using microsatellite markers evenly covering the candidate regions on chromosomes 14q and 9p with an average intermarker distance of 1.1 cM. Transmission disequilibrium tests were used to analyze the data, and empirical P values were estimated by permutation testing. On chromosome 14q, a significant association (empirical P = 0.0033) was found with a haplotype formed by markers D14S1014 and D14S1017 when analyzing all families. On chromosome 9p, no significant association in the sample of all families and only marginally significant associations were detected, with a haplotype involving markers D9S1846-D9S171 in a subset of South European trios and with a haplotype at D9S156-D9S157 in a subset of Central European trios (P = 0.0086 and 0.0077, respectively). These results represent the first confirmation of these loci in a mixed European population. Variable results observed in families of different ethnic groups further corroborate the genetic complexity of RLS. PMID:17133505

  2. Association of adiponectin promoter variants with traits and clusters of metabolic syndrome in Arabs: family-based study.

    PubMed

    Zadjali, F; Al-Yahyaee, S; Hassan, M O; Albarwani, S; Bayoumi, R A

    2013-09-25

    Plasma levels of adiponectin are decreased in type 2 diabetes, obesity and hypertension. Our aim was to use a family-based analysis to identify the genetic variants of the adiponectin (ADIPOQ) gene that are associated with obesity, insulin resistance, dyslipidemia and hypertension, among Arabs. We screened 328 Arabs in one large extended family for single nucleotide polymorphisms (SNPs) in the promoter region of the ADIPOQ gene. Two common SNPs were detected: rs17300539 and rs266729. Evidences of association between traits related to the metabolic syndrome and the SNPs were studied by implementing quantitative genetic association analysis. Results showed that SNP rs266729 was significantly associated with body weight (p-value=0.001), waist circumference (p-value=0.037), BMI (p-value=0.015) and percentage of total body fat (p-value=0.003). Up to 4.1% of heritability of obesity traits was explained by the rs266729 locus. Further cross-sectional analysis showed that carriers of the G allele had significantly higher values of waist circumference, BMI and percentage of total body fat (p-values 0.014, 0.004 and 0.032, respectively). No association was detected between SNP rs266729 and other clusters of metabolic syndrome or their traits except for HOMA-IR and fasting plasma insulin levels, p-values 0.035 and 0.004, respectively. In contrast, both measured genotype and cross-sectional analysis failed to detect an association between the SNP rs17300539 with traits and clusters of metabolic syndrome. In conclusion, we showed family-based evidence of association of SNP rs266729 at ADIPOQ gene with traits defining obesity in Arab population. This is important for future prediction and prevention of obesity in population where obesity is in an increasing trend. PMID:23845780

  3. Brugada syndrome and right ventricle morphofunctional abnormalities on echocardiography in young male with family anamnesis of sudden cardiac death.

    PubMed

    Steiner, Robert; Makarovic, Sandra; Makarovic, Zorin; Bilic-Curcic, Ines

    2014-03-01

    First presented by Brugada and Brugada in 1992, Brugada Syndrome (BrS) is a primary electrical disease of the heart that causes sudden cardiac death or life-threatening ventricular arrhythmias. This disease is hereditary autosomic dominant transmitted and genetically determined. The syndrome has been linked to mutations in SCN5A, the gene encoding for the a-subunit of the sodium channel. Electrocardiogram (ECG) abnormalities indicating Brugada syndrome, include repolarization and depolarization abnormalities in the absence of identifiable structural cardiac abnormalities or other conditions or agents known to lead to ST-segment elevation in the right precordial leads (V1-V3). Intravenous administration of sodium channel blocking drugs may modify the ECG pattern. Ajmaline, flecainide, procainamide and propafenone exaggerate the ST-segment elevation or unmask it when it is initially absent. An implantable cardioverter-defibrillator (ICD) is the only proven effective device treatment for the disease. Although BrS is primary electrical disease, some authors have suggested the presence of morphological and functional abnormalities mainly located in the right ventricle (RV), notably in the outflow tract (RVOT). In this short report we will present a young male, with predisposition and positive family history of sudden cardiac death, with complete diagnostic procedure including propafenon testing unmasking Brugada syndrome. An echosonography revealed dilated apical right ventricle, suggesting BrS is not only electrical disorder, but may include morphofunctional abnormalities, described in previous reports. In addition, we reviewed the possible connection between Brugada syndrome and morphological abnormalities in RV. PMID:24851643

  4. [Marinesco-Sjögren syndrome--report of two patients in a family with muscle CT study].

    PubMed

    Higuchi, S; Taku, K; Fukuhara, N; Hozumi, I; Yamazaki, M

    1993-01-01

    Two patients with Marinesco-Sjögren syndrome in a family were characterized by autosomal recessive inheritance, congenital cataract, cerebellar ataxia, mental retardation, short stature and variable skeletal abnormalities. Muscle biopsy specimens showed replacement of muscle fibers by fat and fibrous tissue, a marked variation of fiber size and a rimmed vacuole formation. Nerve biopsy specimens showed a reduced number of myelinated nerve fibers in the sural nerves. Muscle CT revealed atrophy of the quadriceps femoris, semitendinosus, gastrocnemius and soleus muscles. Accordingly, extensor muscles in the thighs were more preferentially involved than flexor muscles in the legs. PMID:8334784

  5. Lesch-Nyhan Syndrome in a Family with a Deletion Followed by an Insertion within the HPRT1 Gene.

    PubMed

    Nguyen, Khue Vu; Nyhan, William L

    2015-01-01

    Lesch-Nyhan syndrome (LNS) is a rare X-linked inherited neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase(HGprt) is defective. The authors report a novel mutation which led to LNS in a family with a deletion followed by an insertion (INDELS) via the serial replication slippage mechanism: c.428_432delTGCAGinsAGCAAA, p.Met143Lysfs*12 in exon 6 of HPRT1 gene. Molecular diagnosis discloses the genetic heterogeneity of HPRT1 gene responsible for HGprt deficiency. It allows fast, accurate carrier detection and genetic counseling. PMID:25965333

  6. A novel missense mutation in the NSDHL gene identified in a Lithuanian family by targeted next-generation sequencing causes CK syndrome.

    PubMed

    Preiksaitiene, Egle; Caro, Alfonso; Benušienė, Eglė; Oltra, Silvestre; Orellana, Carmen; Morkūnienė, Aušra; Roselló, Mónica Pilar; Kasnauskiene, Jurate; Monfort, Sandra; Kučinskas, Vaidutis; Mayo, Sonia; Martinez, Francisco

    2015-06-01

    The NSDHL gene encodes 3β-hydroxysteroid dehydrogenase involved in one of the later steps of the cholesterol biosynthetic pathway. Mutations in this gene can cause CHILD syndrome (OMIM 308050) and CK syndrome (OMIM 300831). CHILD syndrome is an X-linked dominant, male lethal disorder caused by mutations in the NSDHL gene that result in the loss of the function of the NSDHL protein. CK syndrome is an allelic X-linked recessive disorder. So far, 13 patients with CK syndrome from two families have been reported on. We present a new five-generation family with affected males manifesting clinical features of CK syndrome. Next generation sequencing was targeted to a custom panel of 542 genes with known or putative implication on intellectual disability. Missense mutation p.Gly152Asp was identified in the NSDHL gene in the DNA sample of the affected male. Mutation carrier status was confirmed for all the obligate carriers in the family. The clinical features of the affected males in the family manifested as weak fetal movements, severe intellectual disability, seizures, spasticity, atrophy of optic discs, microcephaly, plagiocephaly, skeletal abnormalities, and minor facial anomalies, including a high nasal bridge, strabismus, and micrognathia. A highly significant preferential transmission of the mutation was observed in this and previous families segregating CK syndrome. Our report expands the clinical spectrum of this syndrome to include weak fetal movements, spasticity, and plagiocephaly, and transmission ratio distortion. The various findings in these patients increase our understanding of the diversity of the clinical presentation of cholesterol biosynthesis disorders. PMID:25900314

  7. Families' Resources and Accommodations: Toddlers with Down Syndrome, Cerebral Palsy, and Developmental Delay

    ERIC Educational Resources Information Center

    Diamond, Karen E.; Kontos, Susan

    2004-01-01

    Constructing and maintaining a supportable daily routine is an important task for families with young children, particularly when the child has a disability. In this study, we examined relationships between children's developmental needs, disability diagnosis, and families' resources and accommodations. Participants included families with infants…

  8. The "Dance" of Communication: Counseling Families and Children with Asperger's Syndrome

    ERIC Educational Resources Information Center

    Lozzi-Toscano, Bettina

    2004-01-01

    Counselors are trained to deal with many issues within the realm of human experience; many specialize in helping families cope with a variety of internal and external stressors. However, counselors are seldom given all the tools to handle the myriad possible difficulties families may encounter. When counselors are asked to help families cope with…

  9. A comparison of salivary IgA in children with Down syndrome and their family members.

    PubMed

    Balaji, Karthika; Milne, Trudy J; Drummond, Bernadette K; Cullinan, Mary P; Coates, Dawn E

    2016-07-01

    The aim of this study was to compare total IgA in the whole saliva of children with Down syndrome with levels in sibling and parent groups. IgA measurements were presented as the concentration in saliva (μg/ml) and also adjusted for salivary flow rate (SFR; μg/min). Twenty children with Down syndrome, ten siblings and twenty parents were recruited. Stimulated whole saliva was collected from the participants and SFR calculated. The measurement of salivary IgA (sIgA) was carried out using an indirect competitive Enzyme-Linked Immunosorbent Assay. The difference in the mean SFR between children with Down syndrome, parents and siblings were not statistically significant. The mean salivary concentration of IgA was higher in children with Down syndrome (95.1μg/ml) compared with siblings (48.3μg/ml; p=0.004). When adjusted for SFR children with Down syndrome had mean sIgA levels of 98.8μg/min and the siblings 48.6μg/min (p=0.008). The children with Down syndrome had sIgA levels similar to those of the parents (92.5μg/ml; 93.2μg/min). There was a positive correlation between age and sIgA concentration in the siblings (p=0.008) but not for children with Down syndrome (p=0.363). This suggests that under similar environmental influences, the levels of sIgA in children with Down syndrome are higher than in the siblings, from a very young age. PMID:27023400

  10. How Do Families of Children with Down Syndrome Perceive Speech Intelligibility in Turkey?

    PubMed Central

    Toğram, Bülent

    2015-01-01

    Childhood verbal apraxia has not been identified or treated sufficiently in children with Down syndrome but recent research has documented that symptoms of childhood verbal apraxia can be found in children with Down syndrome. But, it is not routinely diagnosed in this population. There is neither an assessment tool in Turkish nor any research on childhood verbal apraxia although there is a demand not only for children with Down syndrome but also for normally developing children. The study examined if it was possible to determine oral-motor difficulties and childhood verbal apraxia features in children with Down syndrome through a survey. The survey was a parental report measure. There were 329 surveys received. Results indicated that only 5.6% of children with Down syndrome were diagnosed with apraxia, even though many of the subject children displayed clinical features of childhood verbal apraxia. The most frequently reported symptoms of childhood verbal apraxia in literature were displayed by the children with Down syndrome in the study. Parents could identify childhood verbal apraxia symptoms using parent survey. This finding suggests that the survey can be developed that could serve as a screening tool for a possible childhood verbal apraxia diagnosis in Turkey. PMID:25977925

  11. How do families of children with Down syndrome perceive speech intelligibility in Turkey?

    PubMed

    Toğram, Bülent

    2015-01-01

    Childhood verbal apraxia has not been identified or treated sufficiently in children with Down syndrome but recent research has documented that symptoms of childhood verbal apraxia can be found in children with Down syndrome. But, it is not routinely diagnosed in this population. There is neither an assessment tool in Turkish nor any research on childhood verbal apraxia although there is a demand not only for children with Down syndrome but also for normally developing children. The study examined if it was possible to determine oral-motor difficulties and childhood verbal apraxia features in children with Down syndrome through a survey. The survey was a parental report measure. There were 329 surveys received. Results indicated that only 5.6% of children with Down syndrome were diagnosed with apraxia, even though many of the subject children displayed clinical features of childhood verbal apraxia. The most frequently reported symptoms of childhood verbal apraxia in literature were displayed by the children with Down syndrome in the study. Parents could identify childhood verbal apraxia symptoms using parent survey. This finding suggests that the survey can be developed that could serve as a screening tool for a possible childhood verbal apraxia diagnosis in Turkey. PMID:25977925

  12. Familial Klippel-Feil syndrome and paracentric inversion inv(8)(q22.2q23.3)

    SciTech Connect

    Clarke, R.A.; Kearsley, J.H.; Singh, S.

    1995-12-01

    Klippel-Feil syndrome (KFS) is characterized by congenital vertebral fusion believed to result from faulty segmentation along the embryo`s developing axis. KFS appears to be a heterogeneous disease often associated with craniofacial malformation. Here we provide the first evidence of a familial KFS gene locus on 8q, where an inv(8)(q22.2q23.3) has been found segregating with congenital vertebral fusion. The four-generation KF2-01 family present with a dominant form of the KFS where the sequence of vertebral fusion was confined to the cervical spine (always including the C2-3 fusion and reduced expression of the C4-5 and C6-7 fusions) in association with malformation of laryngeal cartilages and mild-to-severe vocal impairment. 32 refs., 4 figs., 1 tab.

  13. Nonimmune fetal hydrops and placentomegaly: Diagnosis of familial Wiedemann-Beckwith syndrome with trisomy 11p15 using FISH

    SciTech Connect

    Drut, R.M.; Drut, R.

    1996-03-15

    We have studied a family in which four members of the same generation were affected with Wiedemann-Beckwith syndrome (WBS). Trisomy 11p15 was demonstrated using molecular probes in interphase nuclei of formalin-fixed paraffin-embedded placenta from a stillborn fetus and in peripheral blood lymphocytes from two liveborn female relatives. Clinical examination showed nonimmune hydrops and placentomegaly in two siblings and multiple phenotypic abnormalities consistent with WBS in the two other relatives. Paternal karyotype of the stillborn infants demonstrated a reciprocal translocation (46,XY,t(10;11) (q26;p15)) explaining the origin of the extra 11p15 material. This study illustrates the advantages of FISH for interphase analysis of chromosome aberrations otherwise not detected even by conventional cytogenetic analysis and documents that nonimmune hydrops associated with placentomegaly may be presenting features in familial WBS. 24 refs., 6 figs.

  14. Dominant Paternal Transmission of Cornelia de Lange Syndrome: A New Case and Review of 25 Previously Reported Familial Recurrences

    PubMed Central

    Russell, Karen L.; Ming, Jeffrey E.; Patel, Ketan; Jukofsky, Lori; Magnusson, Mark; Krantz, Ian D.

    2016-01-01

    The Cornelia de Lange syndrome (CdLS) is an autosomal dominant multisystem disorder characterized by somatic and cognitive retardation, characteristic facial features, limb abnormalities, hearing loss, and other organ system involvement. The vast majority of cases (99%) are sporadic, with rare familial occurrences having been reported. Most individuals with CdLS do not reproduce as a result of the severity of the disorder. Maternal transmission has been well documented, as have several cases of multiple-affected children being born to apparently unaffected parents. Paternal transmission has rarely been reported. A case is reported here of a father with classic features of CdLS with a similarly affected daughter. A review of the reported familial cases of CdLS is summarized. PMID:11754058

  15. Sanfilippo syndrome

    MedlinePlus

    ... for families who have a child with Sanfilippo syndrome, to help them understand the condition and possible treatments. Prenatal testing is available. Alternative Names MPS III References Pyeritz ...

  16. Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease.

    PubMed

    van der Crabben, Saskia N; Hennus, Marije P; McGregor, Grant A; Ritter, Deborah I; Nagamani, Sandesh C S; Wells, Owen S; Harakalova, Magdalena; Chinn, Ivan K; Alt, Aaron; Vondrova, Lucie; Hochstenbach, Ron; van Montfrans, Joris M; Terheggen-Lagro, Suzanne W; van Lieshout, Stef; van Roosmalen, Markus J; Renkens, Ivo; Duran, Karen; Nijman, Isaac J; Kloosterman, Wigard P; Hennekam, Eric; Orange, Jordan S; van Hasselt, Peter M; Wheeler, David A; Palecek, Jan J; Lehmann, Alan R; Oliver, Antony W; Pearl, Laurence H; Plon, Sharon E; Murray, Johanne M; van Haaften, Gijs

    2016-08-01

    The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood. PMID:27427983

  17. Erysipelas-like erythema of familial Mediterranean fever syndrome: a case report with emphasis on histopathologic diagnostic clues.

    PubMed

    Kolivras, Athanassios; Provost, Philippe; Thompson, Curtis T

    2013-06-01

    We report histopathological findings in a case of familial Mediterranean fever (FMF) syndrome with an erysipelas-like erythema (ELE). ELE is the only pathognomic cutaneous manifestation of FMF. ELE is characterized by well-demarcated, tender, erythematous and infiltrated plaques recurring on the same site and resolving spontaneously within 48-72 h. FMF is a monogenic autoinflammatory syndrome highlighted by recurrent fever associated with polyserositis involving mainly the peritoneum, synovium and pleura. FMF results from a mutation of the MEFV gene, which encodes for pyrin, leading to Il-1β activation and promoting neutrophil migration into the dermis. Histopathological findings in our case showed a sparse superficial perivascular and interstitial lymphocytic infiltrate admixed with some neutrophils, no eosinophils and mild papillary dermal edema. Venules and lymphatics were dilated, though no vasculitis was identified. Neutrophils are the most common cutaneous marker of autoinflammation, and cutaneous manifestations of monogenic autoinflammatory syndromes are represented by the spectrum of aseptic neutrophilic dermatoses. Neutrophils in the presence of recurrent fever and in the correct clinical context of recurrent erysipelas in the same site are a diagnostic clue for FMF. PMID:23521609

  18. 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.

  19. Easing the Burden: Describing the Role of Social, Emotional and Spiritual Support in Research Families with Li-Fraumeni Syndrome.

    PubMed

    Peters, June A; Kenen, Regina; Bremer, Renee; Givens, Shannon; Savage, Sharon A; Mai, Phuong L

    2016-06-01

    This study presents findings of a mixed-method descriptive exploration of the role of friends and spirituality/religiosity in easing the burden of families with the rare inherited disorder, Li-Fraumeni Syndrome (LFS). LFS is caused by germline mutations in the TP53 gene and is associated with very high lifetime risk of developing one or more malignancies. During the first clinical visit we assessed several types of social support among a subset of study participants (N = 66) using an established interactive research tool called the Colored Eco-Genetic Relationship Map (CEGRM). We performed both quantitative and qualitative analyses of social relationships with LFS family members and close non-kin. Distress scores (N = 59) were mostly low normal, with some outliers. We found that reported friendships varied widely, that the friendships were often deep and enduring, and were important sources of informational, tangible, emotional and spiritual support. Confidantes tended to be best friends and/or spouses. Organized religion was important in selected families, typically from mainstream traditions. However, a number of people identified themselves as "spiritual" and reported spiritual and humanist explorations. Our results shed preliminary light on how some people in families with LFS cope in the face of tremendous medical, social and emotional challenges. PMID:26621765

  20. Novel and recurrent mutations in the TAT gene in Tunisian families affected with Richner-Hanhart syndrome.

    PubMed

    Bouyacoub, Yosra; Zribi, Hela; Azzouz, Hatem; Nasrallah, Fehmi; Abdelaziz, Rim Ben; Kacem, Monia; Rekaya, Ben; Messaoud, Olfa; Romdhane, Lilia; Charfeddine, Cherine; Bouziri, Mustapha; Bouziri, Sonia; Tebib, Neji; Mokni, Mourad; Kaabachi, Naziha; Boubaker, Samir; Abdelhak, Sonia

    2013-10-15

    Tyrosinemia type II, also designated as oculocutaneous tyrosinemia or Richner-Hanhart syndrome (RHS), is a very rare autosomal recessive disorder. In the present study, we report clinical features and molecular genetic investigation of the tyrosine aminotransferase (TAT) gene in two young patients, both born to consanguineous unions between first-degree cousins. These two unrelated families originated from Northern and Southern Tunisia. The clinical diagnosis was based on the observation of several complications related to Richner-Hanhart syndrome: recurrent eye redness, tearing and burning pain, photophobia, bilateral pseudodendritic keratitis, an erythematous and painful focal palmo-plantar hyperkeratosis and a mild delay of mental development. The diagnosis was confirmed by biochemical analysis. Sequencing of the TAT gene revealed the presence of a previously reported missense mutation (c.452G>A, p.Cys151Tyr) in a Tunisian family, and a novel G duplication (c.869dupG, p.Trp291Leufs 6). Early diagnosis of RHS and protein-restricted diet are crucial to reduce the risk and the severity of long-term complications of hypertyrosinemia such as intellectual disability. PMID:23954227

  1. Familial recurrent hypersomnia: two siblings with Kleine-Levin syndrome and menstrual-related hypersomnia.

    PubMed

    Rocamora, Rodrigo; Gil-Nagel, Antonio; Franch, Oriol; Vela-Bueno, Antonio

    2010-11-01

    Kleine-Levin syndrome and menstrual-related hypersomnia are rare idiopathic sleep disorders occurring primarily in adolescence. They are characterized by intermittent periods of excessive sleepiness, cognitive disturbances, and behavioral abnormalities. In both, the etiology remains unknown but autoinmune, hormonal, infectious, and inflammatory mechanisms have been proposed. The authors describe, for the first time, the association of Kleine-Levin syndrome and menstrual-related hypersomnia in 2 adolescent siblings who shared the human leukocyte antigen (HLA) loci DQB1*0501. The same haplotype has been associated with sleepwalking and with rapid eye movement (REM) sleep behavior disorder. This gender differences in the manifestation of a probably genetic influenced sleep disorder suggests that hormonal mechanisms could be implicated in the phenotypical expression of this sleep disorder. The male sibling with Kleine-Levin syndrome was easily controlled with carbamazepine in low doses, but his sister could be only efficaciously treated with oral contraceptives. PMID:20404354

  2. Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD.

    PubMed

    Beck, Bodo B; Trachtman, Howard; Gitman, Michael; Miller, Ilene; Sayer, John A; Pannes, Andrea; Baasner, Anne; Hildebrandt, Friedhelm; Wolf, Matthias T F

    2011-11-01

    Homozygous or compound heterozygous mutations in renin (REN) cause renal tubular dysgenesis, which is characterized by death in utero due to kidney failure and pulmonary hypoplasia. The phenotype resembles the fetopathy caused by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy. Recently, heterozygous REN mutations were shown to result in early-onset hyperuricemia, anemia, and chronic kidney disease (CKD). To date, only 3 different heterozygous REN mutations have been published. We report mutation analysis of the REN gene in 39 kindreds with hyperuricemia and CKD who previously tested negative for mutations in the UMOD (uromodulin) and HNF1B (hepatocyte nuclear factor 1β) genes. We identified one kindred with a novel thymidine to cytosine mutation at position 28 in the REN complementary DNA, corresponding to a tryptophan to arginine substitution at amino acid 10, which is found within the signal sequence (c.28T>C; p.W10R). On this basis, we conclude that REN mutations are rare events in patients with CKD. Within the kindred, we found affected individuals over 4 generations who carried the novel REN mutation and were characterized by significant anemia, hyperuricemia, and CKD. Anemia was severe and disproportional to the degree of decreased kidney function. Because all heterozygous REN mutations that have been described are localized in the signal sequence, screening of the REN gene for patients with CKD with hyperuricemia and anemia may best be focused on sequencing of exon 1, which encodes the signal peptide. PMID:21903317

  3. An Incompletely Penetrant Novel Mutation in COL7A1 Causes Epidermolysis Bullosa Pruriginosa and Dominant Dystrophic Epidermolysis Bullosa Phenotypes in an Extended Kindred

    PubMed Central

    Yang, Catherine S; Lu, Yin; Farhi, Anita; Nelson-Williams, Carol; Kashgarian, Michael; Glusac, Earl J; Lifton, Richard P; Antaya, Richard J; Choate, Keith A

    2012-01-01

    Epidermolysis bullosa pruriginosa (EBP) is a rare subtype of dystrophic epidermolysis bullosa (DEB) characterized by intense pruritus, nodular or lichenoid lesions, and violaceous linear scarring, most prominently on the extensor extremities. Remarkably, identical mutations in COL7A1, which encodes an anchoring fibril protein present at the dermal–epidermal junction, can cause both DEB and EBP with either autosomal dominant or recessive inheritance. We present one family with both dystrophic and pruriginosa phenotypes of epidermolysis bullosa. The proband is a 19-year-old Caucasian woman who initially presented in childhood with lichenoid papules affecting her extensor limbs and intense pruritus consistent with EBP. Her maternal grandmother saw a dermatologist for similar skin lesions that developed without any known triggers at age 47 and mostly resolved spontaneously after approximately 10 years. The proband’s younger brother developed a small crop of pruritic papules on his elbows, dorsal hands, knees, and ankles at age 13. Her second cousin once removed, however, reported a mild blistering disease without pruritus consistent with DEB. Genetic sequencing of the kindred revealed a single dominant novel intron 47 splice site donor G>A mutation, c.4668 + 1 G>A, which we predict leads to exon skipping. Incomplete penetrance is confirmed in her clinically unaffected mother, who carries the same dominant mutation. The wide diversity of clinical phenotypes with one underlying genotype demonstrates that COL7A1 mutations are incompletely penetrant and strongly suggests that other genetic and environmental factors influence clinical presentation. PMID:22515571

  4. A Williams syndrome patient with a familial t(6;7) translocation and deletion of the elastin gene

    SciTech Connect

    Pober, B.R.; Gibson, L.H.; Yang-Feng, T.L.

    1994-09-01

    Discovery of a {open_quotes}balanced{close_quotes} reciprocal translocation [46,XX,t(6;7)(q11.2;q11.23)] on routine amniocentesis prompted clinical and cytogenetic study of additional family members. The same t(6;7) translocation was found in the clincally normal father and in a sibling with Williams syndrome (WS). WS had been diagnosed previously according to clinical criteria including distinctive facial features, supravalvar aortic stenosis requiring surgical repair, dental abnormalties and developmental delay. A clinically normal female was delivered and the translocation was confirmed with a cord blood specimen. Hemizygosity for the gene, elastin, (which has been mapped to the chromosome 7 translocation breakpoint, 7q11.23, in this family) appears to be a cause of WS. We therefore investigated whether the t(6;7) in the phenotypically normal father represented more than a simple reciprocal translocation. FISH using a chromosome 7 specific library revealed no differences between the cytogenetically identical, yet phenotypically distinct, father and son. Hybridization with a cosmid MR127D4 containing elastin sequence showed that the WS patient was missing one allele from the derivative chromosome 7 whereas both his mother and father had two copies of the elastin gene. This family indicates that the de novo loss of one copy of the elastin gene produces the recognizable phenotype of Williams syndrome. Molecular characterization (with additional probes) of the extent of this de novo deletion near the translocation breakpoint is in progress. This information will be valuable for defining the WS-critical region and will lead to a better understanding of the molecular basis for WS.

  5. Fetal Alcohol Syndrome and Fetal Alcohol Effects-- Support for Teachers and Families.

    ERIC Educational Resources Information Center

    Duckworth, Susanna V.; Norton, Terry L.

    2000-01-01

    Reviews genesis of fetal alcohol syndrome and fetal alcohol effects in children. Identifies physical characteristics and behavioral indicators found and provides three checklists of observable signs for both disorders. Recommends seven steps for educators to follow in seeking assistance with these conditions. (DLH)

  6. Infundibulopelvic stenosis, multicystic kidney, and calyectasis in a kindred: Clinical observations and genetic analysis

    SciTech Connect

    Kobayashi, M.; Kaplan, B.S.; Sartore, M.

    1995-11-06

    Congenital obstructive anomalies of the urinary tract usually occur sporadically. We describe inheritance in a three-generation kindred of a spectrum of kidney anomalies consistent with an autosomal-dominant mode of transmission, with incomplete penetrance, calyectasis (maternal grandmother), infundibulopelvic stenosis (uncle), and multicystic kidney (male proband, age 4 years). The proband`s mother, father and half sister had normal renal imaging studies. Inheritance of informative polymorphic markers (3{prime}-HVR, GGG1, GGG9, SM-7, KG8, and CW3) mapping close to the adult polycystic kidney disease type 1 (PKD-1) and tuberous sclerosis (TSC-2) loci on chromosome 16p was evaluated by Southern blot typing for linkage to phenotype. The 3 affected individuals, as well as the unaffected mother (obligate carrier) and unaffected half-sister, inherit a common chromosome haplotype linked to the PKD1 locus. Our findings support the hypothesis that these anomalies may be part of a spectrum of obstructive renal dysplasia which are inherited as a simple Mendelian trait exhibiting an autosomal-dominant mode of transmission with variable expressions and incomplete penetrance. 23 refs., 4 figs.

  7. Infundibulopelvic stenosis, multicystic kidney, and calyectasis in a kindred: clinical observations and genetic analysis.

    PubMed

    Kobayashi, M; Kaplan, B S; Bellah, R D; Sartore, M; Rappaport, E; Steele, M W; Mansfield, E; Gasparini, P; Surrey, S; Fortina, P

    1995-11-01

    Congenital obstructive anomalies of the urinary tract usually occur sporadically. We describe inheritance in a three-generation kindred of a spectrum of kidney anomalies consistent with an autosomal-dominant mode of transmission, with incomplete penetrance, calyectasis (maternal grandmother), infundibulopelvic stenosis (uncle), and multicystic kidney (male proband, age 4 years). The proband's mother, father and half sister had normal renal imaging studies. Inheritance of informative polymorphic markers (3'-HVR, GGG1, GGG9, SM-7, KG8, and CW3) mapping close to the adult polycystic kidney disease type 1 (PKD-1) and tuberous sclerosis (TSC-2) loci on chromosome 16p was evaluated by Southern blot studies and by PCR-based, fluorescent genotyping for linkage to phenotype. The 3 affected individuals, as well as the unaffected mother (obligate carrier) and unaffected half-sister, inherit a common chromosome haplotype linked to the PKD1 locus. Our findings support the hypothesis that these anomalies may be part of a spectrum of obstructive renal dysplasia which are inherited as a simple Mendelian trait exhibiting an autosomal-dominant mode of transmission with variable expression and incomplete penetrance. PMID:8588589

  8. Family history of mental illness or alcohol abuse and the irritable bowel syndrome

    PubMed Central

    Knight, James R.; Locke, G. Richard; Zinsmeister, Alan R.; Schleck, Cathy D.; Talley, Nicholas J.

    2015-01-01

    Objective We have observed that many patients with IBS drink very little alcohol, and postulated this may reflect membership in families affected by alcoholism and mental illness. We aimed to evaluate whether a family history of substance or alcohol abuse, or psychiatric illness, is associated with IBS. Methods A valid GI questionnaire was mailed to a randomly selected population-based cohort to identify IBS and healthy controls. The electronic medical record was reviewed to record the subjects’ self-reported personal and family health histories. Results 2300 subjects responded (response rate 55%; IBS 13% n=287). 230 subjects with IBS and 318 controls were eligible. Family history of alcohol/substance abuse was reported by 33% of cases and 25% of controls (OR 1.4, 95% CI 1.0–2.1, p=0.06). Family history of psychiatric illness was reported by 37% of cases and 22% of controls (OR 2.0, 95% CI 1.3–2.9, p<0.001). In the absence of a personal history of alcohol use, a family history of alcohol/substance abuse was predictive of IBS status (OR adjusted for age and gender 1.5, 95% CI 1.0–2.3, p=0.05). In the absence of a personal history of alcohol use, reporting both a family history of alcohol/substance abuse and anxiety/depression/mental illness was clearly predictive of IBS status (OR 2.5, 95% CI 1.4–4.5; p<0.005). Substance abuse as a child was associated with an increased risk of IBS (OR 2.3, 95% CI 1.1–4.8; p<0.03). Conclusion IBS is independently associated with a family history of psychiatric illness and may be linked to a family history of alcohol/substance abuse. PMID:25582802

  9. Further delineation of facioaudiosymphalangism syndrome: Description of a family with a novel NOG mutation and without hearing loss.

    PubMed

    Bayat, Allan; Fijalkowski, Igor; Andersen, Tobias; Abdulmunem, Sura Azhar; van den Ende, Jenneke; Van Hul, Wim

    2016-06-01

    Mutations in the NOG gene give rise to a wide range of clinical phenotypes. Noggin, the protein encoded by this gene is a secreted modulator of multiple pathways involved in both bone and joint development. Proximal symphalangism is commonly observed in patients bearing mutations in this gene, however secondary symptomes are often found including typical facies with hemicylindrical nose with bulbous tip, hyperopia, reduced mobility of multiple joints, hearing loss due to stapes fixation, and recurrent pain from affected joints. With large variation of the phenotype both within and between affected families careful delineation of the genotype-phenotype correlation is needed. In this work we describe a Danish family suffering from SYNS1 due to a novel NOG gene mutation (C230Y). We provide detailed clinical description of the family members presenting rare phenotype of the shoulders shared by affected individuals but no hearing loss, further adding to the phenotypic variability of the syndrome. With these findings we broaden the understanding of NOG-related-symphalangism spectrum disorder. © 2016 Wiley Periodicals, Inc. PMID:26994744

  10. Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes

    PubMed Central

    Pengelly, Reuben J.; Arias, Liliana; Martínez, Julio; Upstill-Goddard, Rosanna; Seaby, Eleanor G.; Gibson, Jane; Ennis, Sarah; Collins, Andrew; Briceño, Ignacio

    2016-01-01

    Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting. PMID:27456059

  11. Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes.

    PubMed

    Pengelly, Reuben J; Arias, Liliana; Martínez, Julio; Upstill-Goddard, Rosanna; Seaby, Eleanor G; Gibson, Jane; Ennis, Sarah; Collins, Andrew; Briceño, Ignacio

    2016-01-01

    Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting. PMID:27456059

  12. Clinical aspects of familial forms of frontotemporal dementia associated with parkinsonism.

    PubMed

    Fujioka, Shinsuke; Wszolek, Zbigniew K

    2011-11-01

    Frontotemporal dementia is the second most common dementia among people under the age of 65. Fifty percent of affected patients have an associated family history. Several pathogenic genes have been identified for frontotemporal dementia associated with parkinsonism, including microtubule-associated protein tau, progranulin, and chromatin modifying protein 2B, and fused in sarcoma. It has also been reported that frontotemporal dementia associated with parkinsonism can be linked to chromosome 9p. In addition, there are families with frontotemporal dementia associated with a parkinsonian phenotype but unknown genetic status. Some of these kindreds have been diagnosed clinically as familial progressive supranuclear palsy, hereditary diffuse leukoencephalopathy with axonal spheroids, "overlap" syndrome, and others. Clinical presentation of frontotemporal dementia associated with parkinsonism is variable at age of symptomatic disease onset, disease duration, symptoms, and their occurrence during the disease course. Clinically, it is often difficult to sort out the different genetic forms of frontotemporal dementia associated with parkinsonism. However, with available clinical genetic testing for known genes, the precise diagnosis can be accomplished in some cases. PMID:21656039

  13. [5 children with hypokalemia, hypomagnesemia and hypocalciuria (Gitelman syndrome) in one family].

    PubMed

    Schweizer, J J; van Collenburg, J J

    1997-08-30

    Gitelman's syndrome was diagnosed in five siblings. The parents were relatives in the third remove. Gitelman's syndrome is a rare autosomal recessive hereditary magnesium reabsorption defect in the distal tubule. It is characterized by episodes of muscle weakness, usually accompanied by abdominal pain and vomiting. Tetany may occur during a febrile illness. Patients are of normal height and weight and have normal blood pressures. Sometimes eczematous skin lesions are found. Biochemically there is hypokalaemia, hypomagnesaemia and alkalosis. Urinary excretion rates of potassium and magnesium are elevated, the excretion of calcium is diminished. Treatment consists of oral suppletion of magnesium, sometimes also with oral potassium. A potassium-sparing diuretic may be used. The prognosis appears to be good. PMID:9543787

  14. Familial skin cancer syndromes: Increased risk of nonmelanotic skin cancers and extracutaneous tumors.

    PubMed

    Jaju, Prajakta D; Ransohoff, Katherine J; Tang, Jean Y; Sarin, Kavita Y

    2016-03-01

    Nonmelanoma skin cancers (NMSCs) represent the most common malignancies worldwide, with reported incidence rising each year. Both cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC), as well as other NMSCs, represent complex diseases with a combination of environmental and genetic risk factors. In general, hereditary cancer syndromes that increase the risk of NMSC fall under several broad categories: those associated with immunodeficiencies, those that affect skin pigmentation, and those that perturb key molecular pathways involved in the pathogenesis of NMSCs. Many of the syndromes are also associated with extracutaneous manifestations, including internal malignancies; therefore, most require a multidisciplinary management approach with a medical geneticist. Finally, dermatologists play a critical role in the diagnosis and management of these conditions, because cutaneous findings are often the presenting manifestations of disease. PMID:26892653

  15. Phenotypic discordance in a family with monozygotic twins and non-syndromic cleft lip and palate

    SciTech Connect

    Wyszynski, D.F. |; Lewanda, A.F. |; Beaty, T.H.

    1996-12-30

    Despite considerable research, the cause of non-syndromic cleft lip with or without cleft palate (NSCLP) is still an enigma. Case-control and cohort studies have searched for environmental factors that might influence the development of this common malformation, such as maternal cigarette smoking, periconceptional supplementation of folic acid and multivitamins, agricultural chemical use, and place of residence, among others. However, these studies are subject to numerous biases, and their results have often been contradictory and inconclusive. 41 refs., 1 fig.

  16. Congenital familial myasthenic syndromes: disease and course in an affected dizygotic twin pair

    PubMed Central

    Pavone, Piero; Praticò, Andrea Domenico; Pavone, Vito; Falsaperla, Raffaele

    2013-01-01

    The present report describes clinical variability in an affected dizygotic twin pair. Twin 1 showed classical features of the congenital myasthenic syndromes (CMS), that is, ptosis, dysphonia, asthenia and hypotonia. In twin 2, these clinical signs were less pronounced, but subtle resulting in severe lumbar hyperlordosis. Molecular analysis, performed for both twins, revealed the presence of three polymorphisms in the heterozygous form in RAPSN gene. The present report highlights the clinical variability of the CMS. PMID:23365176

  17. The Shwachman-Bodian-Diamond Syndrome Protein Family Is Involved in RNA Metabolism

    SciTech Connect

    Savchenko, A; Krogan, Nevan; Cort, John R.; Evdokimova, Elena; Lew, Jocelyne M.; Yee, Adelinda; Sanchez-Pulido, Luis; Andrade, Miguel; Bochkarev, Alexey; Watson, James D.; Kennedy, Michael A.; Greenblatt, Jack; Hughes, Timothy; Arrowsmith, Cheryl H.; Rommens, Johanna M.; Edwards, Aled M.

    2005-05-13

    A combination of structural, biochemical, and genetic studies in model organisms was used to infer a cellular role for the human protein (SBDS) responsible for Shwachman-Bodian-Diamond syndrome. The crystal structure of the SBDS homologue in Archaeoglobus fulgidus, AF0491, revealed a three domain protein. The N-terminal domain, which harbors the majority of disease-linked mutations, has a novel three-dimensional fold.

  18. Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population

    PubMed Central

    Mumtaz, Sara; Riaz, Hafiza Fizzah; Touseef, Mohammad; Basit, Sulman; Haque, Muhammad Faiyaz Ul; Malik, Sajid

    2015-01-01

    Grebe syndrome (OMIM-200700) is a very rare type of acromesomelic dysplasia with autosomal recessive inheritance. We studied a Pakistani family with two affected individuals having typical features of Grebe chondrodysplasia. Patients were observed with short and deformed limbs having a proximo-distal gradient of severity. Hind-limbs were more severely affected than fore-limbs. Digits on autopods were very short and nonfunctional. Index subject also had nearsightedness. However, symptoms in the craniofacial and axial skeleton were minimal. Genetic analysis revealed four base pair insertion mutation (c.1114insGAGT) in gene coding cartilage-derived morphogenetic protein-1 (CDMP1). This mutation was predicted to cause premature stop codon. The clinical presentation in this study broadens the range of phenotypes associated with CDMP1 mutation in Pakistani population. PMID:26870132

  19. Recurrent mutation in CDMP1 in a family with Grebe chondrodysplasia: broadening the phenotypic manifestation of syndrome in Pakistani population.

    PubMed

    Mumtaz, Sara; Riaz, Hafiza Fizzah; Touseef, Mohammad; Basit, Sulman; Faiyaz Ul Haque, Muhammad; Malik, Sajid

    2015-01-01

    Grebe syndrome (OMIM-200700) is a very rare type of acromesomelic dysplasia with autosomal recessive inheritance. We studied a Pakistani family with two affected individuals having typical features of Grebe chondrodysplasia. Patients were observed with short and deformed limbs having a proximo-distal gradient of severity. Hind-limbs were more severely affected than fore-limbs. Digits on autopods were very short and nonfunctional. Index subject also had nearsightedness. However, symptoms in the craniofacial and axial skeleton were minimal. Genetic analysis revealed four base pair insertion mutation (c.1114insGAGT) in gene coding cartilage-derived morphogenetic protein-1 (CDMP1). This mutation was predicted to cause premature stop codon. The clinical presentation in this study broadens the range of phenotypes associated with CDMP1 mutation in Pakistani population. PMID:26870132

  20. Psychological Well-Being of Mothers and Siblings in Families of Girls and Women with Rett Syndrome.

    PubMed

    Cianfaglione, Rina; Hastings, Richard P; Felce, David; Clarke, Angus; Kerr, Michael P

    2015-09-01

    Few published studies have reported on the psychological well-being of family members of individuals with Rett syndrome (RTT). Eighty-seven mothers of girls and women with RTT completed a questionnaire survey about their daughters' behavioral phenotype, current health, and behavior problems, and their own and a sibling's well-being. Mothers reported increased anxiety but similar levels of depression when compared to a normative sample. Across all problem domains on the Strengths and Difficulties Questionnaire, child and adolescent siblings (n = 39) were reported by mothers to have fewer difficulties than a normative sample. The severity of their daughters' RTT behavioral phenotype predicted increased anxiety and stress for mothers. Increased RTT daughters' current health problems predicted more maternal perceptions of positive gain. PMID:25911307

  1. Pulmonary cysts of Birt-Hogg-Dubé syndrome: a clinicopathologic and immunohistochemical study of 9 families.

    PubMed

    Furuya, Mitsuko; Tanaka, Reiko; Koga, Shunsuke; Yatabe, Yasushi; Gotoda, Hiroko; Takagi, Seiji; Hsu, Yung-Hsiang; Fujii, Takeshi; Okada, Akira; Kuroda, Naoto; Moritani, Suzuko; Mizuno, Hideki; Nagashima, Yoji; Nagahama, Kiyotaka; Hiroshima, Kenzo; Yoshino, Ichiro; Nomura, Fumio; Aoki, Ichiro; Nakatani, Yukio

    2012-04-01

    Birt-Hogg-Dubé (BHD) syndrome is an autosomal dominant disorder characterized by fibrofolliculomas, renal tumors, and pulmonary cysts with recurrent pneumothorax. Multiple pulmonary cysts and pneumothorax are the key signs for diagnosing BHD syndrome. The pathologic features of BHD pulmonary cysts, however, are poorly understood. This disorder is caused by mutations in the gene that encodes folliculin (FLCN). FLCN is regarded as a tumor suppressor; it mediates cellular activities by interacting with the mammalian target of rapamycin (mTOR). In this study, we investigated the lungs of 11 patients from 9 BHD families. The majority of patients consulting doctors were women between 30 and 60 years of age who had pulmonary cysts and repeated pneumothoraces. Genomic DNA testing revealed 5 different mutation patterns. Histopathologic examination found that the inner surface of cysts was lined by epithelial cells, sometimes with a predominance of type II pneumocyte-like cuboidal cells. The cysts occasionally contained internal septa consisting of alveolar walls or showed an "alveoli within an alveolus" pattern. The cells constituting the cysts stained positive for phospho-S6 ribosomal protein expression, suggesting activation of the mTOR pathway. Although BHD pulmonary cysts are frequently misdiagnosed as nonspecific cystic diseases, they are distinctly different in histopathology from other bullous changes. Mechanical stress such as rupture and postrupture remodeling allows mesothelial invagination and fibrosis. Such modified BHD pulmonary cysts are virtually indistinguishable from nonspecific blebs and bullae. We propose a new insight, namely, that the BHD syndrome-associated pulmonary cyst may be considered a hamartoma-like cystic alveolar formation associated with deranged mTOR signaling. PMID:22441547

  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. Disease-Targeted Sequencing of Ion Channel Genes identifies de novo mutations in Patients with Non-Familial Brugada Syndrome

    PubMed Central

    Juang, Jyh-Ming Jimmy; Lu, Tzu-Pin; Lai, Liang-Chuan; Ho, Chia-Chuan; Liu, Yen-Bin; Tsai, Chia-Ti; Lin, Lian-Yu; Yu, Chih-Chieh; Chen, Wen-Jone; Chiang, Fu-Tien; Yeh, Shih-Fan Sherri; Lai, Ling-Ping; Chuang, Eric Y.; Lin, Jiunn-Lee

    2014-01-01

    Brugada syndrome (BrS) is one of the ion channelopathies associated with sudden cardiac death (SCD). The most common BrS-associated gene (SCN5A) only accounts for approximately 20–25% of BrS patients. This study aims to identify novel mutations across human ion channels in non-familial BrS patients without SCN5A variants through disease-targeted sequencing. We performed disease-targeted multi-gene sequencing across 133 human ion channel genes and 12 reported BrS-associated genes in 15 unrelated, non-familial BrS patients without SCN5A variants. Candidate variants were validated by mass spectrometry and Sanger sequencing. Five de novo mutations were identified in four genes (SCNN1A, KCNJ16, KCNB2, and KCNT1) in three BrS patients (20%). Two of the three patients presented SCD and one had syncope. Interestingly, the two patients presented with SCD had compound mutations (SCNN1A:Arg350Gln and KCNB2:Glu522Lys; SCNN1A:Arg597* and KCNJ16:Ser261Gly). Importantly, two SCNN1A mutations were identified from different families. The KCNT1:Arg1106Gln mutation was identified in a patient with syncope. Bioinformatics algorithms predicted severe functional interruptions in these four mutation loci, suggesting their pivotal roles in BrS. This study identified four novel BrS-associated genes and indicated the effectiveness of this disease-targeted sequencing across ion channel genes for non-familial BrS patients without SCN5A variants. PMID:25339316

  4. [Familial syndrome combining short small intestine, intestinal malrotation, pyloric hypertrophy and brain malformation. 3 anatomoclinical case reports].

    PubMed

    Nezelof, C; Jaubert, F; Lyon, G

    1976-01-01

    Anatomoclinical study of 3 cases of an exceptional malformative condition characterized by: --extreme shortness of the small intestine, --mesenterium commune, --hypertrophic pylorus, --malformation of the central nervous system (heterotopia, absence of operculum temporale). Clinically this malformative condition is characterized by failure and inertia of the intestinal peristalsis producing at intervals of 10-15 days episodes of subocclusion, the repetition of which causes death. The syndrome is familial and seems to be of autosomal recessive inheritance. The absence of mechanical obstruction, the repeated failure of colostomy and ileostomy, the normal aspect of the myenteric plexuses verified by cytoenzymatic and silver stains allow to individualize this anatomoclinical syndrome and to rule out the hypothesis of Hirschsprung's disease, Chagas' disease, idiopathic megacolon or hypoplasia of the myenteric plexuses. The association of cerebral malformations leads to consider the responsibility of a lack of synthesis of a same specific intermediate factor which is up to now poorly determined, implicated in the neuronal migration and neuromuscular transmission. PMID:1023783

  5. A novel mutation in the endothelin B receptor gene in a moroccan family with shah-waardenburg syndrome.

    PubMed

    Doubaj, Yassamine; Pingault, Véronique; Elalaoui, Siham C; Ratbi, Ilham; Azouz, Mohamed; Zerhouni, Hicham; Ettayebi, Fouad; Sefiani, Abdelaziz

    2015-02-01

    Waardenburg syndrome (WS) is a neurocristopathy disorder combining sensorineural deafness and pigmentary abnormalities. The presence of additional signs defines the 4 subtypes. WS type IV, also called Shah-Waardenburg syndrome (SWS), is characterized by the association with congenital aganglionic megacolon (Hirschsprung disease). To date, 3 causative genes have been related to this congenital disorder. Mutations in the EDNRB and EDN3 genes are responsible for the autosomal recessive form of SWS, whereas SOX10 mutations are inherited in an autosomal dominant manner. We report here the case of a 3-month-old Morrocan girl with WS type IV, born to consanguineous parents. The patient had 3 cousins who died in infancy with the same symptoms. Molecular analysis by Sanger sequencing revealed the presence of a novel homozygous missense mutation c.1133A>G (p.Asn378Ser) in the EDNRB gene. The proband's parents as well as the parents of the deceased cousins are heterozygous carriers of this likely pathogenic mutation. This molecular diagnosis allows us to provide genetic counseling to the family and eventually propose prenatal diagnosis to prevent recurrence of the disease in subsequent pregnancies. PMID:25852447

  6. Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

    PubMed Central

    Ulucan, Hakan; Gül, Davut; Sapp, Julie C; Cockerham, John; Johnston, Jennifer J; Biesecker, Leslie G

    2008-01-01

    Background Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance. Methods Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the EVC/EVC2 locus. The results did not exclude linkage, so samples were sequenced for mutations. Results We identified a c.1868T>C mutation in EVC, which predicts p.L623P, and was homozygous in affected individuals. Conclusion We conclude that this EVC mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. EVC mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome. PMID:18947413

  7. UMD-MLH1/MSH2/MSH6 databases: description and analysis of genetic variations in French Lynch syndrome families

    PubMed Central

    Grandval, Philippe; Fabre, Aurélie J.; Gaildrat, Pascaline; Baert-Desurmont, Stéphanie; Buisine, Marie-Pierre; Ferrari, Anthony; Wang, Qing; Béroud, Christophe; Olschwang, Sylviane

    2013-01-01

    Lynch syndrome is an autosomal dominant disease caused by germ line heterozygous mutations mainly involving the MSH2, MLH1 and MSH6 genes that belong to the DNA MisMatch Repair (MMR) genes family. The French network counting the 16 licensed laboratories involved in Lynch syndrome genetic testing developed three locus-specific databases with the UMD® software (www.umd.be/MLH1/, www.umd.be/MSH2/ and www.umd.be/MSH6/) that presently contain a total of 7047 sequence variations including 707 distinct variations of a priori unknown functional significance (VUS) that were identified through complete mutation screening or targeted predictive testing. Mutation carriers are at high risk for developing early-onset colorectal and endometrial adenocarcinomas. Consensus clinical guidelines have been proposed, allowing the efficient detection of curable lesions. The major challenge of genetic testing is to reliably classify the genomic variations in those patients who seek genetic counseling. Combining the interactive tools of the software, the relevant published data and mainly original information produced by the French MisMatch Repair network, the UMD-MLH1/MSH2/MSH6 databases provide interpretation data for the 707 VUS that were classified according to the IARC 5-Class system. These public databases are regularly updated to improve the classification of all registered VUS, exploring their role in cancer pre-disposition based on structural and functional approaches. PMID:23729658

  8. Association of the Family Environment with Behavioural and Cognitive Outcomes in Children with Chromosome 22q11.2 Deletion Syndrome

    ERIC Educational Resources Information Center

    Allen, T. M.; Hersh, J.; Schoch, K.; Curtiss, K.; Hooper, S. R.; Shashi, V.

    2014-01-01

    Background: Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this paediatric population. Method: Guardians of children with 22q11DS…

  9. 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,…

  10. Familial interstitial Xq27.3q28 duplication encompassing the FMR1 gene but not the MECP2 gene causes a new syndromic mental retardation condition

    PubMed Central

    Rio, Marlène; Malan, Valérie; Boissel, Sarah; Toutain, Annick; Royer, Ghislaine; Gobin, Stéphanie; Morichon-Delvallez, Nicole; Turleau, Catherine; Bonnefont, Jean-Paul; Munnich, Arnold; Vekemans, Michel; Colleaux, Laurence

    2010-01-01

    X-linked mental retardation is a common disorder that accounts for 5–10% of cases of mental retardation in males. Fragile X syndrome is the most common form resulting from a loss of expression of the FMR1 gene. On the other hand, partial duplication of the long arm of the X chromosome is uncommon. It leads to functional disomy of the corresponding genes and has been reported in several cases of mental retardation in males. In this study, we report on the clinical and genetic characterization of a new X-linked mental retardation syndrome characterized by short stature, hypogonadism and facial dysmorphism, and show that this syndrome is caused by a small Xq27.3q28 interstitial duplication encompassing the FMR1 gene. This family broadens the phenotypic spectrum of FMR1 anomalies in an unexpected manner, and we suggest that this condition may represent the fragile X syndrome «contre-type». PMID:19844254

  11. Two siblings with familial chylomicronemia syndrome: disease course and effectiveness of early treatment.

    PubMed

    Al Azkawi, Hanan; Alalwan, Ibrahim

    2010-01-01

    There are no adequate data that evaluate the safety and effectiveness of lowering triglyceride levels in very young children. The authors report a family with two male siblings, 7 and 4 years old, affected by familial hyperchylomicronemia. The oldest was diagnosed at birth during evaluation of jaundice, and the youngest showed asymptomatic hypertriglyceridemia by 6 months of age. Due to high triglyceride levels, Gemfibrozil (a fibric acid derivative) was started at diagnosis. Close clinical followup and laboratory monitoring of these children showed no side effects from the drug, and the risk of acute pancreatitis was significantly reduced. PMID:21209733

  12. 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.

  13. Postural Orthostatic Tachycardia Syndrome (POTS) - A novel member of the autoimmune family.

    PubMed

    Dahan, S; Tomljenovic, L; Shoenfeld, Y

    2016-04-01

    Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic nervous system in which a change from the supine position to an upright position causes an abnormally large increase in heart rate or tachycardia (30 bpm within 10 min of standing or head-up tilt). This response is accompanied by a decrease in blood flow to the brain and hence a spectrum of symptoms associated with cerebral hypoperfusion.(1) Many of these POTS-related symptoms are also observed in chronic anxiety and panic disorders, and therefore POTS is frequently under- and misdiagnosed.(2,3). PMID:26846691

  14. Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon 22, Q[22]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in...

  15. A novel FGD1 mutation in a family with Aarskog–Scott syndrome and predominant features of congenital joint contractures

    PubMed Central

    Griffin, Laurie Beth; Farley, Frances A.; Antonellis, Anthony; Keegan, Catherine E.

    2016-01-01

    Mutations in FGD1 cause Aarskog–Scott syndrome (AAS), an X-linked condition characterized by abnormal facial, skeletal, and genital development due to abnormal embryonic morphogenesis and skeletal formation. Here we report a novel FGD1 mutation in a family with atypical features of AAS, specifically bilateral upper and lower limb congenital joint contractures and cardiac abnormalities. The male proband and his affected maternal uncle are hemizygous for the novel FGD1 mutation p.Arg921X. This variant is the most carboxy-terminal FGD1 mutation identified in a family with AAS and is predicted to truncate the FGD1 protein at the second to last amino acid of the carboxy-terminal pleckstrin homology (PH) domain. Our study emphasizes the importance of the 3′ peptide sequence in the structure and/or function of the FGD1 protein and further demonstrates the need to screen patients with X-linked congenital joint contractures for FGD1 mutations. PMID:27551683

  16. Subjective face recognition difficulties, aberrant sensibility, sleeping disturbances and aberrant eating habits in families with Asperger syndrome

    PubMed Central

    Nieminen-von Wendt, Taina; Paavonen, Juulia E; Ylisaukko-Oja, Tero; Sarenius, Susan; Källman, Tiia; Järvelä, Irma; von Wendt, Lennart

    2005-01-01

    Background The present study was undertaken in order to determine whether a set of clinical features, which are not included in the DSM-IV or ICD-10 for Asperger Syndrome (AS), are associated with AS in particular or whether they are merely a familial trait that is not related to the diagnosis. Methods Ten large families, a total of 138 persons, of whom 58 individuals fulfilled the diagnostic criteria for AS and another 56 did not to fulfill these criteria, were studied using a structured interview focusing on the possible presence of face recognition difficulties, aberrant sensibility and eating habits and sleeping disturbances. Results The prevalence for face recognition difficulties was 46.6% in individuals with AS compared with 10.7% in the control group. The corresponding figures for subjectively reported presence of aberrant sensibilities were 91.4% and 46.6%, for sleeping disturbances 48.3% and 23.2% and for aberrant eating habits 60.3% and 14.3%, respectively. Conclusion An aberrant processing of sensory information appears to be a common feature in AS. The impact of these and other clinical features that are not incorporated in the ICD-10 and DSM-IV on our understanding of AS may hitherto have been underestimated. These associated clinical traits may well be reflected by the behavioural characteristics of these individuals. PMID:15826308

  17. Erythrocyte catechol-O-methyltransferase activity: genetic analysis in nuclear families with one child affected by Down syndrome.

    PubMed

    Brahe, C; Serra, A; Morton, N E

    1985-06-01

    Erythrocyte catechol-O-methyltransferase (COMT) activity was measured in 142 members of 32 nuclear families in which one child had Down syndrome (DS). The mean activity in subjects with trisomy 21 appears higher than in parents and sibs, though not significantly so. However, this fact does not seem to modify the properties expected for a trait genetically controlled in a diploid population. The commingling analysis of the COMT activity in the whole group, and in each subgroup of relatives, suggests a mixture of two or, more likely, three components, the latter being in agreement with a transmission model of genes without dominance. The most parsimonious hypothesis supported by the mixed model segregation analysis is that of an additive major locus (d = 0.5) with an estimated frequency of 0.40 +/- 0.03 for the COMTH gene, to which a small polygenic effect (H = 0.067) can be added. This hypothesis is supported further by the analysis of family resemblance, r = 0.45 +/- 0.12 being the maximum likelihood estimator of the intraclass correlation among sibs. The higher COMT activity in DS subjects may reflect a situation of general enzyme disorder only indirectly connected with trisomy of chromosome 21. PMID:3160238

  18. Linkage analysis in a family with Stickler syndrome leads to the exclusion of the COL2A1 locus

    SciTech Connect

    Mottes, M.; Zolezzi, F.; Pignatti, P.F.

    1994-09-01

    Hereditary arthro-ophtalmopathy (AO) or Stickler Syndrome (MIM No. 10830) is a dominantly inherited disorder characterized by vitro-retinal degeneration and other connective tissue disturbances. Mutations in the COL2A1 gene, coding for type II collagen chains, have been described in a few patients. The wide spectrum of clinical manifestations is presumably due to genetic heterogeneity, since only about 50% of the Stickler families so far studied show cosegregation of the disease with the COL2A1 locus. We have investigated a large pedigree (19 individuals of whom 9 are affected) in which severe myopia with vitro-retinal degeneration consegregated with joint laxity, recurrent inguinal hernias, and degenerative changes of the hip and the knee. The 3{prime} end COL2A1 VNTR polymorphism was utilized for linkage analysis. In order to get the maximum informativity, we have analyzed the allelic microheterogeneity of this VNTR, due to the repeat sequence variation, by means of a single strand polymorphism. Mendelian inheritance of the different single strands was observed as expected. Discordance of segregation between the disease and the COL2A1 locus was thus established inequivocally in this family.

  19. Clinical characterization and identification of duplication breakpoints in a Japanese family with Xq28 duplication syndrome including MECP2.

    PubMed

    Fukushi, Daisuke; Yamada, Kenichiro; Nomura, Noriko; Naiki, Misako; Kimura, Reiko; Yamada, Yasukazu; Kumagai, Toshiyuki; Yamaguchi, Kumiko; Miyake, Yoshishige; Wakamatsu, Nobuaki

    2014-04-01

    Xq28 duplication syndrome including MECP2 is a neurodevelopmental disorder characterized by axial hypotonia at infancy, severe intellectual disability, developmental delay, mild characteristic facial appearance, epilepsy, regression, and recurrent infections in males. We identified a Japanese family of Xq28 duplications, in which the patients presented with cerebellar ataxia, severe constipation, and small feet, in addition to the common clinical features. The 488-kb duplication spanned from L1CAM to EMD and contained 17 genes, two pseudo genes, and three microRNA-coding genes. FISH and nucleotide sequence analyses demonstrated that the duplication was tandem and in a forward orientation, and the duplication breakpoints were located in AluSc at the EMD side, with a 32-bp deletion, and LTR50 at the L1CAM side, with "tc" and "gc" microhomologies at the duplication breakpoints, respectively. The duplicated segment was completely segregated from the grandmother to the patients. These results suggest that the duplication was generated by fork-stalling and template-switching at the AluSc and LTR50 sites. This is the first report to determine the size and nucleotide sequences of the duplicated segments at Xq28 of three generations of a family and provides the genotype-phenotype correlation of the patients harboring the specific duplicated segment. PMID:24478188

  20. Mapping of the gene for cleidocranial dysplasia in the historical Cape Town (Arnold) kindred and evidence for locus homogeneity.

    PubMed Central

    Ramesar, R S; Greenberg, J; Martin, R; Goliath, R; Bardien, S; Mundlos, S; Beighton, P

    1996-01-01

    Cleidocranial dysplasia (CCD) is an autosomal dominant disorder, features of which include a patient anterior fontanelle, a bulging calvarium, hypoplasia or aplasia of the clavicles, a wide public symphysis, dental anomalies, vertebral malformation, and short stature. The Cape Town kindred which is under our genetic management was originally described more than four decades ago and now consists of more than 1000 people. Following reports of rearrangements on chromosomes 6 and 8 in people with CCD, we have carried out linkage analyses between highly information microsatellite dinucleotide repeat markers in the rearranged regions and the disorder in a branch of this South African CCD kindred, consisting of 38 subjects, 18 of whom are affected. Maximum lod scores (at theta = 0.00) of 7.14 (for marker D6S459), 4.32 (TCTE), 4.99 (D6S452), 5.97 (D6S269), and 3.95 (D6S465) confirm linkage of the disorder to the short arm of chromosome 6. Our data indicate that the CCD gene is located within a minimal region of approximately 10 cM flanked by the marker D6S451 distally and D6S466 proximally. This information is vital towards isolating and characterising the gene for CCD, and is being used to construct a physical map of 6p21.1-6p21.3. More importantly, mapping of the locus in the South African kindred of mixed ancestry, in which the "founder" of the disorder was of Chinese origin, suggests that a single locus is responsible for classic CCD. Images PMID:8782054

  1. Mapping of the gene for cleidocranial dysplasia in the historical Cape Town (Arnold) kindred and evidence for locus homogeneity.

    PubMed

    Ramesar, R S; Greenberg, J; Martin, R; Goliath, R; Bardien, S; Mundlos, S; Beighton, P

    1996-06-01

    Cleidocranial dysplasia (CCD) is an autosomal dominant disorder, features of which include a patient anterior fontanelle, a bulging calvarium, hypoplasia or aplasia of the clavicles, a wide public symphysis, dental anomalies, vertebral malformation, and short stature. The Cape Town kindred which is under our genetic management was originally described more than four decades ago and now consists of more than 1000 people. Following reports of rearrangements on chromosomes 6 and 8 in people with CCD, we have carried out linkage analyses between highly information microsatellite dinucleotide repeat markers in the rearranged regions and the disorder in a branch of this South African CCD kindred, consisting of 38 subjects, 18 of whom are affected. Maximum lod scores (at theta = 0.00) of 7.14 (for marker D6S459), 4.32 (TCTE), 4.99 (D6S452), 5.97 (D6S269), and 3.95 (D6S465) confirm linkage of the disorder to the short arm of chromosome 6. Our data indicate that the CCD gene is located within a minimal region of approximately 10 cM flanked by the marker D6S451 distally and D6S466 proximally. This information is vital towards isolating and characterising the gene for CCD, and is being used to construct a physical map of 6p21.1-6p21.3. More importantly, mapping of the locus in the South African kindred of mixed ancestry, in which the "founder" of the disorder was of Chinese origin, suggests that a single locus is responsible for classic CCD. PMID:8782054

  2. 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

  3. A New Role for LOC101928437 in Non-Syndromic Intellectual Disability: Findings from a Family-Based Association Test.

    PubMed

    Zhou, Shaohe; Shi, Zhangyan; Cui, Meng; Li, Junlin; Ma, Zhe; Shi, Yuanyu; Zheng, Zijian; Zhang, Fuchang; Jin, Tianbo; Geng, Tingting; Chen, Chao; Guo, Yale; Zhou, Jianping; Huang, Shaoping; Guo, Xingli; Gao, Lin; Gong, Pingyuan; Gao, Xiaocai; Zhang, Kejin

    2015-01-01

    Non-syndromic intellectual disability (NSID) is mental retardation in persons of normal physical appearance who have no recognisable features apart from obvious deficits in intellectual functioning and adaptive ability; however, its genetic etiology of most patients has remained unknown. The main purpose of this study was to fine map and identify specific causal gene(s) by genotyping a NSID family cohort using a panel of markers encompassing a target region reported in a previous work. A total of 139 families including probands, parents and relatives were included in the household survey, clinical examinations and intelligence tests, recruited from the Qinba mountain region of Shannxi province, western China. A collection of 34 tagged single nucleotide polymorphisms (tSNPs) spanning five microsatellite marker (STR) loci were genotyped using an iPLEX Gold assay. The association between tSNPs and patients was analyzed by family-based association testing (FBAT) and haplotype analysis (HBAT). Four markers (rs5974392, rs12164331, rs5929554 and rs3116911) in a block that showed strong linkage disequilibrium within the first three introns of the LOC101928437 locus were found to be significantly associated with NSID (all P<0.01) by the FBAT method for a single marker in additive, dominant and recessive models. The results of haplotype tests of this block also revealed a significant association with NSID (all P<0.05) using 2-window and larger HBAT analyses. These results suggest that LOC101928437 is a novel candidate gene for NSID in Han Chinese individuals of the Qinba region of China. Although the biological function of the gene has not been well studied, knowledge about this gene will provide insights that will increase our understanding of NSID development. PMID:26287547

  4. Extrapyramidal features in advanced Down's syndrome: clinical evaluation and family history.

    PubMed Central

    Vieregge, P; Ziemens, G; Freudenberg, M; Piosinski, A; Muysers, A; Schulze, B

    1991-01-01

    Extrapyramidal, frontal release, and other neurological signs were studied in 54 demented and non-demented patients with Down's syndrome (DS). Fourteen patients were demented and five showed extrapyramidal signs, mainly of the rigid-hypokinetic spectrum and similar to Parkinsonian features in advanced Alzheimer's disease (AD). None of the non-demented patients had Parkinsonian signs. The mean age of the demented DS patients with extrapyramidal signs was significantly higher than that of the patients without. Frontal release signs were present in demented and non-demented patients. A questionnaire showed no increase in either the proportion of early- or senile-onset dementia or Parkinsonism among first- and second-degree relatives of DS patients. Parkinsonian signs appear to be present at a lower frequency in DS than in advanced AD. A speculative hypothesis about a gene dosage effect of Cu/Zn-superoxide dismutase in preventing toxic radical formation in the substantia nigra of DS patients is presented. PMID:1826326

  5. Fraccaro syndrome: report of two Iranian cases: an infant and an adult in a family.

    PubMed

    Hadipour, Fatemeh; Shafeghati, Yousef; Bagherizadeh, Eiman; Behjati, Farkhondeh; Hadipour, Zahra

    2013-01-01

    49,XXXXY is rare chromosomal pattern and these patients have mental retardation, small penis, cryptorchidism and skeletal anomalies. We reported a 10 month-old boy who has hypotonia, microcephaly, hypertelorism, depressed nasal bridge, epicanthic folds and bilateral multiple ear tags, high arched palate, down set ears, micrognathia and congenital heart disease such as patent ductus arteriosus (PDA), Atrial septal defect (ASD), mild pulmonary stenosis. Among the skeletal anomalies, he has kyphoscoliosis, clinodactyly of the fourth and fifth fingers of both hands, and bilateral club foot and unilateral dysplasia of the hip. Karyotype was found as 49,XXXXY[44]/48,XXXY[6] and this cytogenetic analysis was help to establish clinical diagnosis Fraccaro syndrome. PMID:24442548

  6. A Plakophilin-1 Gene Mutation in an Egyptian Family with Ectodermal Dysplasia-Skin Fragility Syndrome

    PubMed Central

    Abdalla, Ebtesam M.; Has, Cristina

    2014-01-01

    Ectodermal dysplasia-skin fragility syndrome (ED-SFS) is a rare genodermatosis caused by mutations in the PKP1 gene, encoding the desmosomal plaque protein plakophilin-1. Since its initial description in 1997, few individuals with this disorder have been reported to date. Here, we present the first Egyptian cases of ED-SFS, carrying a novel homozygous mutation in the PKP1 gene. Direct sequencing of the amplified DNA from the affected cases disclosed a G-to-T transversion at nucleotide position c.203-1 within intron 1 of PKP1 (c.203-1G>T). To the best of our knowledge, this mutation has not been previously described in the databases. PMID:25565931

  7. Fragile X syndrome and the (CGG)[sub n] mutation: Two families with discordant MZ twins

    SciTech Connect

    Kruyer, H.; Estivill, X.; Mila, M.; Ballesta, F.; Glover, G.; Carbonell, P. )

    1994-03-01

    The fragile X phenotype has been found, in the majority of cases, to be due to the expansion of a CGG repeat in the 5'UTR region of the FMR-1 gene, accompanied by methylation of the adjacent CpG island and inactivation of the FMR-1 gene. Although several important aspects of genetics of fragile X have been resolved, it remains to be elucidated at which stage in development the transition from the premutation to the full mutation occurs. The authors present two families in which discordance between two sets of MZ twins illustrates two important genetic points. In one family, two affected MZ brothers differed in the number of CGG repeats, demonstrating in vivo mitotic instability of this CGG repeat and suggesting that the transition to the full mutation occurred postzygotically. In the second family, two MZ sisters had the same number of repeats, but only one was mentally retarded. When the methylation status of the FMR-1 CpG island was studied, the authors found that the majority of normal chromosomes had been inactivated in the affected twin, thus leading to the expression of the fragile X phenotype. 29 refs., 3 figs., 1 tab.

  8. Prenatal Diagnosis of Walker–Warburg Syndrome Using Single Nucleotide Polymorphism Array: A Clinical Experience from Three Related Palestinian Families with Congenital Hydrocephalus

    PubMed Central

    Abumansour, Iman S.; Al Sulmi, Eman; Chodirker, Bernard N.; Hunt, Jennifer C.

    2015-01-01

    Background Congenital hydrocephalus is a common and often disabling disorder. Various syndromic forms of hydrocephalus have been reported in the Palestinian population including Walker–Warburg syndrome (WWS), Carpenter syndrome, and Meckel syndrome. Aim In this report we discuss the antenatal diagnosis of congenital hydrocephalus in three related Palestinian families. Method Single nucleotide polymorphism (SNP) array was performed prenatally for the third affected fetus. Results A diagnosis of WWS was found and molecular testing revealed a known pathogenic mutation in the POMT2 gene. An affected fetus from the other family was diagnosed and tested postnatally in light of this finding. Testing of another affected stillborn offspring was performed and revealed the same mutation. Conclusions Here, we show that the use of prenatal SNP array testing can be helpful in elucidating the etiology of congenital hydrocephalus and in guiding appropriate perinatal care. Also, testing for this specific POMT2 mutation should be considered in cases of prenatally detected hydrocephalus in Palestinian families. PMID:26495167

  9. Genotype-phenotype relationships in fragile X syndrome: A family study

    SciTech Connect

    Loesch, D.Z.; Hay, D.A.; Huggins, R.; Gedeon, A.K.; Mulley, J.C.; Sutherland, G.R.

    1993-11-01

    Relationships between the measures of intellectual and physical status in the fragile X syndrome and the size of amplification of the fragile X-specific fragment, equivalent to the number of CCG repeats within the FMR1 locus, were studied by a maximum-likelihood scoring technique for analysis of pedigree data. This allows for estimation of random effects (genetic and environmental variance) concurrently with other (fixed) effects in a quantitative trait. FMR1 expression is usually shut down in males penetrant for the fragile X syndrome who have hypermethylated CCG amplifications of [ge] 0.6 kb. The assumption of the step versus curvilinear function representing this relationship was tested by the likelihood-ratio criterion. The maximum-likelihood parameters were based on the most appropriate model for each measure. The results were indicative of the presence of a curvilinear relationship between the amplification size and the two intellectual scores, the Peabody Picture Vocabulary Test and Block Design Test, measuring verbal and spatial abilities, respectively. Reasons for the unexpected curvilinear regression between the amplification size and intellectual scores were explained further by methylation analysis of fragile X males with amplifications of 0.6 < [delta] [le] 1.2 kb who appeared to be responsible for the curvilinearity of the relationship. Four of these showed unmethylated status of the amplified bands in lymphocytes, which were presumably transcriptionally active. Removal of the aberrant individuals led to the anticipated step function between amplification and intellectual scores. For the combined anthropometric score, as well as for several single physical measures, the step function was the most appropriate model regardless of the inclusion or omission of the aberrant individuals in the pedigree sample. 35 refs., 3 figs., 3 tabs.

  10. Chromosome 14 and late-onset familial alzheimer disease (FAD)

    SciTech Connect

    Schellenberg, G.D.; Anderson, L.; Nemens, E.; Bird, T.D.; Wijsman, E.M.; Martin, G.M.; Payami, H.; Orr, H.T.; White, J.A.; Alonso, M.E.

    1993-09-01

    Familial Alzheimer disease (FAD) is genetically heterogeneous. Two loci responsible for early-onset FAD have been identified: the amyloid precursor protein gene on chromosome 21 and the as-yet-unidentified locus on chromosome 14. The genetics of late-onset FAD is unresolved. Maximum-likelihood, affected-pedigree-member (APM), and sib-pair analysis were used, in 49 families with a mean age at onset [>=]60 years, to determine whether the chromosome 14 locus is responsible for late-onset FAD. The markers used were D14S53, D14S43, and D14S52. The LOD score method was used to test for linkage of late-onset FAD to the chromosome 14 markers, under three different models: age-dependent penetrance, an affected-only analysis, and age-dependent penetrance with allowance for possible age-dependent sporadic cases. No evidence for linkage was obtained under any of these conditions for the late-onset kindreds, and strong evidence against linkage (LOD score [>=]2.0) to this region was obtained. Heterogeneity tests of the LOD score results for the combined group of families (early onset, Volga Germans, and late onset) favored the hypothesis of linkage to chromosome 14 with genetic heterogeneity. The positive results are primarily from early-onset families. APM analysis gave significant evidence for linkage of D14S43 and D14S52 to FAD in early-onset kindreds (P<.02). No evidence for linkage was found for the entire late-onset family group. Significant evidence for linkage to D14S52, however, was found for a subgroup of families of intermediate age at onset (mean age at onset [>=]60 years and <70 years). These results indicate that the chromosome 14 locus is not responsible for Alzheimer disease in most late-onset FAD kindreds but could play a role in a subset of these kindreds. 37 refs., 1 fig., 6 tabs.

  11. Novel heterozygous mutation c.4282G>T in the SCN5A gene in a family with Brugada syndrome

    PubMed Central

    ZHU, JIAN-FANG; DU, LI-LI; TIAN, YUAN; DU, YI-MEI; ZHANG, LING; ZHOU, TAO; TIAN, LI

    2015-01-01

    Brugada syndrome (BrS) is a rare, inherited arrhythmia syndrome. The most well-known gene that is responsible for causing BrS is SCN5A, which encodes the human cardiac Na+ channel (Nav1.5) α subunit. To date, it has been reported that >100 mutations in SCN5A can cause BrS. In the present study, a novel BrS-associated Nav1.5 mutation, A1428S, was identified in a proband who was successfully resuscitated from an episode of sudden collapse during walking. This mutation was further confirmed by polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis, which showed that the PCR fragment containing the mutation A1428S could be cut by the restriction enzyme Nsi1, yielding two shorter DNA fragments of 329 and 159 bp, which were not present in family members homozygous for the wild-type (WT) allele. Furthermore, the electrophysiological properties were analyzed by patch clamp technique. Current density was decreased in the A1428S mutant compared that in the WT. However, neither the steady-state activation or inactivation, nor the recovery from inactivation exhibited changes between the A1428S mutant and the WT. In conclusion, the results of this study are consistent with the hypothesis that a reduction in Nav1.5 channel function is involved in the pathogenesis of BrS. The structural-functional study of the Nav1.5 channel enhances the present understanding the pathophysiological function of the channel. PMID:26136871

  12. Pigmentary Markers in Danes – Associations with Quantitative Skin Colour, Nevi Count, Familial Atypical Multiple-Mole, and Melanoma Syndrome

    PubMed Central

    Johansen, Peter; Andersen, Jeppe Dyrberg; Madsen, Linnea Nørgård; Ullum, Henrik; Glud, Martin; Børsting, Claus; Gniadecki, Robert; Morling, Niels

    2016-01-01

    To investigate whether pigmentation genes involved in the melanogenic pathway (melanogenesis) contributed to melanoma predisposition, we compared pigmentary genetics with quantitative skin pigmentation measurements, the number of atypical nevi, the total nevus count, and the familial atypical multiple mole and melanoma (FAMMM) syndrome. We typed 32 pigmentary SNP markers and sequenced MC1R in 246 healthy individuals and 116 individuals attending periodic control for malignant melanoma development, 50 of which were diagnosed with FAMMM. It was observed that individuals with any two grouped MC1R variants (missense, NM_002386:c. 456C > A (p.TYR152*), or NM_002386:c.83_84insA (p.Asn29Glnfs*14) had significantly (p<0.001) lighter skin pigmentation of the upper-inner arm than those with none or one MC1R variant. We did not observe any significant association of the MC1R variants with constitutive pigmentation measured on the buttock area. We hypothesize that the effect of MC1R variants on arm pigmentation is primarily reflecting the inability to tan when subjected to UVR. A gender specific effect on skin pigmentation was also observed, and it was found that the skin pigmentation of females on average were darker than that of males (p<0.01). We conclude that MC1R variants are associated with quantitative skin colour in a lightly pigmented Danish population. We did not observe any association between any pigmentary marker and the FAMMM syndrome. We suggest that the genetics of FAMMM is not related to the genetics of the pigmentary pathway. PMID:26938746

  13. A comparison of family financial and employment impacts of fragile X syndrome, autism spectrum disorders, and intellectual disability.

    PubMed

    Ouyang, Lijing; Grosse, Scott D; Riley, Catharine; Bolen, Julie; Bishop, Ellen; Raspa, Melissa; Bailey, Donald B

    2014-07-01

    This study compares the family financial and employment impacts of having a child with fragile X syndrome (FXS), autism spectrum disorder (ASD), or intellectual disabilities (ID). Data from a 2011 national survey of families of children with FXS were matched with data from the National Survey of Children with Special Health Care Needs 2009-2010 to form four analytic groups: children with FXS (n=189), children with special health care needs with ASD only (n=185), ID only (n=177), or both ASD and ID (n=178). Comparable percentages of parents of children with FXS (60%) and parents of children with both ASD and ID (52%) reported that their families experienced a financial burden as a result of the condition, both of which were higher than the percentages of parents of children with ASD only (39%) or ID only (29%). Comparable percentages of parents of children with FXS (40%) and parents of children with both ASD and ID (46%) reported quitting employment because of the condition, both of which were higher than the percentages of parents of children with ID only (25%) or ASD only (25%). In multivariate analyses controlling for co-occurring conditions and functional difficulties and stratified by age, adjusted odds ratios for the FXS group aged 12-17 years were significantly elevated for financial burden (2.73, 95% CI 1.29-5.77), quitting employment (2.58, 95% CI 1.18-5.65) and reduced hours of work (4.34, 95% CI 2.08-9.06) relative to children with ASD only. Among children aged 5-11 years, the adjusted odds ratios for the FXS group were elevated but statistically insignificant for financial burden (1.63, 95% CI 0.85-3.14) and reducing hours of work (1.34, 95% CI 0.68-2.63) relative to children with ASD only. Regardless of condition, co-occurring anxiety or seizures, limits in thinking, reasoning, or learning ability, and more irritability were significantly associated with more caregiver financial and employment impacts. Proper management of anxiety or seizures and

  14. Autosomal Dominant Mutation in the Signal Peptide of Renin in a Kindred with Anemia, Hyperuricemia, and CKD

    PubMed Central

    Beck, Bodo B.; Trachtman, Howard; Gitman, Michael; Miller, Ilene; Sayer, John A.; Pannes, Andrea; Baasner, Anne; Hildebrandt, Friedhelm; Wolf, Matthias T.F.

    2012-01-01

    Homozygous or compound heterozygous Renin (REN) mutations cause renal tubular dysgenesis (RTD), which is characterized by death in utero due to renal failure and pulmonary hypoplasia. The phenotype resembles the fetopathy caused by angiotensin-converting enzyme inhibitor or angiotensin receptor blocker intake during pregnancy. Recently, heterozygous REN mutations were shown to result in early-onset hyperuricemia, anemia and chronic renal failure. So far, only three different heterozygous REN mutations were reported. We performed mutation analysis of the REN gene in 39 kindreds with hyperuricemia and chronic kidney disease (CKD) previously tested negative for mutations in the UMOD and HNF1β genes. We identified one kindred with a novel c.28T>C (p.W10R) REN mutation in the signal sequence, concluding that REN mutations are rare events in CKD patients. Affected individuals over four generations were identified carrying the novel REN mutation and were characterized by significant anemia, hyperuricemia and CKD. Anemia was severe and disproportional to the degree of renal impairment. Moreover all heterozygous REN mutations are localized in the signal sequence. Therefore, screening of the REN gene for CKD patients with hyperuricemia and anemia may be focusing on exon 1 sequencing, which encodes the signal peptide. PMID:21903317

  15. Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families.

    PubMed

    Steinke, Verena; Holzapfel, Stefanie; Loeffler, Markus; Holinski-Feder, Elke; Morak, Monika; Schackert, Hans K; Görgens, Heike; Pox, Christian; Royer-Pokora, Brigitte; von Knebel-Doeberitz, Magnus; Büttner, Reinhard; Propping, Peter; Engel, Christoph

    2014-07-01

    Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome. PMID:24493211

  16. Screening of DFNB3 in Iranian families with autosomal recessive non-syndromic hearing loss reveals a novel pathogenic mutation in the MyTh4 domain of the MYO15A gene in a linked family

    PubMed Central

    Reiisi, Somayeh; Tabatabaiefar, Mohammad Amin; Sanati, Mohammad Hosein; Chaleshtori, Morteza Hashemzadeh

    2016-01-01

    Objective(s): Non-syndromic sensorineural hearing loss (NSHL) is a common disorder affecting approximately 1 in 500 newborns. This type of hearing loss is extremely heterogeneous and includes over 100 loci. Mutations in the GJB2 gene have been implicated in about half of autosomal recessive non-syndromic hearing loss (ARNSHL) cases, making this the most common cause of ARNSHL. For the latter form of deafness, most frequent genes proposed include GJB2, SLC26A4, MYO15A, OTOF, and CDH23 worldwide. Materials and Methods: The aim of the present study was to define the role and frequency of MYO15A gene mutation in Iranian families. In this study 30 Iranian families were enrolled with over three deaf children and negative for GJB2. Then linkage analysis was performed by six DFNB3 short tandem repeat markers. Following that, mutation detection accomplished using DNA sequencing. Results: One family (3.33%) showed linkage to DFNB3 and a novel mutation was identified in the MYO15A gene (c.6442T>A): as the disease-causing mutation. Mutation co-segregated with hearing loss in the family but was not present in the 100 ethnicity-matched controls. Conclusion: Our results confirmed that the hearing loss of the linked Iranian family was caused by a novel missense mutation in the MYO15A gene. This mutation is the first to be reported in the world and affects the first MyTH4 domain of the protein.

  17. Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1.

    PubMed

    Monroe, Glen R; Harakalova, Magdalena; van der Crabben, Saskia N; Majoor-Krakauer, Danielle; Bertoli-Avella, Aida M; Moll, Frans L; Oranen, Björn I; Dooijes, Dennis; Vink, Aryan; Knoers, Nine V; Maugeri, Alessandra; Pals, Gerard; Nijman, Isaac J; van Haaften, Gijs; Baas, Annette F

    2015-06-01

    Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation. PMID:25845371

  18. Single TCR-Vβ2 evaluation discloses the circulating T cell clone in Sezary syndrome: one family fits all!

    PubMed

    Scala, Enrico; Abeni, Damiano; Pomponi, Debora; Russo, Nicoletta; Russo, Giandomenico; Narducci, Maria Grazia

    2015-08-01

    Sézary Syndrome (SS/L-CTCL) is a rare but aggressive variant of cutaneous T cell lymphoma (CTCL), characterized by erythroderma, lymphadenopathy, and the presence of a circulating memory CD4(+) T cell malignant clone with a skin homing behavior, lacking CD26 and CD49d and over-expressing CD60. The availability of a panel of monoclonal antibodies recognizing distinct TCR-Vβ families, allows to typify the clone by flow cytometry in about 70 % of cases. The TCR-Vβ repertoire of 533 individuals, comprising 308 patients affected by CTCL, 50 healthy donors, and subjects affected by various non-neoplastic dermatological affections was evaluated by flow cytometry. Statistical analyses were performed using the SPSS statistical software package for Microsoft Windows (SPSS, version 21, Chicago, IL). TCR-Vβ2 levels below 5.4 % or above 39.5 %, within total CD4(+) T cells, showed the best balance between sensitivity (98.1 %) and specificity (96 %) to identify the presence of a clone in the peripheral blood of patients affected by SS. Based on this observation, a "two-step" procedure in the detection of the malignant T cell clone in CTCLs is herein suggested. TCR-Vβ2 assessment in all cases (first step). In the case of TCR-Vβ2 levels above 39.5 %, the presence of a clonal expansion of this family is suggested, deserving further confirmation by means of T cell gene rearrangement evaluation. In patients having a TCR-Vβ2 reactivity below 5.4 % (second step), the entire TCR-Vβ repertoire should be evaluated to typify the expanded clone. In conclusion, the single TCR-Vβ2 expression check, instead of the entire repertoire assessment, represents an easy and cost-effective method for the recognition of CTCL aggressive leukemic variant. PMID:25733488

  19. Two sisters with clinical diagnosis of Wiskott-Aldrich Syndrome: Is the condition in the family autosomal recessive?

    SciTech Connect

    Kondoh, T.; Hayashi, K.; Matsumoto, T.

    1995-10-09

    We report two sisters in a family representing manifestations of Wiskott-Aldrich syndrome (WAS), an X-linked immunodeficiency disorder. An elder sister had suffered from recurrent infections, small thrombocytopenic petechiae, purpura, and eczema for 7 years. The younger sister had the same manifestations as the elder sister`s for a 2-year period, and died of intracranial bleeding at age 2 years. All the laboratory data of the two patients were compatible with WAS, although they were females. Sialophorin analysis with the selective radioactive labeling method of this protein revealed that in the elder sister a 115-KD band that should be specific for sialophorin was reduced in quantity, and instead an additional 135-KD fragment was present as a main band. Polymerase chain reaction (PCR) analysis of the sialophorin gene and single-strand conformation polymorphism (SSCP) analysis of the PCR product demonstrated that there were no detectable size-change nor electrophoretic mobility change in the DNA from both patients. The results indicated that their sialophorin gene structure might be normal. Studies on the mother-daughter transmission of X chromosome using a pERT84-MaeIII polymorphic marker mapped at Xp21 and HPRT gene polymorphism at Xq26 suggested that each sister had inherited a different X chromosome from the mother. Two explanations are plausible for the occurrence of the WAS in our patients: the WAS in the patients is attributable to an autosomal gene mutation which may regulate the sialophorin gene expression through the WAS gene, or, alternatively, the condition in this family is an autosomal recessive disorder separated etiologically from the X-linked WAS. 17 refs., 6 figs., 1 tab.

  20. Familial 1.3-Mb 11p15.5p15.4 Duplication in Three Generations Causing Silver-Russell and Beckwith-Wiedemann Syndromes

    PubMed Central

    Vals, Mari-Anne; Kahre, Tiina; Mee, Pille; Muru, Kai; Kallas, Eha; Žilina, Olga; Tillmann, Vallo; Õunap, Katrin

    2015-01-01

    Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 opposite growth-affecting disorders. The common molecular cause for both syndromes is an abnormal regulation of genes in chromosomal region 11p15, where 2 imprinting control regions (ICR) control fetal and postnatal growth. Also, many submicroscopic chromosomal disturbances like duplications in 11p15 have been described among SRS and BWS patients. Duplications involving both ICRs cause SRS or BWS, depending on which parent the aberration is inherited from. We describe to our knowledge the smallest familial pure 1.3-Mb duplication in chromosomal region 11p15.5p15.4 that involves both ICRs and is present in 3 generations causing an SRS or BWS phenotype. PMID:26732610

  1. Familial 1.3-Mb 11p15.5p15.4 Duplication in Three Generations Causing Silver-Russell and Beckwith-Wiedemann Syndromes.

    PubMed

    Vals, Mari-Anne; Kahre, Tiina; Mee, Pille; Muru, Kai; Kallas, Eha; Žilina, Olga; Tillmann, Vallo; Õunap, Katrin

    2015-09-01

    Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) are 2 opposite growth-affecting disorders. The common molecular cause for both syndromes is an abnormal regulation of genes in chromosomal region 11p15, where 2 imprinting control regions (ICR) control fetal and postnatal growth. Also, many submicroscopic chromosomal disturbances like duplications in 11p15 have been described among SRS and BWS patients. Duplications involving both ICRs cause SRS or BWS, depending on which parent the aberration is inherited from. We describe to our knowledge the smallest familial pure 1.3-Mb duplication in chromosomal region 11p15.5p15.4 that involves both ICRs and is present in 3 generations causing an SRS or BWS phenotype. PMID:26732610

  2. Rett Syndrome and Beyond: Recurrent Spontaneous and Familial MECP2 Mutations at CpG Hotspots

    PubMed Central

    Wan, Mimi; Lee, Stephen Sung Jae; Zhang, Xianyu; Houwink-Manville, Isa; Song, Hae-Ri; Amir, Ruthie E.; Budden, Sarojini; Naidu, SakkuBai; Pereira, Jose Luiz P.; Lo, Ivan F. M.; Zoghbi, Huda Y.; Schanen, N. Carolyn; Francke, Uta

    1999-01-01

    Summary Rett syndrome (RTT) is a neurodevelopmental disorder characterized by loss of acquired skills after a period of normal development in infant girls. The responsible gene, encoding methyl-CpG binding protein 2 (MeCP2), was recently discovered. Here we explore the spectrum of phenotypes resulting from MECP2 mutations. Both nonsense (R168X and R255X) and missense (R106W and R306C) mutations have been found, with multiple recurrences. R168X mutations were identified in six unrelated sporadic cases, as well as in two affected sisters and their normal mother. The missense mutations were de novo and affect conserved domains of MeCP2. All of the nucleotide substitutions involve C→T transitions at CpG hotspots. A single nucleotide deletion, at codon 137, that creates a L138X stop codon within the methyl-binding domain was found in an individual with features of RTT and incontinentia pigmenti. An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy. Thus, some males with RTT-causing MECP2 mutations may survive to birth, and female heterozygotes with favorably skewed X-inactivation patterns may have little or no involvement. Therefore, MECP2 mutations are not limited to RTT and may be implicated in a much broader phenotypic spectrum. PMID:10577905

  3. A novel mutation of the MITF gene in a family with Waardenburg syndrome type 2: A case report

    PubMed Central

    SHI, YUNFANG; LI, XIAOZHOU; JU, DUAN; LI, YAN; ZHANG, XIULING; ZHANG, YING

    2016-01-01

    Waardenburg syndrome (WS) is an autosomal dominant disorder with varying degrees of sensorineural hearing loss, and accumulation of pigmentation in hair, skin and iris. There are four types of WS (WS1–4) with differing characteristics. Mutations in six genes [paired box gene 3 (PAX3), microphthalmia-associated transcription factor (MITF), endothelin 3 (END3), endothelin receptor type B (EDNRB), SRY (sex determining region Y)-box 10 (SOX10) and snail homolog 2 (SNAI2)] have been identified to be associated with the various types. This case report describes the investigation of genetic mutations in three patients with WS2 from a single family. Genomic DNA was extracted, and the six WS-related genes were sequenced using next-generation sequencing technology. In addition to mutations in PAX3, EDNRB and SOX10, a novel heterozygous MITF mutation, p.Δ315Arg (c.944_946delGAA) on exon 8 was identified. This is predicted to be a candidate disease-causing mutation that may affect the structure and function of the enzyme. PMID:27073475

  4. A new family with an SLC9A6 mutation expanding the phenotypic spectrum of Christianson syndrome.

    PubMed

    Masurel-Paulet, Alice; Piton, Amélie; Chancenotte, Sophie; Redin, Claire; Thauvin-Robinet, Christel; Henrenger, Yvan; Minot, Delphine; Creppy, Audrey; Ruffier-Bourdet, Marie; Thevenon, Julien; Kuentz, Paul; Lehalle, Daphné; Curie, Aurore; Blanchard, Gaelle; Ghosn, Ezzat; Bonnet, Marlene; Archimbaud-Devilliers, Mélanie; Huet, Frédéric; Perret, Odile; Philip, Nicole; Mandel, Jean-Louis; Faivre, Laurence

    2016-08-01

    Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression. The proband and his maternal uncle both have an attenuated phenotype with mild ID, attention deficit disorder, speech difficulties, and mild asymptomatic cerebellar atrophy. The proband also have microcephaly. The mutation cosegregated with learning disabilities and speech difficulties in the female carriers (mother and three sisters of the proband). Detailed neuropsychological, speech, and occupational therapy investigations in the female carriers revealed impaired oral and written language acquisition, with dissociation between verbal and performance IQ. An abnormal phenotype, ranging from learning disability with predominant speech difficulties to mild intellectual deficiency, has been described previously in a large proportion of female carriers. Besides broadening the clinical spectrum of SLC9A6 gene mutations, we present an example of a monogenic origin of mild learning disability. © 2016 Wiley Periodicals, Inc. PMID:27256868

  5. Genome-wide copy number scan identifies IRF6 involvement in Van der Woude syndrome in an Indian family.

    PubMed

    Manjegowda, Dinesh S; Prasad, Manu; Veerappa, Avinash M; Ramachandra, Nallur B

    2014-01-01

    Summary Van der Woude syndrome (VWS) is an autosomal dominant developmental malformation presenting with bilateral lower lip pits related to cleft lip, cleft palate and other malformations. We performed a whole-genome copy number variations (CNVs) scan in an Indian family with members suffering from VWS using 2·6 million combined SNP and CNV markers. We found CNVs affecting IRF6, a known candidate gene for VWS, in all three cases, while none of the non-VWS members showed any CNVs in the IRF6 region. The duplications and deletions of the chromosomal critical region in 1q32-q41 confirm the involvement of CNVs in IRF6 in South Indian VWS patients. Molecular network analysis of these and other cleft lip/palate related module genes suggests that they are associated with cytokine-mediated signalling pathways and response to interferon-gamma mediated signalling pathways. This is a maiden study indicating the involvement of CNVs in IRF6 in causing VWS in the Indian population. PMID:25579819

  6. Whole-Exome Sequencing Identifies Homozygous GPR161 Mutation in a Family with Pituitary Stalk Interruption Syndrome

    PubMed Central

    Karaca, Ender; Buyukkaya, Ramazan; Pehlivan, Davut; Charng, Wu-Lin; Yaykasli, Kursat O.; Bayram, Yavuz; Gambin, Tomasz; Withers, Marjorie; Atik, Mehmed M.; Arslanoglu, Ilknur; Bolu, Semih; Erdin, Serkan; Buyukkaya, Ayla; Yaykasli, Emine; Jhangiani, Shalini N.; Muzny, Donna M.; Gibbs, Richard A.

    2015-01-01

    Context: Pituitary stalk interruption syndrome (PSIS) is a rare, congenital anomaly of the pituitary gland characterized by pituitary gland insufficiency, thin or discontinuous pituitary stalk, anterior pituitary hypoplasia, and ectopic positioning of the posterior pituitary gland (neurohypophysis). The clinical presentation of patients with PSIS varies from isolated growth hormone (GH) deficiency to combined pituitary insufficiency and accompanying extrapituitary findings. Mutations in HESX1, LHX4, OTX2, SOX3, and PROKR2 have been associated with PSIS in less than 5% of cases; thus, the underlying genetic etiology for the vast majority of cases remains to be determined. Objective: We applied whole-exome sequencing (WES) to a consanguineous family with two affected siblings who have pituitary gland insufficiency and radiographic findings of hypoplastic (thin) pituitary gland, empty sella, ectopic neurohypophysis, and interrupted pitiutary stalk—characteristic clinical diagnostic findings of PSIS. Design and Participants: WES was applied to two affected and one unaffected siblings. Results: WES of two affected and one unaffected sibling revealed a unique homozygous missense mutation in GPR161, which encodes the orphan G protein–coupled receptor 161, a protein responsible for transducing extracellular signals across the plasma membrane into the cell. Conclusion: Mutations of GPR161 may be implicated as a potential novel cause of PSIS. PMID:25322266

  7. A missense mutation in TMEM67 causes Meckel-Gruber syndrome type 3 (MKS3): a family from China

    PubMed Central

    Zhang, Manli; Cheng, Jing; Liu, Aijun; Wang, Longxia; Xiong, Lihua; Chen, Meixia; Sun, Yi; Li, Jianzhong; Lu, Yu; Yuan, Huijun; Li, Yali; Lu, Yanping

    2015-01-01

    Meckel-Gruber syndrome (MKS) is a lethal autosomal recessive condition characterized by renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. Genetic heterogeneity has been demonstrated at eleven loci, MKS1-11. Here, we present the clinical and molecular characteristics of a Chinese MKS3 family with occipital encephalocele and kidney enlargement. DNA sequencing of affected fetuses revealed a homozygous c.1645C>T substitution in exon 16 of TMEM67, leading to a p.R549C substitution in meckelin. The R549 residue is highly conserved across human, rat, mouse, zebrafish, chicken, wolf and platypus genomes. Hha I restriction analysis demonstrated that the c.1645C>T mutation was absent in 200 unrelated control chromosomes of Chinese background, supporting the hypothesis that it represents causative mutation, not rare polymorphism. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype understanding of MKS. PMID:26191240

  8. A missense mutation in TMEM67 causes Meckel-Gruber syndrome type 3 (MKS3): a family from China.

    PubMed

    Zhang, Manli; Cheng, Jing; Liu, Aijun; Wang, Longxia; Xiong, Lihua; Chen, Meixia; Sun, Yi; Li, Jianzhong; Lu, Yu; Yuan, Huijun; Li, Yali; Lu, Yanping

    2015-01-01

    Meckel-Gruber syndrome (MKS) is a lethal autosomal recessive condition characterized by renal cysts and variably associated features, including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly. Genetic heterogeneity has been demonstrated at eleven loci, MKS1-11. Here, we present the clinical and molecular characteristics of a Chinese MKS3 family with occipital encephalocele and kidney enlargement. DNA sequencing of affected fetuses revealed a homozygous c.1645C>T substitution in exon 16 of TMEM67, leading to a p.R549C substitution in meckelin. The R549 residue is highly conserved across human, rat, mouse, zebrafish, chicken, wolf and platypus genomes. Hha I restriction analysis demonstrated that the c.1645C>T mutation was absent in 200 unrelated control chromosomes of Chinese background, supporting the hypothesis that it represents causative mutation, not rare polymorphism. Our data provide additional molecular and clinical information for establishing a better genotype-phenotype understanding of MKS. PMID:26191240

  9. Adaptive-filtering of trisomy 21: risk of Down syndrome depends on family size and age of previous child

    NASA Astrophysics Data System (ADS)

    Neuhäuser, Markus; Krackow, Sven

    2007-02-01

    The neonatal incidence rate of Down syndrome (DS) is well-known to accelerate strongly with maternal age. This non-linearity renders mere accumulation of defects at recombination during prolonged first meiotic prophase implausible as an explanation for DS rate increase with maternal age, but might be anticipated from chromosomal drive (CD) for trisomy 21. Alternatively, as there is selection against genetically disadvantaged embryos, the screening system that eliminates embryos with trisomy 21 might decay with maternal age. In this paper, we provide the first evidence for relaxed filtering stringency (RFS) to represent an adaptive maternal response that could explain accelerating DS rates with maternal age. Using historical data, we show that the proportion of aberrant live births decrease with increased family size in older mothers, that inter-birth intervals are longer before affected neonates than before normal ones, and that primiparae exhibit elevated levels of DS incidence at higher age. These findings are predicted by adaptive RFS but cannot be explained by the currently available alternative non-adaptive hypotheses, including CD. The identification of the relaxation control mechanism and therapeutic restoration of a stringent screen may have considerable medical implications.

  10. A family of RTHβ with p.R316C mutation presenting occasional syndrome of inappropriate secretion of TSH.

    PubMed

    Ueda, Yohei; Tagami, Tetsuya; Tamanaha, Tamiko; Kakita, Maiko; Tanase-Nakao, Kanako; Nanba, Kazutaka; Usui, Takeshi; Naruse, Mitsuhide; Shimatsu, Akira

    2015-01-01

    The syndrome of inappropriate secretion of thyrotropin (SITSH) is a hallmark of resistance to thyroid hormone (RTH) due to mutations in the β isoform of the thyroid hormone receptor (TRβ). Here, we report on a family of RTH due to a TRβ mutation (RTHβ) and presenting occasional SITSH. The proband was a 16 year-old girl with a goiter, detected at a school physical examination. She was initially diagnosed as having euthyroid Hashimoto thyroiditis because her thyroid function was normal with a positive anti-thyroglobulin antibody. Follow-up examinations resulted in mild SITSH on some occasions and euthyroid on the other occasions. A magnetic resonance imaging (MRI) revealed a normal pituitary gland. Because her mother also had mild SITSH, genetic analysis was performed and revealed a heterozygous point mutation in TRβ (p.R316C). Previously, the p.R316C had only been found in severe RTH cases with homozygous mutations or with an ectopic thyroid. Her mother with a heterozygous mutation showed variable RTH phenotype on T3 suppression testing. In conclusion, the prevalence of RTHβ might be underestimated and occasional SITSH could also suggest RTHβ. TRβ gene mutation is not always correlated with the RTH phenotype. PMID:25502991

  11. SETD5 loss-of-function mutation as a likely cause of a familial syndromic intellectual disability with variable phenotypic expression.

    PubMed

    Szczałuba, Krzysztof; Brzezinska, Monika; Kot, Justyna; Rydzanicz, Małgorzata; Walczak, Anna; Stawiński, Piotr; Werner, Bożena; Płoski, Rafał

    2016-09-01

    Loss-of-function de novo mutations in the SETD5 gene, encoding a putative methyltransferase, are an important cause of moderate/severe intellectual disability as evidenced by the results of sequencing large patient cohorts. We present the first familial case of a SETD5 mutation contributing to a phenotype of congenital heart defects and dysmorphic features, with variable expression, in two siblings and their father. Interestingly, the father demonstrated only mild intellectual impairment. Family based exome sequencing combined to careful parental phenotyping may reveal a more complex clinical picture in newly recognized syndromes. © 2016 Wiley Periodicals, Inc. PMID:27375234

  12. Sporadic and familial blepharophimosis -ptosis-epicanthus inversus syndrome: FOXL2 mutation screen and MRI study of the superior levator eyelid muscle.

    PubMed

    Dollfus, H; Stoetzel, C; Riehm, S; Lahlou Boukoffa, W; Bediard Boulaneb, F; Quillet, R; Abu-Eid, M; Speeg-Schatz, C; Francfort, J J; Flament, J; Veillon, F; Perrin-Schmitt, F

    2003-02-01

    The analysis of the FOXL2 gene (3q23) in a series of two families and two sporadic cases affected with Blepharophimosis-Ptosis-Epicanthus Inversus Syndrome (BPES) is presented. This study detected two novel FOXL2 mutations (missence and nonsens mutations) and confirmed the recurrence of a previously described duplication. Magnetic Resonance Imaging (MRI) of the orbit, in one family, showed absence or hypotrophy of the eyelid superior levator muscle suggesting a possible role of FOXL2 in the development of this extra-ocular muscle. PMID:12630957

  13. In situ hybridisation detects pro-apoptotic gene expression of a Bcl-2 family member in white syndrome-affected coral.

    PubMed

    Ainsworth, T D; Knack, B; Ukani, L; Seneca, F; Weiss, Y; Leggat, W

    2015-12-01

    White syndrome has been described as one of the most prolific diseases on the Great Barrier Reef. Previously, apoptotic cell death has been described as the mechanism driving the characteristic rapid tissue loss associated with this disease, but the molecular mechanisms controlling apoptotic cell death in coral disease have yet to be investigated. In situ methods were used to study the expression patterns of 2 distinct regulators of apoptosis in Acropora hyacinthus tissues undergoing white syndrome and apoptotic cell death. Apoptotic genes within the Bcl-2 family were not localized in apparently healthy coral tissues. However, a Bcl-2 family member (bax-like) was found to localize to cells and tissues affected by white syndrome and those with morphological evidence for apoptosis. A potential up-regulation of pro-apoptotic or bax-like gene expression in tissues with apoptotic cell death adjacent to disease lesions is consistent with apoptosis being the primary cause of rapid tissue loss in coral affected by white syndrome. Pro-apoptotic (bax-like) expression in desmocytes and the basal tissue layer, the calicodermis, distant from the disease lesion suggests that apoptosis may also underlie the sloughing of healthy tissues associated with the characteristic, rapid spread of tissue loss, evident of this disease. This study also shows that in situ hybridisation is an effective tool for studying gene expression in adult corals, and wider application of these methods should allow a better understanding of many aspects of coral biology and disease pathology. PMID:26648107

  14. Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome

    PubMed Central

    Mele, Caterina; Lemaire, Mathieu; Iatropoulos, Paraskevas; Piras, Rossella; Bresin, Elena; Bettoni, Serena; Bick, David; Helbling, Daniel; Veith, Regan; Valoti, Elisabetta; Donadelli, Roberta; Murer, Luisa; Neunhäuserer, Maria; Breno, Matteo; Frémeaux-Bacchi, Véronique; Lifton, Richard; Noris, Marina

    2015-01-01

    Background and objectives Genetic and acquired abnormalities causing dysregulation of the complement alternative pathway contribute to atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute kidney failure. However, in a substantial proportion of patients the disease-associated alterations are still unknown. Design, setting, participants, & measurements Whole-exome and whole-genome sequencing were performed in two unrelated families with infantile recessive aHUS. Sequencing of cDNA from affected individuals was used to test for the presence of aberrant mRNA species. Expression of mutant diacylglycerol kinase epsilon (DGKE) protein was evaluated with western blotting. Results Whole-exome sequencing analysis with conventional variant filtering parameters did not reveal any obvious candidate mutation in the first family. The report of aHUS-associated mutations in DGKE, encoding DGKE, led to re-examination of the noncoding DGKE variants obtained from next-generation sequencing, allowing identification of a novel intronic DGKE mutation (c.888+40A>G) that segregated with disease. Sequencing of cDNA from affected individuals revealed aberrant forms of DGKE mRNA predicted to cause profound abnormalities in the protein catalytic site. By whole-genome sequencing, the same mutation was found in compound heterozygosity with a second nonsense DGKE mutation in all affected siblings of another unrelated family. Homozygous and compound heterozygous patients presented similar clinical features, including aHUS presentation in the first year of life, multiple relapsing episodes, and proteinuria, which are prototypical of DGKE-associated aHUS. Conclusions This is the first report of a mutation located beyond the exon-intron boundaries in aHUS. Intronic mutations such as these are underreported because conventional filtering parameters used to process next-generation sequencing data routinely

  15. Encyclopaedia of tumour-associated familial disorders. Part I: from AIMAH to CHIME syndrome

    PubMed Central

    Sijmons, Rolf H

    2008-01-01

    Cancer is associated with a wide range of hereditary disorders. Recognizing these disorders in cancer patients may be of great importance for the medical management of both patients and their relatives. Conversely, recognizing the fact that cancer may develop as a complication of a particular hereditary disorder which has already been diagnosed may be important for the same reason. The Familial Cancer Database (FaCD) is a web-based application which has been developed at our department with the intention to assist clinicians and genetic counsellors in making a genetic differential diagnosis in cancer patients, as well as in becoming aware of the tumour spectrum associated with hereditary disorders that have already been diagnosed in their patients. This encyclopaedia is published in parts and discusses the disorders included in the FaCD database in alphabetical order. It lists names, synonyms, OMIM number, mode of inheritance, associated genes, phenotype, clinical discussion and references. The purpose of presenting this encyclopaedia in paper format is simply that we hope that you as clinicians and researchers find it helpful to browse through it and familiarize yourself even better with the scope of genetic disorders that have been associated with increased tumour risk. PMID:19706204

  16. Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio.

    PubMed

    Bodian, Dale L; Solomon, Benjamin D; Khromykh, Alina; Thach, Dzung C; Iyer, Ramaswamy K; Link, Kathleen; Baker, Robin L; Baveja, Rajiv; Vockley, Joseph G; Niederhuber, John E

    2014-11-01

    Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, most often the mother-father-proband trio, using bioinformatics pipelines that filter genetic variants by mode of inheritance. However, current pipelines are limited to Mendelian inheritance patterns and do not specifically address disorders caused by mutations in imprinted genes, such as forms of Angelman syndrome and Beckwith-Wiedemann syndrome. Using publicly available tools, we implemented a genetic inheritance search mode to identify imprinted-gene mutations. Application of this search mode to whole-genome sequences from a family trio led to a diagnosis for a proband for whom extensive clinical testing and Mendelian inheritance-based sequence analysis were nondiagnostic. The condition in this patient, IMAGe syndrome, is likely caused by the heterozygous mutation c.832A>G (p.Lys278Glu) in the imprinted gene CDKN1C. The genotypes and disease status of six members of the family are consistent with maternal expression of the gene, and allele-biased expression was confirmed by RNA-Seq for the heterozygotes. This analysis demonstrates that an imprinted-gene search mode is a valuable addition to genome sequence analysis pipelines for identifying disease-causative variants. PMID:25614875

  17. Diagnosis of an imprinted-gene syndrome by a novel bioinformatics analysis of whole-genome sequences from a family trio

    PubMed Central

    Bodian, Dale L; Solomon, Benjamin D; Khromykh, Alina; Thach, Dzung C; Iyer, Ramaswamy K; Link, Kathleen; Baker, Robin L; Baveja, Rajiv; Vockley, Joseph G; Niederhuber, John E

    2014-01-01

    Whole-genome sequencing and whole-exome sequencing are becoming more widely applied in clinical medicine to help diagnose rare genetic diseases. Identification of the underlying causative mutations by genome-wide sequencing is greatly facilitated by concurrent analysis of multiple family members, most often the mother–father–proband trio, using bioinformatics pipelines that filter genetic variants by mode of inheritance. However, current pipelines are limited to Mendelian inheritance patterns and do not specifically address disorders caused by mutations in imprinted genes, such as forms of Angelman syndrome and Beckwith–Wiedemann syndrome. Using publicly available tools, we implemented a genetic inheritance search mode to identify imprinted-gene mutations. Application of this search mode to whole-genome sequences from a family trio led to a diagnosis for a proband for whom extensive clinical testing and Mendelian inheritance-based sequence analysis were nondiagnostic. The condition in this patient, IMAGe syndrome, is likely caused by the heterozygous mutation c.832A>G (p.Lys278Glu) in the imprinted gene CDKN1C. The genotypes and disease status of six members of the family are consistent with maternal expression of the gene, and allele-biased expression was confirmed by RNA-Seq for the heterozygotes. This analysis demonstrates that an imprinted-gene search mode is a valuable addition to genome sequence analysis pipelines for identifying disease-causative variants. PMID:25614875

  18. Scheie syndrome

    MedlinePlus

    ... for families who have a child with Scheie syndrome, to help them understand the condition and possible treatments. Prenatal testing is available. Alternative Names Mucopolysaccharidosis type I S; MPS ...

  19. Reifenstein syndrome

    MedlinePlus

    ... with the gene will be affected. Every female child has a 50% chance of carrying the gene. Family history is important in determining risk factors. The syndrome is estimated to affect 1 in 99,000 people.

  20. Waardenburg syndrome

    MedlinePlus

    ... conditions passed down through families. The syndrome involves deafness and pale skin, hair, and eye color. ... Symptoms may include: Cleft lip (rare) Constipation Deafness (more ... that don't match ( heterochromia ) Pale color skin, hair, and ...

  1. Hunter syndrome

    MedlinePlus

    Genetic counseling is recommended for couples who want to have children and who have a family history of Hunter syndrome. Prenatal testing is available. Carrier testing for female relatives of affected males is available at a few centers.

  2. Down syndrome

    MedlinePlus

    ... their limitations, they may also feel frustration and anger. Many different medical conditions are seen in people ... syndrome and their families deal with the frustration, anger, and compulsive behavior that often occur. Parents and ...

  3. Exclusion of Linkage to the CDL1 Gene Region on Chromosome 3q26.3 in Some Familial Cases of Cornelia de Lange Syndrome

    PubMed Central

    Krantz, Ian D.; Tonkin, Emma; Smith, Melanie; Devoto, Marcella; Bottani, Armand; Simpson, Claire; Hofreiter, Mary; Abraham, Vinod; Jukofsky, Lori; Conti, Brian P.; Strachan, Tom; Jackson, Laird

    2016-01-01

    Cornelia de Lange Syndrome (CdLS) is a complex developmental disorder consisting of characteristic facial features, limb abnormalities, hirsutism, ophthalmologic involvement, gastroesophageal dysfunction, hearing loss, as well as growth and neuro-developmental retardation. Most cases of CdLS appear to be sporadic. Familial cases are rare and indicate autosomal dominant inheritance. Several individuals with CdLS have been reported with chromosomal abnormalities, suggesting candidate genomic regions within which the causative gene(s) may lie. A CdLS gene location (CDL1) has been assigned to 3q26.3 based on phenotypic overlap with the duplication 3q syndrome (critical region 3q26.2-q27) and the report of a CdLS individual with a balanced de novo t(3;17)(q26.3;q23.1). It has been postulated that a gene within the dup3q critical region results in the CdLS when deleted or mutated. We have performed a linkage analysis to the minimal critical region for the dup3q syndrome (that encompasses the translocation breakpoint) on chromosome 3q in 10 rare familial cases of CdLS. Nineteen markers spanning a region of approximately 40 Mb (37 cM) were used. Results of a multipoint linkage analysis demonstrated total lod-scores that were negative across the chromosome 3q26-q27 region. In 4/10 families, lod-scores were less than −2 in the 2 cM region encompassing the translocation, while in the remaining 6/10 families, lod-scores could not exclude linkage to this region. These studies indicate that in some multicase families, the disease gene does not map to the CDL1 region at 3q26.3. PMID:11391654

  4. 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.

  5. Mutations of the AMH type II receptor in two extended families with persistent Müllerian duct syndrome: lack of phenotype/genotype correlation.

    PubMed

    Abduljabbar, Mohammad; Taheini, Khalid; Picard, Jean-Yves; Cate, Richard L; Josso, Nathalie

    2012-01-01

    Our goal was to compare phenotype and genotype in two extended Middle-Eastern families affected by persistent Müllerian duct syndrome due to mutations of the type II anti-Müllerian hormone receptor (AMHR-II). The first, consanguineous, family consisted of 6 boys and 2 girls, the second consisted of 4 girls and 2 boys. In family I, 4 boys and 1 girl were homozygous for a stop mutation in the 9th exon of AMHR-II, removing part of the intracellular domain of the protein. In family II, 1 girl and 1 boy were homozygous for a transversion changing conserved histidine 254 into a glutamine. Both homozygous girls were normal. In the homozygous males, the degree of development of Müllerian derivatives was variable. The uterus was well developed in 2 boys of family I and in the patient from family II; however, in 1 subject from family I, Müllerian derivatives were undetectable. Taken together, the diversity of clinical symptoms within the same sibship and the lack of correlation between the development of the Müllerian derivatives and the severity of the molecular defects suggest highly variable penetrance of the abnormal alleles and/or the existence of other genetic or epigenetic modifiers of gene expression. PMID:22584735

  6. Two Li-Fraumeni syndrome families with novel germline p53 mutations: loss of the wild-type p53 allele in only 50% of tumours.

    PubMed Central

    Sedlacek, Z.; Kodet, R.; Kriz, V.; Seemanova, E.; Vodvarka, P.; Wilgenbus, P.; Mares, J.; Poustka, A.; Goetz, P.

    1998-01-01

    We describe two Li-Fraumeni syndrome families. Family A was remarkable for two early childhood cases of adrenocortical tumours, family B for a high incidence of many characteristic cancers, including a childhood case of choroid plexus tumour. Using direct sequencing, we analysed exons 5-9 of the p53 gene in constitutional DNA of individuals from both families and found two novel germline mutations in exon 5. In family A, we detected a point substitution in codon 138 (GCC to CCC), which resulted in the replacement of the alanine by a proline residue. Family B harboured a single-base pair deletion in codon 178 (CAC to -AC), resulting in a frameshift and premature chain termination. Three out of six tumours examined from both families, a renal cell carcinoma, a rhabdomyosarcoma and a breast cancer, showed loss of heterozygosity and contained only the mutant p53 allele. The remaining three neoplasms, both adrenocortical tumours and the choroid plexus tumour retained heterozygosity. Immunohistochemistry with anti-p53 antibody confirmed accumulation of p53 protein in tumours with loss of heterozygosity, while the remaining tumours were p53 negative. These results support the view that complete loss of activity of the wild-type p53 need not be the initial event in the formation of all tumours in Li-Fraumeni individuals. Images Figure 3 PMID:9569035

  7. Marfan Syndrome

    MedlinePlus

    ... thin, and loose jointed. Most people with Marfan syndrome have heart and blood vessel problems, such as a weakness in the aorta or heart valves that leak. They may also have problems with ... diagnose Marfan syndrome. Your doctor may use your medical history, family ...

  8. Deletion of the steroid-binding domain of the human androgen receptor gene in one family with complete androgen insensitivity syndrome: Evidence for further genetic heterogeneity in this syndrome

    SciTech Connect

    Brown, T.R.; Lubahn, D.B.; Wilson, E.M.; Joseph, D.R.; French, F.S.; Migeon, C.J. )

    1988-11-01

    The cloning of a cDNA for the human androgen receptor gene has resulted in the availability for cDNA probes that span various parts of the gene, including the entire steroid-binding domain and part of the DNA-binding domain, as well as part of the 5' region of the gene. The radiolabeled probes were used to screen for androgen receptor mutations on Southern blots prepared by restriction endonuclease digestion of genomic DNA from human subjects with complete androgen insensitivity syndrome (AIS). In this investigation, the authors considered only patients presenting complete AIS and with the androgen receptor (-) form as the most probably subjects to show a gene deletion. One subject from each of six unrelated families with the receptor (-) form of complete AIS and 10 normal subjects were studied. In the 10 normal subjects and in 5 of the 6 patients, identical DNA restriction fragment patterns were observed with EcoRI and BamHI. Analysis of other members of this family confirmed the apparent gene deletion. The data provide direct proof that complete AIS in some families can result from a deletion of the androgen receptor structural gene. However, other families do not demonstrate such a deletion, suggesting that point mutations may also result in the receptor (-) form of complete AIS, adding further to the genetic heterogeneity of this syndrome.

  9. A novel mutation in the MITF may be digenic with GJB2 mutations in a large Chinese family of Waardenburg syndrome type II.

    PubMed

    Yan, Xukun; Zhang, Tianyu; Wang, Zhengmin; Jiang, Yi; Chen, Yan; Wang, Hongyan; Ma, Duan; Wang, Lei; Li, Huawei

    2011-12-20

    Waardenburg syndrome type II (WS2) is associated with syndromic deafness. A subset of WS2, WS2A, accounting for approximately 15% of patients, is attributed to mutations in the microphthalmia-associated transcription factor (MITF) gene. We examined the genetic basis of WS2 in a large Chinese family. All 9 exons of the MITF gene, the single coding exon (exon 2) of the most common hereditary deafness gene GJB2 and the mitochondrial DNA (mtDNA) 12S rRNA were sequenced. A novel heterozygous mutation c.[742_743delAAinsT;746_747delCA] in exon 8 of the MITF gene co-segregates with WS2 in the family. The MITF mutation results in a premature termination codon and a truncated MITF protein with only 247 of the 419 wild type amino acids. The deaf proband had this MITF gene heterozygous mutation as well as a c.[109G>A]+[235delC] compound heterozygous pathogenic mutation in the GJB2 gene. No pathogenic mutation was found in mtDNA 12S rRNA in this family. Thus, a novel compound heterozygous mutation, c.[742_743delAAinsT;746_747delCA] in MITF exon 8 was the key genetic reason for WS2 in this family, and a digenic effect of MITF and GJB2 genes may contribute to deafness of the proband. PMID:22196401

  10. Long-term survival and transmission of INI1-mutation via nonpenetrant males in a family with rhabdoid tumour predisposition syndrome

    PubMed Central

    Ammerlaan, A C J; Ararou, A; Houben, M P W A; Baas, F; Tijssen, C C; Teepen, J L J M; Wesseling, P; Hulsebos, T J M

    2007-01-01

    Rhabdoid tumour predisposition syndrome (RTPS) is a rare syndrome caused by inheritance of a mutated INI1 gene for which only two multigeneration families have been reported. To further characterise the genotype and phenotype of RTPS, we present a third family in which at least three cousins developed an atypical teratoid/rhabdoid tumour (AT/RT) at a young age. Two of these patients showed unusual long survival, and one of these developed an intracranial meningioma and a myoepithelioma of the lip in adulthood. Mutation analysis of INI1 revealed a germline G>A mutation in the donor splice site of exon 4 (c.500+1G>A) in the patients and in their unaffected fathers. This mutation prevents normal splicing and concomitantly generates a stop codon, resulting in nonsense-mediated mRNA decay. Biallelic inactivation of INI1 in the tumours, except for the meningioma, was confirmed by absence of nuclear INI1-protein staining. The myoepithelioma of one of the patients carried an identical somatic rearrangement in the NF2 gene as the AT/RT, indicating that both tumours originated from a common precursor cell. In conclusion, this study demonstrates for the first time transmission of a germline INI1-mutation in a RTPS family via nonpenetrant males, long-term survival of two members of this family with an AT/RT, and involvement of INI1 in the pathogenesis of myoepithelioma. PMID:18087273

  11. Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21.1 in an Extended Belgian Family

    PubMed Central

    Syx, Delfien; Symoens, Sofie; Steyaert, Wouter; De Paepe, Anne; Coucke, Paul J.; Malfait, Fransiska

    2015-01-01

    Joint hypermobility is a common, mostly benign, finding in the general population. In a subset of individuals, however, it causes a range of clinical problems, mainly affecting the musculoskeletal system. Joint hypermobility often appears as a familial trait and is shared by several heritable connective tissue disorders, including the hypermobility subtype of the Ehlers-Danlos syndrome (EDS-HT) or benign joint hypermobility syndrome (BJHS). These hereditary conditions provide unique models for the study of the genetic basis of joint hypermobility. Nevertheless, these studies are largely hampered by the great variability in clinical presentation and the often vague mode of inheritance in many families. Here, we performed a genome-wide linkage scan in a unique three-generation family with an autosomal dominant EDS-HT phenotype and identified a linkage interval on chromosome 8p22-8p21.1, with a maximum two-point LOD score of 4.73. Subsequent whole exome sequencing revealed the presence of a unique missense variant in the LZTS1 gene, located within the candidate region. Subsequent analysis of 230 EDS-HT/BJHS patients resulted in the identification of three additional rare variants. This is the first reported genome-wide linkage analysis in an EDS-HT family, thereby providing an opportunity to identify a new disease gene for this condition. PMID:26504261

  12. Birth of a child with Down syndrome in a family transmitting an unusual chromosome 22 arising from a translocation between chromosomes 21 and an inverted chromosome 22

    SciTech Connect

    Aviv, H.A.; Desposito, F.; Lieber, C.

    1994-09-01

    Chromosomal analysis of a child with Down syndrome resulted in the identification of a family with an unusual translocation and in the definition of the translocation breakpoints. Studies were performed on the child, his siblings, mother, mother`s sister, and grandmother. All of the family members were carriers of the translocation. We performed G-banding, silver stain, C-banding, and hybridization with the following FISH probes (Oncor): {alpha}-satellite 13/21; {beta}-satellite, coatasome 21 and 22, and the probes for chromosome 22 at 22q11 (DiGeorge region) and 22q13.3 (control region). Using the banding techniques and probes, we characterized the karyotype as: 45,XX,-21,-22,+der(22),t(21;22)(22qter{r_arrow}22q11.2::22p13{r_arrow}22q11.2::21q11.2{r_arrow}21qter). The effect of deletion of 21q11.2 and the break of chromosome 22 in the DiGeorge region in this family is not clear. However, the presence of the translocation increases the risk of family members of conceiving children with Down syndrome.

  13. Ehlers-Danlos Syndrome, Hypermobility Type, Is Linked to Chromosome 8p22-8p21.1 in an Extended Belgian Family.

    PubMed

    Syx, Delfien; Symoens, Sofie; Steyaert, Wouter; De Paepe, Anne; Coucke, Paul J; Malfait, Fransiska

    2015-01-01

    Joint hypermobility is a common, mostly benign, finding in the general population. In a subset of individuals, however, it causes a range of clinical problems, mainly affecting the musculoskeletal system. Joint hypermobility often appears as a familial trait and is shared by several heritable connective tissue disorders, including the hypermobility subtype of the Ehlers-Danlos syndrome (EDS-HT) or benign joint hypermobility syndrome (BJHS). These hereditary conditions provide unique models for the study of the genetic basis of joint hypermobility. Nevertheless, these studies are largely hampered by the great variability in clinical presentation and the often vague mode of inheritance in many families. Here, we performed a genome-wide linkage scan in a unique three-generation family with an autosomal dominant EDS-HT phenotype and identified a linkage interval on chromosome 8p22-8p21.1, with a maximum two-point LOD score of 4.73. Subsequent whole exome sequencing revealed the presence of a unique missense variant in the LZTS1 gene, located within the candidate region. Subsequent analysis of 230 EDS-HT/BJHS patients resulted in the identification of three additional rare variants. This is the first reported genome-wide linkage analysis in an EDS-HT family, thereby providing an opportunity to identify a new disease gene for this condition. PMID:26504261

  14. Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert Syndrome

    PubMed Central

    Hernández, Gualberto; Barrera, Alejandro; Ospina, Sandra; Prada, Rolando

    2015-01-01

    Introduction: Apert syndrome (AS) is a craniosynostosis condition caused by mutations in the Fibroblast Growth Factor Receptor 2 (FGFR2) gene. Clinical features include cutaneous and osseous symmetric syndactily in hands and feet, with variable presentations in bones, brain, skin and other internal organs. Methods: Members of two families with an index case of Apert Syndrome were assessed to describe relevant clinical features and molecular analysis (sequencing and amplification) of exons 8, 9 and 10 of FGFR2 gen. Results: Family 1 consists of the mother, the index case and half -brother who has a cleft lip and palate. In this family we found a single FGFR2 mutation, S252W, in the sequence of exon 8. Although mutations were not found in the study of the patient affected with cleft lip and palate, it is known that these diseases share signaling pathways, allowing suspected alterations in shared genes. In the patient of family 2, we found a sequence variant T78.501A located near the splicing site, which could interfere in this process, and consequently with the protein function. PMID:26600631

  15. X-linked retinitis pigmentosa: Report of a large kindred with loss of central vision and preserved peripheral function

    SciTech Connect

    Shastry, B.S.; Trese, M.T.

    1995-11-20

    X-linked retinitis pigmentosa (XLRP) is the most severe form of the inherited forms of retinitis pigmentosa and is clinically variable and genetically heterogeneous. It affects one in 20,000 live births. The affected individuals manifest degeneration of the peripheral retina during the first two decades of life on the basis of night blindness. Central vision usually is preserved until age 50, when the disease advances, affecting central vision and ultimately leading to complete loss of sight. Linkage analysis has shown two loci with a possibility of a third locus on the human X chromosome. The genetic abnormality that causes XLRP is not known at present. Here we describe a large kindred which manifests central loss of field with the preservation of peripheral vision. 5 refs., 1 fig.

  16. 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

  17. Multiple Loss-of-Function Mechanisms Contribute to SCN5A-Related Familial Sick Sinus Syndrome

    PubMed Central

    Jones, Richard P. O.; Trump, Dorothy; Zimmer, Thomas; Lei, Ming

    2010-01-01

    Background To identify molecular mechanisms underlying SCN5A-related sick sinus syndrome (SSS), a rare type of SSS, in parallel experiments we elucidated the electrophysiological properties and the cell surface localization of thirteen human Nav1.5 (hNav1.5) mutant channels previously linked to this disease. Methodology/Principal Findings Mutant hNav1.5 channels expressed by HEK293 cells and Xenopus oocytes were investigated by whole-cell patch clamp and two-microelectrode voltage clamp, respectively. HEK293 cell surface biotinylation experiments quantified the fraction of correctly targeted channel proteins. Our data suggested three distinct mutant channel subtypes: Group 1 mutants (L212P, P1298L, DelF1617, R1632H) gave peak current densities and cell surface targeting indistinguishable from wild-type hNav1.5. Loss-of-function of these mutants resulted from altered channel kinetics, including a negative shift of steady-state inactivation and a reduced voltage dependency of open-state inactivation. Group 2 mutants (E161K, T220I, D1275N) gave significantly reduced whole-cell currents due to impaired cell surface localization (D1275N), altered channel properties at unchanged cell surface localization (T220I), or a combination of both (E161K). Group 3 mutant channels were non-functional, due to an almost complete lack of protein at the plasma membrane (T187I, W1421X, K1578fs/52, R1623X) or a probable gating/permeation defect with normal surface localisation (R878C, G1408R). Conclusions/Significance This study indicates that multiple molecular mechanisms, including gating abnormalities, trafficking defects, or a combination of both, are responsible for SCN5A-related familial SSS. PMID:20539757

  18. An African-American family with dystonia.

    PubMed

    Puschmann, Andreas; Xiao, Jianfeng; Bastian, Robert W; Searcy, Jill A; LeDoux, Mark S; Wszolek, Zbigniew K

    2011-08-01

    The genetic cause of late-onset focal and segmental dystonia remains unknown in most individuals. Recently, mutations in Thanatos-associated protein domain containing, apoptosis associated protein 1 (THAP1) have been described in DYT6 dystonia and associated with some cases of familial and sporadic late-onset dystonia in Caucasians. We are not aware of any previous descriptions of familial dystonia in African-Americans or reports of THAP1 mutations in African-Americans. Herein, we characterize an African-American (AA) kindred with late-onset primary dystonia, clinically and genetically. The clinical phenotype included cervical, laryngeal and hand-forearm dystonia. Symptoms were severe and disabling for several family members, whereas others only displayed mild signs. There were no accompanying motor or cognitive signs. In this kindred, age of onset ranged from 45 to 50 years and onset was frequently sudden, with symptoms developing within weeks or months. DYT1 was excluded as the cause of dystonia in this kindred. The entire genomic region of THAP1, including non-coding regions, was sequenced. We identified 13 sequence variants in THAP1, although none co-segregated with dystonia. A novel THAP1 variant (c.-237-3G>T/A) was found in 3/84 AA dystonia patient alleles and 3/212 AA control alleles, but not in 5870 Caucasian alleles. In summary, although previously unreported, familial primary dystonia does occur in African-Americans. Genetic analysis of the entire genomic region of THAP1 revealed a novel variant that was specific for African-Americans. Therefore, genetic testing for dystonia and future studies of candidate genes must take genetic background into consideration. PMID:21601506

  19. An African-American Family with Dystonia

    PubMed Central

    Puschmann, Andreas; Xiao, Jianfeng; Bastian, Robert W.; Searcy, Jill A.; LeDoux, Mark S.; Wszolek, Zbigniew K.

    2011-01-01

    The genetic cause of late-onset focal and segmental dystonia remains unknown in most individuals. Recently, mutations in Thanatos-associated protein domain containing, apoptosis associated protein 1 (THAP1) have been described in DYT6 dystonia and associated with some cases of familial and sporadic late-onset dystonia in Caucasians. We are not aware of any previous descriptions of familial dystonia in African Americans or reports of THAP1 mutations in African Americans. Herein, we characterize an African-American (AA) kindred with late-onset primary dystonia, clinically and genetically. The clinical phenotype included cervical, laryngeal and hand-forearm dystonia. Symptoms were severe and disabling for several family members, whereas others only displayed mild signs. There were no accompanying motor or cognitive signs. In this kindred, age of onset ranged from 45 to 50 years and onset was frequently sudden, with symptoms developing within weeks or months. DYT1 was excluded as the cause of dystonia in this kindred. The entire genomic region of THAP1, including non-coding regions, was sequenced. We identified 13 sequence variants in THAP1, although none co-segregated with dystonia. A novel THAP1 variant (c.-237-3G>T/A) was found in 3/84 AA dystonia patient alleles and 3/212 AA control alleles, but not in 5,870 Caucasian alleles. In summary, although previously unreported, familial primary dystonia does occur in African Americans. Genetic analysis of the entire genomic region of THAP1 revealed a novel variant that was specific for African Americans. Therefore, genetic testing for dystonia and future studies of candidate genes must take genetic background into consideration. PMID:21601506

  20. 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

  1. BHD mutations, clinical and molecular genetic investigations of Birt–Hogg–Dubé syndrome: a new series of 50 families and a review of published reports

    PubMed Central

    Toro, J R; Wei, M-H; Glenn, G M; Weinreich, M; Toure, O; Vocke, C; Turner, M; Choyke, P; Merino, M J; Pinto, P A; Steinberg, S M; Schmidt, L S; Linehan, W M

    2008-01-01

    Background: Birt–Hogg–Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations. Objective: To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS. Methods: Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences. Results: The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with

  2. A clinical variant in SCN1A inherited from a mosaic father cosegregates with a novel variant to cause Dravet syndrome in a consanguineous family.

    PubMed

    Tuncer, Feyza N; Gormez, Zeliha; Calik, Mustafa; Altiokka Uzun, Gunes; Sagiroglu, Mahmut S; Yuceturk, Betul; Yuksel, Bayram; Baykan, Betul; Bebek, Nerses; Iscan, Akin; Ugur Iseri, Sibel A; Ozbek, Ugur

    2015-07-01

    A consanguineous family from Turkey having two children with intellectual disability exhibiting myoclonic, febrile and other generalized seizures was recruited to identify the genetic origin of these phenotypes. A combined approach of SNP genotyping and exome sequencing was employed both to screen genes associated with Dravet syndrome and to detect homozygous variants. Analysis of exome data was extended further to identify compound heterozygosity. Herein, we report identification of two paternally inherited genetic variants in SCN1A (rs121917918; p.R101Q and p.I1576T), one of which was previously implicated in Dravet syndrome. Interestingly, the previously reported clinical variant (rs121917918; p.R101Q) displayed mosaicism in the blood and saliva of the father. The study supported the genetic diagnosis of affected children as Dravet syndrome possibly due to the combined effect of one clinically associated (rs121917918; p.R101Q) and one novel (p.I1576T) variants in SCN1A gene. This finding is important given that heterozygous variants may be overlooked in standard exome scans of consanguineous families. Thus, we are presenting an interesting example, where the inheritance of the condition may be misinterpreted as recessive and identical by descent due to consanguinity and mosaicism in one of the parents. PMID:25986186

  3. Familial pheochromocytoma, hypercalcemia, and von Hippel-Lindau disease. A ten year study of a large family.

    PubMed

    Atuk, N O; McDonald, T; Wood, T; Carpenter, J T; Walzak, M P; Donaldson, M; Gillenwater, J Y

    1979-05-01

    Long-term epidemiological and laboratory studies were carried out in a kindred with familial pheochromocytoma associated with von Hippel-Lindau disease. Thirteen members were affected by the syndrome and the trait appears to be transmitted in an autosomal dominant fashion. Of 13 patients, 7 had pheochromocytoma alone. Of the remaining six patients, one had pheochromocytoma combined with von Hippel-Lindau disease, four had pheochromocytoma with retinal disease only, and a single patient had a retinal lesion without pheochromocytoma. In four patients, pheochromocytoma antedated the development of retinal lesions. Ten members also had mild hypercalcemia without accompanying elevations of PTH in the 4 patients in whom this was determined. In all, hypercalcemia was corrected with removal of tumors, and no patient had a return of hypercalcemia in the absence of recurrent increases in urinary catecholamines. The clinical presentations in 12 patients varied markedly, as did their urinary excretion rates of norepinephrine, epinephrine and their metabolites. However, an analysis of the data revealed significant correlations not previously described between the urinary excretion of free catecholamines (norepinephrine plus epinephrine), blood pressure, the free catecholamine content of the tumor and the age of the patient. Urinary excretion of free norepinephrine plus epinephrine appear to be decreased with advancing age (p less than 0.001). Both systolic and diastolic blood pressures and the age of the patient were inversely correlated (p less than 0.01). A significant inverse relationship between the tumor content of free catecholamines and the age of the patients was, although to a lesser degree, also present (p less than 0.05). As a whole, the size of the tumors and their norepinephrine content were not correlated. We present a concept that, in familial pheochromocytoma, the metabolism of catecholamines is altered by the process of aging, and that this change modifies the

  4. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16

    SciTech Connect

    Tromp, G.; Kuivaniemi, H.; Ala-Kokko, L.

    1996-11-01

    Blau syndrome (MIM 186580), first described in a large, three-generation kindred, is an autosomal, dominantly inherited disease characterized by multiorgan, tissue-specific inflammation. Its clinical phenotype includes granulomatous arthritis, skin rash, and uveitis and probably represents a subtype of a group of clinical entities referred to as {open_quotes}familial granulomatosis.{close_quotes} It is the sole human model with recognizably Mendelian inheritance for a variety of multisystem inflammatory diseases affecting a significant percentage of the population. A genomewide search for the Blau susceptibility locus was undertaken after karyotypic analysis revealed no abnormalities. Sixty-two of the 74-member pedigree were genotyped with dinucleotide-repeat markers. Linkage analysis was performed under dominant model of inheritance with reduced penetrance. The marker D16S298 gave a maximum LOD score of 3.75 at {theta} = .04, with two-point analysis. LOD scores for flanking markers were consistent and placed the Blau susceptibility locus within the 16p12-q21 interval. 46 refs., 3 figs., 3 tabs.

  5. First Independent Replication of the Involvement of LARS2 in Perrault Syndrome by Whole-Exome Sequencing of an Italian Family

    PubMed Central

    Soldà, Giulia; Caccia, Sonia; Robusto, Michela; Chiereghin, Chiara; Castorina, Pierangela; Ambrosetti, Umberto; Duga, Stefano; Asselta, Rosanna

    2015-01-01

    Perrault syndrome (MIM #233400) is a rare autosomal recessive disorder characterized by ovarian dysgenesis and primary ovarian insufficiency in females, and progressive hearing loss in both genders. Recently, mutations in five genes (HSD17B4, HARS2, CLPP, LARS2, and C10ORF2) were found to be responsible for Perrault syndrome, although they do not account for all cases of this genetically heterogeneous condition. We used whole-exome sequencing to identify pathogenic variants responsible for Perrault syndrome in an Italian pedigree with two affected siblings. Both patients were compound heterozygous for two novel missense variants within the mitochondrial leucyl-tRNA synthetase (LARS2), NM_015340.3:c.899C>T(p.Thr300Met) and c.1912G>A(p.Glu638Lys). Both variants co-segregated with the phenotype in the family. p.Thr300 and p.Glu638 are evolutionary conserved residues, and are located respectively within the editing domain and immediately before the catalytically important KMSKS motif. Homology modeling using as template the E. coli leucyl-tRNA synthetase provided further insights on the possible pathogenic effects of the identified variants. This represents the first independent replication of the involvement of LARS2 mutations in Perrault syndrome, contributing valuable information for the further understanding of this disease. PMID:26657938

  6. First independent replication of the involvement of LARS2 in Perrault syndrome by whole-exome sequencing of an Italian family.

    PubMed

    Soldà, Giulia; Caccia, Sonia; Robusto, Michela; Chiereghin, Chiara; Castorina, Pierangela; Ambrosetti, Umberto; Duga, Stefano; Asselta, Rosanna

    2016-04-01

    Perrault syndrome (MIM #233400) is a rare autosomal recessive disorder characterized by ovarian dysgenesis and primary ovarian insufficiency in females, and progressive hearing loss in both genders. Recently, mutations in five genes (HSD17B4, HARS2, CLPP, LARS2 and C10ORF2) were found to be responsible for Perrault syndrome, although they do not account for all cases of this genetically heterogeneous condition. We used whole-exome sequencing to identify pathogenic variants responsible for Perrault syndrome in an Italian pedigree with two affected siblings. Both patients were compound heterozygous for two novel missense variants within the mitochondrial leucyl-tRNA synthetase (LARS2): NM_015340.3:c.899C>T(p.Thr300Met) and c.1912G>A(p.Glu638Lys). Both variants cosegregated with the phenotype in the family. p.Thr300 and p.Glu638 are evolutionarily conserved residues, and are located, respectively, within the editing domain and immediately before the catalytically important KMSKS motif. Homology modeling using as template the E. coli leucyl-tRNA synthetase provided further insights on the possible pathogenic effects of the identified variants. This represents the first independent replication of the involvement of LARS2 mutations in Perrault syndrome, contributing valuable information for the further understanding of this disease. PMID:26657938

  7. Infant care practices related to sudden infant death syndrome in South Asian and White British families in the UK.

    PubMed

    Ball, Helen L; Moya, Eduardo; Fairley, Lesley; Westman, Janette; Oddie, Sam; Wright, John

    2012-01-01

    In the UK, infants of South Asian parents have a lower rate of sudden infant death syndrome (SIDS) than White British infants. Infant care and life style behaviours are strongly associated with SIDS risk. This paper describes and explores variability in infant care between White British and South Asian families (of Bangladeshi, Indian or Pakistani origin) in Bradford, UK (the vast majority of which were Pakistani) and identifies areas for targeted SIDS intervention. A cross-sectional telephone interview study was conducted involving 2560 families with 2- to 4-month-old singleton infants enrolled in the Born in Bradford cohort study. Outcome measures were prevalence of self-reported practices in infant sleeping environment, sharing sleep surfaces, breast feeding, use of dummy or pacifier, and life style behaviours. We found that, compared with White British infants, Pakistani infants were more likely to: sleep in an adult bed (OR = 8.48 [95% CI 2.92, 24.63]); be positioned on their side for sleep (OR = 4.42 [2.85, 6.86]); have a pillow in their sleep environment (OR = 9.85 [6.39, 15.19]); sleep under a duvet (OR = 3.24 [2.39, 4.40]); be swaddled for sleep (OR = 1.49 [1.13, 1.97]); ever bed-share (OR = 2.13 [1.59, 2.86]); regularly bed-share (OR = 3.57 [2.23, 5.72]); ever been breast-fed (OR = 2.00 [1.58, 2.53]); and breast-fed for 8+ weeks (OR = 1.65 [1.31, 2.07]). Additionally, Pakistani infants were less likely to: sleep in a room alone (OR = 0.05 [0.03, 0.09]); use feet-to-foot position (OR = 0.36 [0.26, 0.50]); sleep with a soft toy (OR = 0.52 [0.40, 0.68]); use an infant sleeping bag (OR = 0.20 [0.16, 0.26]); ever sofa-share (OR = 0.22 [0.15, 0.34]); be receiving solid foods (OR = 0.22 [0.17, 0.30]); or use a dummy at night (OR = 0.40 [0.33, 0.50]). Pakistani infants were also less likely to be exposed to maternal smoking (OR = 0.07 [0.04, 0.12]) and to alcohol consumption by either parent. No difference was found in the prevalence of prone sleeping (OR = 1

  8. Germline HABP2 Mutation Causing Familial Nonmedullary Thyroid Cancer

    PubMed Central

    Gara, Sudheer Kumar; Jia, Li; Merino, Maria J.; Agarwal, Sunita K.; Zhang, Lisa; Cam, Maggie; Patel, Dhaval; Kebebew, Electron

    2015-01-01

    SUMMARY Familial nonmedullary thyroid cancer accounts for 3 to 9% of all cases of thyroid cancer, but the susceptibility genes are not known. Here, we report a germline variant of HABP2 in seven affected members of a kindred with familial nonmedullary thyroid cancer and in 4.7% of 423 patients with thyroid cancer. This variant was associated with increased HABP2 protein expression in tumor samples from affected family members, as compared with normal adjacent thyroid tissue and samples from sporadic cancers. Functional studies showed that HABP2 has a tumor-suppressive effect, whereas the G534E variant results in loss of function. PMID:26222560

  9. Linkage of the Wiskott-Aldrich syndrome with polymorphic DNA sequences from the human X chromosome

    SciTech Connect

    Peacocke, M.; Siminovitch, K.A.

    1987-05-01

    The Wiskott-Aldrich syndrome (WAS) is one of several human immunodeficiency diseases inherited as an X-linked trait. The location of WAS on the X chromosome is unknown. The authors have studied 10 kindreds segregating for WAS for linkage with cloned, polymorphic DNA markers and have demonstrated significant linkage between WAS and two loci, DXS14 and DXS7, that map to the proximal short arm of the X chromosome. Maximal logarithm of odds (lod scores) for WAS-DXS14 and WAS-DWS7 were 4.29 (at 0 = 0.03) and 4.12 (at 0 = 0.00), respectively. Linkage data between WAS and six markers loci indicate the order of the loci to be (DXYS1-DXS1)-WAS-DXS14-DXS7-(DXS84-OTC). These results suggest that the WAS locus lies within the pericentric region of the X chromosome and provide an initial step toward identifying the WAS gene and improving the genetic counselling WAS families.

  10. Multi-Family Psychoeducational Support Group Therapy for Families with a Member Afflicted with Irreversible Brain Syndrome (Alzheimer's Disease): Report of a Pilot Study.

    ERIC Educational Resources Information Center

    Paley, Evelyn S.; And Others

    Alzheimers Disease (AD), an incurable disability which afflicts older adults, can have devastating emotional consequences for the victim and the family. In an attempt to determine the effectiveness of multifamily psychoeducational support, group therapy (MFPSGT), 22 persons (13 families) from the Alzheimer's Disease and Related Disorders…

  11. Riley-Day syndrome

    MedlinePlus

    Riley-Day syndrome is an inherited disorder that affects nerves throughout the body. ... Riley-Day syndrome is passed down through families (inherited). A person must inherit a copy of the defective gene ...

  12. Dubin-Johnson syndrome

    MedlinePlus

    Dubin-Johnson syndrome is a disorder passed down through families (inherited) in which a person has mild jaundice throughout ... Dubin-Johnson syndrome is a very rare genetic disorder. In order to inherit the condition, a child must get ...

  13. Dubin-Johnson syndrome

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/000242.htm Dubin-Johnson syndrome To use the sharing features on this page, please enable JavaScript. Dubin-Johnson syndrome is a disorder passed down through families ( ...

  14. A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2.

    PubMed Central

    Thierfelder, L; MacRae, C; Watkins, H; Tomfohrde, J; Williams, M; McKenna, W; Bohm, K; Noeske, G; Schlepper, M; Bowcock, A

    1993-01-01

    We report that a gene responsible for familial hypertrophic cardiomyopathy (FHC) in a kindred with a mild degree of cardiac hypertrophy maps to chromosome 15q2. The gene encoding cardiac actin, located on chromosome 15q, was analyzed and excluded as a candidate for FHC at this locus. Two additional families with typical FHC were studied and the disorder in one also maps to the chromosome 15q2 locus. The maximum combined multipoint logarithm of odds score in the two linked families is 6.02. Although these two kindreds reside in the same country, we believe that their disorder is caused by independent mutations in the 15q2 locus because of the clinical and genotypic differences between affected individuals. Mutations in at least four loci can cause FHC: chromosomes 14q1 (beta cardiac myosin heavy chain gene), 1q3, and 15q2 and another unidentified locus, suggesting substantial genetic heterogeneity. PMID:8327508

  15. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping.

    PubMed Central

    Neufeld, E J; Mandel, H; Raz, T; Szargel, R; Yandava, C N; Stagg, A; Fauré, S; Barrett, T; Buist, N; Cohen, N

    1997-01-01

    Thiamine-responsive megaloblastic anemia, also known as "TRMA" or "Rogers syndrome," is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases. PMID:9399900

  16. Influence of loss of function MC1R variants in genetic susceptibility of familial melanoma in Spain.

    PubMed

    de Torre, Carlos; Garcia-Casado, Zaida; Martínez-Escribano, Jorge A; Botella-Estrada, Rafael; Bañuls, Jose; Oliver, Vicente; Mercader, Pedro; Azaña, Jose M; Frias, Javier; Nagore, Eduardo

    2010-08-01

    We explored the presence of germline alterations in CDK4 exon 2, CDKN2A and MC1R in a hospital-based study of 89 melanoma cases from 89 families with at least two members affected by cutaneous melanoma. A total of 30% of the melanoma kindreds studied were carriers of CDKN2A variants, and three of these variants were known predominant alleles that have been identified earlier in Mediterranean populations (p.G101W, p.V59G and c.358delG). We observed a higher frequency of nonsynonymous MC1R variants in these Spanish melanoma kindreds (72%) with respect to the general population (60%). We observed a higher frequency of nonsynonymous MC1R variants in this Spanish melanoma kindred (72%) respect to general population (60%). A new classification of MC1R variants based on their functional effects over melanocortin-1 receptor, including the dominant-negative effect of some of them in heterozygotes, suggested an association of loss of function MC1R variants and multiple primary melanoma cases from melanoma kindred (odds ratio: 6.07, 95% confidence interval: 1.35-27.20). This study proposes the relevance of loss of function MC1R variants in the risk of melanoma in multiple primary melanoma cases with family history from areas with low melanoma incidence rate. PMID:20539244

  17. Signalling to actin assembly via the WASP (Wiskott-Aldrich syndrome protein)-family proteins and the Arp2/3 complex.

    PubMed Central

    Millard, Thomas H; Sharp, Stewart J; Machesky, Laura M

    2004-01-01

    The assembly of a branched network of actin filaments provides the mechanical propulsion that drives a range of dynamic cellular processes, including cell motility. The Arp2/3 complex is a crucial component of such filament networks. Arp2/3 nucleates new actin filaments while bound to existing filaments, thus creating a branched network. In recent years, a number of proteins that activate the filament nucleation activity of Arp2/3 have been identified, most notably the WASP (Wiskott-Aldrich syndrome protein) family. WASP-family proteins activate the Arp2/3 complex, and consequently stimulate actin assembly, in response to extracellular signals. Structural studies have provided a significant refinement in our understanding of the molecular detail of how the Arp2/3 complex nucleates actin filaments. There has also been much progress towards an understanding of the complicated signalling processes that regulate WASP-family proteins. In addition, the use of gene disruption in a number of organisms has led to new insights into the specific functions of individual WASP-family members. The present review will discuss the Arp2/3 complex and its regulators, in particular the WASP-family proteins. Emphasis will be placed on recent developments in the field that have furthered our understanding of actin dynamics and cell motility. PMID:15040784

  18. Association of the family environment with behavioural and cognitive outcomes in children with chromosome 22q11.2 deletion syndrome

    PubMed Central

    Allen, T. M.; Hersh, J.; Schoch, K.; Curtiss, K.; Hooper, S. R.; Shashi, V.

    2014-01-01

    Background Children with 22q11.2 deletion syndrome (22q11DS) are at risk for social-behavioural and neurocognitive sequelae throughout development. The current study examined the impact of family environmental characteristics on social-behavioural and cognitive outcomes in this pediatric population. Method Guardians of children with 22q11DS were recruited through two medical genetics clinics. Con senting guardians were asked to complete several questionnaires regarding their child's social, emotional and behavioural functioning, as well as family social environment and parenting styles. Children with 22q11DS were asked to undergo a cognitive assessment, including IQ and achievement testing, and measures of attention, executive function and memory. Results Modest associations were found between aspects of the family social environment and parenting styles with social-behavioural and cognitive/academic outcomes. Regression models indicated that physical punishment, socioeconomic status, parental control and family organisation significantly predicted social-behavioural and cognitive outcomes in children with 22q11DS. Conclusion Characteristics of the family social environment and parenting approaches appear to be associated with functional outcomes of children with 22q11DS. Understanding the impact of environmental variables on developmental outcomes can be useful in determining more effective targets for intervention. This will be important in order to improve the quality of life of individuals affected by 22q11DS. PMID:23742203

  19. Pitfalls of homozygosity mapping: an extended consanguineous Bardet-Biedl syndrome family with two mutant genes (BBS2, BBS10), three mutations, but no triallelism.

    PubMed

    Laurier, Virginie; Stoetzel, Corinne; Muller, Jean; Thibault, Christelle; Corbani, Sandra; Jalkh, Nadine; Salem, Nabiha; Chouery, Eliane; Poch, Olivier; Licaire, Serge; Danse, Jean-Marc; Amati-Bonneau, Patricia; Bonneau, Dominique; Mégarbané, André; Mandel, Jean-Louis; Dollfus, Hélène

    2006-11-01

    The extensive genetic heterogeneity of Bardet-Biedl syndrome (BBS) is documented by the identification, by classical linkage analysis complemented recently by comparative genomic approaches, of nine genes (BBS1-9) that account cumulatively for about 50% of patients. The BBS genes appear implicated in cilia and basal body assembly or function. In order to find new BBS genes, we performed SNP homozygosity mapping analysis in an extended consanguineous family living in a small Lebanese village. This uncovered an unexpectedly complex pattern of mutations, and led us to identify a novel BBS gene (BBS10). In one sibship of the pedigree, a BBS2 homozygous mutation was identified, while in three other sibships, a homozygous missense mutation was identified in a gene encoding a vertebrate-specific chaperonine-like protein (BBS10). The single patient in the last sibship was a compound heterozygote for the above BBS10 mutation and another one in the same gene. Although triallelism (three deleterious alleles in the same patient) has been described in some BBS families, we have to date no evidence that this is the case in the present family. The analysis of this family challenged linkage analysis based on the expectation of a single locus and mutation. The very high informativeness of SNP arrays was instrumental in elucidating this case, which illustrates possible pitfalls of homozygosity mapping in extended families, and that can be explained by the rather high prevalence of heterozygous carriers of BBS mutations (estimated at one in 50 in Europeans). PMID:16823392

  20. Sister chromatid exchanges, hyperdiploidy and chromosomal rearrangements studied in cells from melanoma-prone individuals belonging to families with the dysplastic nevus syndrome.

    PubMed

    Jaspers, N G; Roza-de Jongh, E J; Donselaar, I G; Van Velzen-Tillemans, J T; van Hemel, J O; Rümke, P; van der Kamp, A W

    1987-01-01

    Cytogenetic investigations were performed on 25 individuals belonging to six melanoma-prone families with multiple melanocytic lesions (the dysplastic nevus syndrome, DNS). Patients having DNS with or without a history of melanoma were compared with clinically normal relatives and unrelated normal controls. The results indicate normal frequencies of hyperdiploidy and spontaneous sister chromatid exchanges in the fibroblasts of all individuals studied. Karyotypic analyses were carried out on the members of one family. The patients with DNS had a normal constitutional karyotype. In lymphocytes or fibroblasts from five patients, however, increased frequencies of cells with random chromosomal rearrangements were observed. These abnormalities, mainly translocations and inversions, were not found in two of the patients' spouses and in six clinically normal relatives. In the fibroblast cultures considerable clonal selection of cytogenetically abnormal cells occurred. PMID:3791172

  1. Peutz-Jeghers Syndrome With Diffuse Gastrointestinal Polyposis: Three Cases in a Family With Different Manifestations and No Evidence of Malignancy During 14 Years Follow Up

    PubMed Central

    Matini, Esfandiar; Houshangi, Hooman; Jangholi, Ehsan; Farjad Azad, Pantea; Najibpour, Reza; Farshad, Ali

    2015-01-01

    Introduction: Peutz-Jeghers syndrome (PJS) is a rare disorder characterized by mucocutaneous perioral pigmentation, gastrointestinal hamartomatous polyposis, and an increased risk of malignancy. Families with PJS may show a variable spectrum of manifestations in spite of their consecutive generations. A probable explanation is novel mutations in contributing genes. Case Presentation: This report describes 3 cases of a family. Two daughters presented the classic PJS, while their father only manifested mucocutaneous perioral pigmentation. The junior daughter was underwent 3 and the eldest daughter 2 laparotomies for intussusception. The patients were visited annually and their medical findings were recorded during a follow-up period of 14 years. They were periodically examined in our hospital and despite conveying diffuse polyposis from the esophagus throughout the rectum in these three cases, even a simple hyperplasia was not found in obtained specimens. Conclusions: The patients with diffuse PJS may be asymptomatic and without gastrointestinal or extragastrointestinal malignancies. PMID:26756003

  2. A Microdeletion of Chromosome 9q33.3 Encompasses the Entire LMX1B Gene in a Chinese Family with Nail Patella Syndrome

    PubMed Central

    Jiang, Shujuan; Zhang, Jiubin; Huang, Dan; Zhang, Yuanyuan; Liu, Xiaoliang; Wang, Yinzhao; He, Rong; Zhao, Yanyan

    2014-01-01

    Nail patella syndrome (NPS) is an autosomal dominant disorder characterized by nail malformations, patellar apoplasia, or patellar hypoplasia. Mutations within the LMX1B gene are found in 85% of families with NPS; thus, this gene has been characterized as the causative gene of NPS. In this study, we identified a heterozygous microdeletion of the entire LMX1B gene using multiplex ligation-dependent probe amplification (MLPA) in a Chinese family with NPS. The determination of the deletion breakpoints by Illumina genome-wide DNA analysis beadchip showed that the deletion was located in chromosome 9q33.3 and spanned about 0.66 Mb in size. This heterozygous deletion provides strong evidence for haploinsufficiency as the pathogenic mechanism of NPS. PMID:25380522

  3. Absence of family history and phenotype-genotype correlation in pediatric Brugada syndrome: more burden to bear in clinical and genetic diagnosis.

    PubMed

    Daimi, Houria; Khelil, Amel Haj; Ben Hamda, Khaldoun; Aranega, Amelia; Chibani, Jemni B E; Franco, Diego

    2015-06-01

    Brugada syndrome (BrS) is an autosomal-dominant genetic cardiac disorder caused in 18-30 % of the cases by SCN5A gene mutations and manifested by an atypical right bundle block pattern with ST segment elevation and T wave inversion in the right precordial leads. The syndrome is usually detected after puberty. The identification of BrS in pediatric patients is thus a rare occurrence, and most of the reported cases are unmasked after febrile episodes. Usually, having a family history of sudden death represents the first reason to perform an ECG in febrile children. However, this practice makes the sporadic cases of cardiac disease and specially the asymptomatic ones excluded from this diagnosis. Here, we report a sporadic case of a 2-month-old male patient presented with vaccination-related fever and ventricular tachycardia associated with short breathing, palpitation and cold sweating. ECG changes were consistent with type 1 BrS. SCN5A gene analysis of the proband and his family revealed a set of mutations and polymorphisms differentially distributed among family members, however, without any clear genotype-phenotype correlation. Based on our findings, we think that genetic testing should be pursued as a routine practice in symptomatic and asymptomatic pediatric cases of BrS, with or without family history of sudden cardiac death. Similarly, our study suggests that pediatrician should be encouraged to perform an ECG profiling in suspicious febrile children and quickly manage fever since it is the most important factor unmasking BrS in children. PMID:25758664

  4. Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette syndrome, by the transmission-disequilibrium test

    SciTech Connect

    Grice, D.E.; Gelernter, J.; Leckman, J.F.; Pauls, D.L.

    1996-09-01

    Dopaminergic abnormalities are implicated in the pathogenesis of Tourette syndrome (TS) and chronic multiple tics. We used the transmission-disequilibrium test (TDT) method to test for linkage disequilibrium between a specific allele (the seven-repeat allele (DRD4*7R) of the exon 3 VNTR polymorphic site) at the D4 dopamine receptor locus (DRD4) and expression of chronic multiple tics and TS. This particular allele had been shown in functional studies to have different binding properties compared with the other common alleles in this DRD4 polymorphic system. We studied 64 family trios (consisting of an affected person and two parents, at least one heterozygous for DRD4*7R), including 12 nuclear family trios and 52 trios from four large TS kindreds. The DRD4*7R allele was transmitted significantly more frequently than expected ({chi}{sup 2}{sub TDT} ranging from 8.47 [P < .004] to 10.80 [P = .001], depending on breadth of disease definition and inclusion or exclusion of inferred genotypes). Confirmation of this finding will depend on either replication in other samples or the identification of a transmitted functional mutation within this sample. 56 refs., 2 figs., 3 tabs.

  5. COL5A1: Genetic mapping and exclusion as candidate gene in families with nail-patella syndrome, tuberous sclerosis 1, hereditary hemorrhagic telangiectasia, and Ehlers-Danlos syndrome type II

    SciTech Connect

    Greenspan, D.S.; Northrup, H.; Au, K.S.

    1995-02-10

    COL5A1, the gene for the {alpha}1 chain of type V collagen, has been considered a candidate gene for certain diseases based on chromosomal location and/or disease phenotype. We have employed 3{prime}-untranslated region RFLPs to exclude COL5A1 as a candidate gene in families with tuberous sclerosis 1, Ehlers-Danlos syndrome type H, and nail-patella syndrome. In addition, we describe a polymorphic simple sequence repeat (SSR) within a COL5A1 intron. This SSR is used to exclude COL5A1 as a candidate gene in hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease) and to add COL5A1 to the existing map of {open_quotes}index{close_quotes} markers of chromosome 9 by evaluation of the COL5A1 locus on the CEPH 40-family reference pedigree set. This genetic mapping places COL5A1 between markers D9S66 and D9S67. 14 refs., 1 fig., 2 tabs.

  6. Familial cutaneous melanoma.

    PubMed

    Hansson, Johan

    2010-01-01

    Approximately 5-10 % of all cutaneous melanomas occur in families with hereditary melanoma predisposition. Worldwide, approximately 20-40% of kindreds with familial elanoma harbor germline mutations in the CDKN2A gene, located on chromosome 9p21, which encodes two different proteins, p16INK4 and p14ARF, both involved in regulation of cell cycle progression and induction of senescence. In different populations several recurring CDKN2A founder mutations have been described. The risk of melanoma in CDKN2A mutations carriers varies between populations and is higher in regions with high sun exposure and high incidence of melanoma in the general population. Some CDKN2A mutations have been associated not only with melanoma but also with increased risk of other malignancies--most notably pancreatic carcinoma. A much smaller number of families have germline mutations in the CDK4 gene on chromosome 12q14, encoding a cyclin dependent kinase which normally interacts with p16INK4A. The management of families with hereditary melanoma is discussed. PMID:20687502

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

    PubMed Central

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

    2010-01-01

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

  8. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.

    PubMed Central

    Ehrmann, D A; Sturis, J; Byrne, M M; Karrison, T; Rosenfield, R L; Polonsky, K S

    1995-01-01

    The increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM) among women with polycystic ovary syndrome (PCOS) has been ascribed to the insulin resistance characteristic of PCOS. This study was undertaken to determine the role of defects in insulin secretion as well as familial factors to the predisposition to NIDDM seen in PCOS. We studied three groups of women: PCOS with a family history of NIDDM (PCOS FHx POS; n = 11), PCOS without a family history of NIDDM (PCOS FHx NEG; n = 13), and women without PCOS who have a family history of NIDDM (NON-PCOS FHx POS; n = 8). Beta cell function was evaluated during a frequently sampled intravenous glucose tolerance test, by a low dose graded glucose infusion, and by the ability of the beta cell to be entrained by an oscillatory glucose infusion. PCOS FHx POS women were significantly less likely to demonstrate appropriate beta cell compensation for the degree of insulin resistance. The ability of the beta cell to entrain, as judged by the spectral power for insulin secretion rate, was significantly reduced in PCOS FHx POS subjects. In conclusion, a history of NIDDM in a first-degree relative appears to define a subset of PCOS subjects with a greater prevalence of insulin secretory defects. The risk of developing NIDDM imparted by insulin resistance in PCOS may be enhanced by these defects in insulin secretion. PMID:7615824

  9. Subclinical Lung Disease, Macrocytosis, and Premature Graying in Kindreds With Telomerase (TERT) Mutations

    PubMed Central

    Diaz de Leon, Alberto; Cronkhite, Jennifer T.; Yilmaz, Cuneyt; Brewington, Cecelia; Wang, Richard; Xing, Chao; Hsia, Connie C. W.

    2011-01-01

    Background: Mutations in the human gene encoding the protein component of telomerase (TERT) are the most common genetic defect in patients with familial idiopathic pulmonary fibrosis (IPF). The subclinical phenotypes of asymptomatic members of these families have not been evaluated with respect to TERT mutation status or telomere length. Methods: We measured a variety of pulmonary, blood, skin, and bone parameters for 20 subjects with heterozygous TERT mutations (carriers) and 20 family members who had not inherited a TERT mutation (noncarriers) to identify the spectrum of phenotypes associated with mutations in this gene. The two groups were matched for sex, age, and cigarette smoking. Three TERT mutation carriers had IPF (IPF carriers). The rest of the carriers were apparently healthy (asymptomatic carriers) and were compared with the noncarriers. Results: Asymptomatic carriers exhibited significantly lower diffusing capacity of lung for carbon monoxide (Dlco), impaired recruitment of Dlco with exercise, radiographic signs of lung fibrosis, and increased fractional lung tissue volume quantified by high-resolution chest CT scan than noncarriers. RBC and platelet counts were significantly lower, and the mean corpuscular volume and mean corpuscular hemoglobin concentration were significantly higher in carriers than in noncarriers. Carriers reported significantly earlier graying of hair than noncarriers. TERT mutation status is more accurately predicted by short telomere lengths than any of these measured phenotypes. Conclusions: TERT mutation carriers exhibit early preclinical signs of lung fibrosis, bone marrow dysfunction, and premature graying. These clinical features and short telomere lengths characterize patients with germline TERT mutations. PMID:21349926

  10. Tumors associated with p53 germline mutations: a synopsis of 91 families.

    PubMed Central

    Kleihues, P.; Schäuble, B.; zur Hausen, A.; Estève, J.; Ohgaki, H.

    1997-01-01

    Although inherited p53 mutations are present in all somatic cells, malignant transformation is limited to certain organs and target cells. The analysis of 475 tumors in 91 families with p53 germline mutations reported since 1990 shows that breast carcinomas are most frequent (24.0%), followed by bone sarcomas (12.6%), brain tumors (12.0%), and soft tissue sarcomas (11.6%). The sporadic counterparts of these tumors also carry a high incidence of p53 mutations, suggesting that in these tissues p53 mutations are capable of initiating the process of malignant transformation. Hematological neoplasms (acute lymphoblastic leukemia and Hodgkin's lymphoma) and adrenocortical carcinomas occurred at a frequency of 4.2 and 3.6%, respectively. One-half of the families fulfilled the diagnostic criteria of the Li-Fraumeni syndrome. There were marked organ-specific differences in the mean age at which carriers of p53 germline mutations present with neoplastic disease: 5 years for adrenocortical carcinomas, 16 years for sarcomas, 25 years for brain tumors, 37 years for breast cancer, and almost 50 years for lung cancer. Analysis of the mutational spectrum showed a predominance of G:C-->A:T transitions at CpG sites, suggesting an endogenous formation, eg, by deamination of 5-methylcytosine, rather than a causation by environmental mutagenic carcinogens. The location of mutations within the p53 gene was found to be similar to that of somatic mutations in sporadic tumors. There is no evidence of an organ or target cell specificity of p53 germline mutations; the occasional familial clustering of certain tumor types is more likely to reflect the genetic background of the respective kindred or the additional influence of environmental and nongenetic host factors. Images Figure 4 PMID:9006316

  11. Florbetapir PET analysis of amyloid-β deposition in the presenilin 1 E280A autosomal dominant Alzheimer’s disease kindred: a cross-sectional study

    PubMed Central

    Fleisher, Adam S; Chen, Kewei; Quiroz, Yakeel T; Jakimovich, Laura J; Gomez, Madelyn Gutierrez; Langois, Carolyn M; Langbaum, Jessica B S; Ayutyanont, Napatkamon; Roontiva, Auttawut; Thiyyagura, Pradeep; Lee, Wendy; Mo, Hua; Lopez, Liliana; Moreno, Sonia; Acosta-Baena, Natalia; Giraldo, Margarita; Garcia, Gloria; Reiman, Rebecca A; Huentelman, Matthew J; Kosik, Kenneth S; Tariot, Pierre N; Lopera, Francisco; Reiman, Eric M

    2012-01-01

    Summary Background Fibrillar amyloid-β (Aβ) is thought to begin accumulating in the brain many years before the onset of clinical impairment in patients with Alzheimer’s disease. By assessing the accumulation of Aβ in people at risk of genetic forms of Alzheimer’s disease, we can identify how early preclinical changes start in individuals certain to develop dementia later in life. We sought to characterise the age-related accumulation of Aβ deposition in presenilin 1 (PSEN1) E280A mutation carriers across the spectrum of preclinical disease. Methods Between Aug 1 and Dec 6, 2011, members of the familial Alzheimer’s disease Colombian kindred aged 18–60 years were recruited from the Alzheimer’s Prevention Initiative’s registry at the University of Antioquia, Medellín, Colombia. Cross-sectional assessment using florbetapir PET was done in symptomatic mutation carriers with mild cognitive impairment or mild dementia, asymptomatic carriers, and asymptomatic non-carriers. These assessments were done at the Banner Alzheimer’s Institute in Phoenix, AZ, USA. A cortical grey matter mask consisting of six predefined regions. was used to measure mean cortical florbetapir PET binding. Cortical-to-pontine standard-uptake value ratios were used to characterise the cross-sectional accumulation of fibrillar Aβ deposition in carriers and non-carriers with regression analysis and to estimate the trajectories of fibrillar Aβ deposition. Findings We enrolled a cohort of 11 symptomatic individuals, 19 presymptomatic mutation carriers, and 20 asymptomatic non-carriers, ranging in age from 20 to 56 years. There was greater florbetapir binding in asymptomatic PSEN1 E280A mutation carriers than in age matched non-carriers. Fibrillar Aβ began to accumulate in PSEN 1E280A mutation carriers at a mean age of 28·2 years (95% CI 27·3–33·4), about 16 years and 21 years before the predicted median ages at mild cognitive impairment and dementia onset, respectively. 18F

  12. Novel Compound Heterozygous Spatacsin Mutations in a Greek Kindred with Hereditary Spastic Paraplegia SPG11 and Dementia.

    PubMed

    Fraidakis, Matthew J; Brunetti, Maura; Blackstone, Craig; Filippi, Massimo; Chiò, Adriano

    2016-01-01

    SPG11 belongs to the autosomal recessive hereditary spastic paraplegias (HSP) and presents during childhood or puberty with a complex clinical phenotype encompassing learning difficulties, ataxia, peripheral neuropathy, amyotrophy, and mental retardation. We hereby present the case of a 30-year-old female patient with complex autosomal recessive HSP with thinning of the corpus callosum (TCC) and dementia that was compound heterozygous with two novel mutations in the SPG11 gene. Sequence analysis of the SPG11 gene revealed two novel mutations in a compound heterozygous state in the index patient (c.2431C>T/p.Gln811Ter and c.6755_6756insT/p.Glu2252Aspfs*88). MRI showed abnormal TCC, white matter (WM) hyperintensities periventricularly, and the 'ears of the lynx' sign. Diffusion tensor imaging showed a mild-to-moderate decrease in fractional anisotropy and an increase in mean diffusivity in WM compared to age-matched controls, while magnetic resonance spectroscopy showed abnormal findings in affected WM with a decrease in N-acetyl-aspartate in WM regions of interest. This is the first SPG11 kindred from the Greek population to be reported in the medical literature. PMID:27318863

  13. Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency)

    SciTech Connect

    Taylor, S.A.M.; Deugau, K.V.; Lillicrap, D.P. )

    1991-01-01

    Studies have shown that hemophilia B (Christmas disease; factor IX deficiency) results from many different mutations in the factor IX gene, of which {gt}95% are single nulceotide substitutions. This study has identified a previously unreported form of hemophilia B in a patient who was a somatic mosaic for a guanine-to-cytosine transversion at nucleotide 31,170 in the factor IX gene. This point mutation changes the codon for residue 350 in the catalytic domain of factor IX from a cysteine to a serine. The authors used differential termination of primer extension to confirm and measure the degree of mosaicism. The study shows that a varying proportion of cells from hepatic, renal, smooth muscle, and hematopoietic populations possessed normal as well as mutant factor IX sequences. These results indicate that the mutation in this patient occurred either as an uncorrected half-chromatid mutation in the female gamete or as a replication or postreplication error in the initial mitotic divisions of the zygote preceding implantation. In addition, this kindred also contains two females in successive generations who have moderately severe factor IX deficiency. The molecular pathogenesis of this latter phenomenon has been studied and seems to relate to the unaccompanied expression of the mutant factor IX gene consequent upon a second, as yet undefined, genetic event that has prevented inactivation of sequences including the mutant factor IX gene on the X chromosome inherited from the affected male.

  14. A novel CYP17A1 deletion causes a functional knockout of the steroid enzyme 17-hydroxylase and 17,20-lyase in a Turkish family and illustrates the precise role of the CYP17A1 gene

    PubMed Central

    Camats, Núria; Üstyol, Ala; Atabek, Mehmet Emre; Dick, Bernhard; Flück, Christa E

    2015-01-01

    Key Clinical Message A novel homozygous long-range deletion of the CYP17A1 gene abolished protein expression and caused the severest form of 17-hydroxylase deficiency in one kindred of a Turkish family. The affected subjects presented with 46,XY sex reversal and 46,XX lack of pubertal development as well as severe hypertension. PMID:26509008

  15. A novel CYP17A1 deletion causes a functional knockout of the steroid enzyme 17-hydroxylase and 17,20-lyase in a Turkish family and illustrates the precise role of the CYP17A1 gene.

    PubMed

    Camats, Núria; Üstyol, Ala; Atabek, Mehmet Emre; Dick, Bernhard; Flück, Christa E

    2015-10-01

    A novel homozygous long-range deletion of the CYP17A1 gene abolished protein expression and caused the severest form of 17-hydroxylase deficiency in one kindred of a Turkish family. The affected subjects presented with 46,XY sex reversal and 46,XX lack of pubertal development as well as severe hypertension. PMID:26509008

  16. Evidence for multiple loci from a genome scan of autism kindreds.

    PubMed

    Schellenberg, G D; Dawson, G; Sung, Y J; Estes, A; Munson, J; Rosenthal, E; Rothstein, J; Flodman, P; Smith, M; Coon, H; Leong, L; Yu, C-E; Stodgell, C; Rodier, P M; Spence, M A; Minshew, N; McMahon, W M; Wijsman, E M

    2006-11-01

    We performed a genome-wide linkage scan using highly polymorphic microsatellite markers. To minimize genetic heterogeneity, we focused on sibpairs meeting the strict diagnosis of autism. In our primary analyses, we observed a strong linkage signal (P=0.0006, 133.16 cM) on chromosome 7q at a location coincident with other linkage studies. When a more relaxed diagnostic criteria was used, linkage evidence at this location was weaker (P=0.01). The sample was stratified into families with only male affected subjects (MO) and families with at least one female affected subject (FC). The strongest signal unique to the MO group was on chromosome 11 (P=0.0009, 83.82 cM), and for the FC group on chromosome 4 (P=0.002, 111.41 cM). We also divided the sample into regression positive and regression negative families. The regression-positive group showed modest linkage signals on chromosomes 10 (P=0.003, 0 cM) and 14 (P=0.005, 104.2 cM). More significant peaks were seen in the regression negative group on chromosomes 3 (P=0.0002, 140.06 cM) and 4 (P=0.0005, 111.41 cM). Finally, we used language acquisition data as a quantitative trait in our linkage analysis and observed a chromosome 9 signal (149.01 cM) of P=0.00006 and an empirical P-value of 0.0008 at the same location. Our work provides strong conformation for an autism locus on 7q and suggestive evidence for several other chromosomal locations. Diagnostic specificity and detailed analysis of the autism phenotype is critical for identifying autism loci. PMID:16880825

  17. The histocompatibility system in juvenile, insulin-dependent diabetic multiplex kindreds.

    PubMed

    Barbosa, J; King, R; Noreen, H; Yunis, E J

    1977-11-01

    We have histocompatibility (HLA) genotyped 24 families with two or more juvenile, insulin-dependent, ketosis-prone diabetic siblings. This criterion for family selection was used to obtain a homogeneous form of diabetes within a sibship, because diabetes appears to be a genetically heterogeneous disease. 58 diabetic and 53 nondiabetic sibs and 40 parents were studied. 55% of the diabetic pairs were concordant for both HLA haplotypes (expected 25%), 40% were concordant for one haplotype (expected 50%), and 5% were discordant for both haplotypes (expected 25%). These values are significantly different from the expected values (P < 0.001). On the other hand, the inheritance of haplotypes among the nondiabetic sibs in these families was not significantly different from the expected mendelian segregation. When comparing 20 pairs of HLA identical (sharing two haplotypes) with 15 pairs of haploidential (sharing one haplotype) diabetic sibs for the intrapair difference in age of onset of disease, we found that the HLA identical sibs were significantly more concordant for age of onset (3.9 yr difference) than the haploidential (7.3 yr difference) (P < 0.05). The same type of analysis for the difference in seasonal incidence in months revealed that the HLA indentical sibs were more concordant (1.8 mo difference) than the haploidentical sibs (3.2 mo difference) (P < 0.025). Furthermore, the HLA identical diabetic sibs were more likely to develop diabetes in the winter months (78%) than the haploidentical diabetic sibs (21%). No particular HLA haplotype or antigen seemed to be associated with any particular clinical feature. These data are compatible with the theory of genetic heterogeneity of juvenile, insulin-dependent diabetes. It is suggested that there are one or more diabetes response genes in the HLA region playing an important role in the pathogenesis of juvenile, insulin-dependent diabetes in the families studied here. It is, however, possible that other genes, not

  18. Genetic mapping of X-linked ocular albinism: Linkage analysis in a large Newfoundland kindred

    SciTech Connect

    Charles, S.J.; Moore, A.T.; Barton, D.E.; Yates, J.R.W. ); Green, J.S. )

    1993-04-01

    Genetic linkage studies in a large Newfoundland family affected by X-linked ocular albinism (OA1) showed linkage to markers from Xp22.3. One recombinant mapped the disease proximal to DXS143 (dic56) and two recombinants mapped the disease distal to DXS85 (782). Combining the data with that from 16 British families previously published confirmed close linkage between OA1 and DXS143 (dic56; Z[sub max] = 21.96 at [theta] = 0.01, confidence interval (CI) 0.0005--0.05) and linkage to DXS85 (782; Z[sub max] = 17.60 at [theta] = 0.07, CI = 0.03--0.13) and DXS237 (GMGX9; Z[sub max] = 15.20 at [theta] = 0.08, CI = 0.03--0.15). Multipoint analysis (LINKMAP) gave the most likely order as Xpter-XG-DXS237-DXS143-OA1-DXS85, with odds of 48:1 over the order Xpter-XG-DXS237-OA1-DXS143-DXS85, and odds exceeding 10[sup 10]:1 over other locations for the disease locus. 11 refs., 1 fig., 1 tab.

  19. The Empty Nest Syndrome in Midlife Families: A Multimethod Exploration of Parental Gender Differences and Cultural Dynamics

    ERIC Educational Resources Information Center

    Mitchell, Barbara A.; Lovegreen, Loren D.

    2009-01-01

    This study explores parental health and well-being in relation to "empty nest" transitions. Focus is placed on the purported empty nest syndrome (i.e., self-reported experiences of depression and emotional distress when children leave home) and variations by parental gender and cultural background. This study is primarily based on in-depth…

  20. Mark Twain and his family's health: Livy Clemens' neurasthenia in the gilded age and chronic fatigue syndrome of today.

    PubMed

    Arcari, Ralph; Crombie, H David

    2003-05-01

    Our purpose is to compare and contrast the 19th century diagnosis and disease neurasthenia with the contemporary illness known as Chronic Fatigue Syndrome. The health of Mark Twain's wife, Olivia (Livy) Clemens, will then be discussed and evaluated with respect to these two medical conditions. PMID:12802844

  1. Familial co-segregation of Coffin-Lowry syndrome inherited from the mother and autosomal dominant Waardenburg type IV syndrome due to deletion of EDNRB inherited from the father.

    PubMed

    Loupe, Jacob; Sampath, Srirangan; Lacassie, Yves

    2014-10-01

    We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.865_866delCA) in codon 289 of RPS6KA3 leading to a frame-shift and premature termination of translation 5 codons downstream (NM_004586.2:p.Gln289ValfsX5). This deletion also was identified in the proposita and her three sisters with a clinical suspicion of CLS, all of whom as carriers for this X-linked disorder had very subtle manifestations. The molecular confirmation of WS type 4 (Shah-Waardenburg; WS4) was not as straightforward. To evaluate WS types 1-4, multiple sequential molecular tests were requested, including Sanger sequencing of all exons, and deletion/duplication analysis using MLPA for PAX3, MITF, SOX10, EDN3 and EDNRB. Although sequencing did not identify any disease causing variants, MLPA identified a heterozygous deletion of the entire EDNRB in the father. This deletion was also found in the proposita and the oldest child. Since the heterozygous deletion was the only change identified in EDNRB, this family represents one of the few cases of an autosomal dominant inheritance of WS4 involving the endothelin pathway. Altogether, clinical evaluation of the family revealed one child to be positive for WS4 and two positive for CLS, while two children were positive for both diseases simultaneously (including the proposita) while another pair test negative for either disease. This kinship is an example of the coincidence of two conditions co-segregating in one family, with variable phenotypes requiring molecular testing to

  2. [Aarskog's syndrome].

    PubMed

    Hromádková, L; Frána, L

    1991-05-01

    The authors described the rare Aarskog syndrome in a 6-year-old boy, associated with left-sided Brown's syndrome. Another 4-year-old boy came from an affected family where the brother suffered also from Aarskog's syndrome and in the mother some microsymptoms were detected. The authors recommend that patients who on examination of a refraction defect or strabism display uncommon features in the face or other parts of the body should be always subjected to a general examination incl. genetic examination. PMID:1913912

  3. 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

  4. Familial glucocorticoid resistance caused by a splice site deletion in the human glucocorticoid receptor gene

    SciTech Connect

    Karl, M.; Lamberts, S.W.J.; Detera-Wadleigh, S.D.; Encio, I.J.; Stratakis, C.A.; Hurley, D.M.; Accili, D.; Chrousos, G.P. Erasmus Univ. of Rotterdam )

    1993-03-01

    The clinical syndrome of generalized, compensated glucocorticoid resistance is characterized by increased cortisol secretion without clinical evidence of hyper- or hypocortisolism, and manifestations of androgen and/or mineralocorticoid excess. This condition results from partial failure of the glucocorticoid receptor (GR) to modulate transcription of its target genes. The authors studied the molecular mechanisms of this syndrome in a Dutch kindred, whose affected members had hypercortisolism and approximately half of normal GRs, and whose proband was a young woman with manifestations of hyperandrogenism. Using the polymerase chain reaction to amplify and sequence each of the nine exons of the GR gene [alpha], along with their 5[prime]- and 3[prime]-flanking regions, the authors identified a 4-base deletion at the 3[prime]-boundary of exon 6 in one GR allele ([Delta][sub 4]), which removed a donor splice site in all three affected members studied. In contrast, the sequence of exon 6 in the two unaffected siblings was normal. A single nucleotide substitution causing an amino acid substitution in the amino terminal domain of the GR (asparagine to serine, codon 363) was also discovered in exon 2 of the other allele (G[sub 1220]) in the proband, in one of her affected brothers and in her unaffected sister. This deletion in the glucocorticoid receptor gene was associated with the expression of only one allele and a decrease of GR protein by 50% in affected members of this glucocorticoid resistant family. The mutation identified in exon 2 did not segregate with the disease and appears to be of no functional significance. The presence of the null allele was apparently compensated for by increased cortisol production at the expense of concurrent hyperandrogenism. 40 refs., 3 figs.

  5. CADASIL presenting with a movement disorder: a clinical study of a Chilean kindred.

    PubMed

    Miranda, Marcelo; Dichgans, Martin; Slachevsky, Andrea; Urbina, Francisco; Mena, Ismael; Venegas, Pablo; Galvez, Marcelo

    2006-07-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary vascular disease that usually begins with migraine, followed by repeated strokes and progressive dementia. We describe an unusual clinical presentation of this condition in members of a Chilean family with an established NOTCH3 mutation. We report early clinical, neuropsychological, transcranial ultrasound, magnetic resonance imaging (MRI), cerebral blood flow, and skin biopsy findings on these patients. Of the patients, 2 presented with facial dystonia, 1 of whom had abnormal single photon emission computed tomography and transcranial ultrasound studies after normal brain MRI scans. Our report emphasizes that CADASIL must be considered in the study of patients with secondary dystonia. PMID:16538621

  6. Familial Isolated Pituitary Adenomas (FIPA) and the Pituitary Adenoma Predisposition due to Mutations in the Aryl Hydrocarbon Receptor Interacting Protein (AIP) Gene

    PubMed Central

    Aaltonen, Lauri A.; Daly, Adrian F.

    2013-01-01

    Pituitary adenomas are one of the most frequent intracranial tumors and occur with a prevalence of approximately 1:1000 in the developed world. Pituitary adenomas have a serious disease burden, and their management involves neurosurgery, biological therapies, and radiotherapy. Early diagnosis of pituitary tumors while they are smaller may help increase cure rates. Few genetic predictors of pituitary adenoma development exist. Recent years have seen two separate, complimentary advances in inherited pituitary tumor research. The clinical condition of familial isolated pituitary adenomas (FIPA) has been described, which encompasses the familial occurrence of isolated pituitary adenomas outside of the setting of syndromic conditions like multiple endocrine neoplasia type 1 and Carney complex. FIPA families comprise approximately 2% of pituitary adenomas and represent a clinical entity with homogeneous or heterogeneous pituitary adenoma types occurring within the same kindred. The aryl hydrocarbon receptor interacting protein (AIP) gene has been identified as causing a pituitary adenoma predisposition of variable penetrance that accounts for 20% of FIPA families. Germline AIP mutations have been shown to associate with the occurrence of large pituitary adenomas that occur at a young age, predominantly in children/adolescents and young adults. AIP mutations are usually associated with somatotropinomas, but prolactinomas, nonfunctioning pituitary adenomas, Cushing disease, and other infrequent clinical adenoma types can also occur. Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients. Study of pituitary adenoma patients with AIP mutations has demonstrated that these cases raise clinical challenges to successful treatment. Extensive research on the biology of AIP and new advances in mouse Aip knockout models demonstrate multiple pathways by which AIP may contribute to tumorigenesis. This review assesses

  7. Characterization of a DNA sequence family in the Prader-Willi/Angelman syndrome chromosome region in 15q11-q13

    SciTech Connect

    Dittrich, B.; Knoblauch, H.; Buiting, K.; Horsthemke, B. )

    1993-04-01

    IR4-3R (D15S11) is an anonymous DNA sequence from human chromosome 15. Using YAC cloning and restriction enzyme analysis, the authors have found that IR4-3R detects five related DNA sequences, which are spread over 700 kb within the Prader-Willi/Angelman syndrome chromosome region in 15q11-q 13. The RsaI and StyI polymorphisms, which were described previously, are associated with the most proximal copy of IR4-3R and are in strong linkage disequilibrium. IR4-3R represents the third DNA sequence family that has been identified in 15q11-q13. 14 refs., 2 figs., 1 tab.

  8. The brain finger protein gene (ZNF179), a member of the RING finger family, maps within the Smith-Magenis syndrome region at 17p11.2

    SciTech Connect

    Kimura, Toshiyuki; Arakawa, Yoshiki; Inazawa, Johji

    1997-03-31

    Smith-Magenis syndrome (SAIS) is caused by a microdeletion of 17p11.2 and comprises developmental and growth delay, facial abnormalities, unusual behavior and sleep problems. This phenotype may be due to haploinsufficiency of several contiguous genes. The human brain finger protein gene (ZNF179), a member of the RING finger protein family, has been isolated and mapped to l7p11.2. FISH analyses of metaphase or interphase chromosomes of 6 patients with SMS show that ZNF179 was deleted in one of the 2 homologs (17p11.2), indicating a possible association of the defect of this gene with the pathogenesis of SMS. Furthermore, using a prophase FISH ordering system, we sublocalized ZNF179 proximally to LLGL which lies on the critical region for SMS. 27 refs., 2 figs.

  9. Abnormal pituitary development and function in three siblings of a Jamaican family: A new syndrome involving the Pit-1 gene

    SciTech Connect

    Sanchez, J.C.; Schiavi, A.; Parks, J.

    1994-09-01

    In 1967 Mckusick et al. reported three siblings in Canada who had combine pituitary hormone deficiencies (CPHD). Since that report there have been several families with multiple affected members who share the common characteristics of autosomal recessive inheritance and clinical expression of pituitary deficiencies at an early age. We report here a CPHD family of Jamaican origin with three affected and two unaffected siblings. The affected siblings have evidence of severe growth failure, growth hormone deficiency, hypothyroidism and variable prolactin deficiency. Recently, in some families with CPHD a defect has been detected in the Pit-1 gene, which encodes a transcription factor involved in the differentiation of the pituitary and the production of growth hormone, TSH and prolactin. We are studying the Pit-1 gene in this family as a candidate gene that may explain the family phenotype. The Pit-1 gene has been analyzed in DNA extracted from blood. No gross deletion were detected in exons 2, 3, 4, 5 and 6 using exon-specific PCR assay developed in our laboratory. Exon 1 is also currently being analyzed. Single stand conformational polymorphism (SSCP) analysis, a screening technique for point mutations within genes, is being used to identify putative base pair changes in the Pit-1 gene. The exon findings will be confirmed using standard DNA sequencing procedures. If a Pit-1 gene is detected, this family would provide a novel presentation, since gonadotropin deficiency appears to be present. Alternatively, this family may represent a mutation on another yet unknown factor involved in normal pituitary development.

  10. Wolcott-Rallison syndrome due to the same mutation (W522X) in EIF2AK3 in two unrelated families and review of the literature.

    PubMed

    Ozbek, M Nuri; Senée, Valérie; Aydemir, Sehnaz; Kotan, L Damla; Mungan, Neslihan O; Yuksel, Bilgin; Julier, Cécile; Topaloglu, A Kemal

    2010-06-01

    Wolcott-Rallison syndrome (WRS) is a rare autosomal recessive disorder characterized by an early-infancy-onset diabetes mellitus associated with a variety of multisystemic clinical manifestations. Here, we present six patients with WRS, carrying the same homozygous mutation (EIF2AK3-W522X), from two unrelated Turkish families. This is the largest series of patients with the same mutation for this rare syndrome. In this communication we compare clinical features of these six patients with the other 34 patients who have been reported to date, and review the clinical features of WRS. All WRS patients presented first with symptoms of insulin dependent diabetes mellitus, with a mean age at onset of 2 months. All patients had skeletal dysplasia or early signs of it, and growth retardation. Many of the patients with WRS have been reported to have developmental delay, mental retardation, and learning difficulties; in contrast, none of our patients showed abnormal development at age up to 30 months. Acute attacks of hepatic failure were reported in 23 cases out of 37 patients; in 15 of those 23 cases an acute attack of renal failure accompanied the liver failure. Exocrine pancreatic deficiency has been reported in only four cases other than our four patients. Central hypothyroidism was observed in six of 28 cases. We propose that central hypothyroidism is not a component of WRS, but rather a reflection of euthyroid sick syndrome. Four of our patients experienced severe neutropenia, compared to only five of the 27 other cases, suggesting that the W522X mutation may be specifically associated with neutropenia. Other than the consistent features of diabetes mellitus and epiphyseal dysplasia, WRS patients are otherwise characterized by extensive phenotypic variability that correlates poorly to genotype. PMID:20202148

  11. Self-reported cancer family history is a useful tool for identification of individuals at risk of hereditary cancer predisposition syndrome at primary care centers in middle-income settings: a longitudinal study

    PubMed Central

    Flória-Santos, Milena; Lopes-Júnior, Luís Carlos; Alvarenga, Larissa de Melo; Ribeiro, Mayara Segundo; Ferraz, Victor Evangelista de Faria; Nascimento, Lucila Castanheira; Pereira-da-Silva, Gabriela

    2016-01-01

    Abstract Analysis of cancer family history (CFH) offers a low-cost genetic tool to identify familial cancer predisposition. In middle-income settings, the scarcity of individual records and database-linked records hinders the assessment of self-reported CFH consistency as an indicator of familial cancer predisposition. We used self-reported CFH to identify those families at risk for hereditary cancer syndromes in community-based primary care centers of a low-income Brazilian area. We also evaluated the consistency of the information collected by reassessing CFH five years later. We interviewed 390 families and constructed their pedigrees for genetic cancer risk assessment. We found 125 families affected by cancer, 35.2% with moderate to high risk of familial susceptibility to cancer, a number that represents a relatively high prevalence of potential hereditary cancer syndromes in the overall study sample. Upon reassessment of CFH in 14/20 families that were previously identified as having at least one first-degree and one second-degree relative affected by cancer, and presented moderate to high risk for developing cancer, 90% of initial pedigrees were confirmed. These results demonstrate the reliability of self-reports as a means of early identification of healthy individuals at risk, encouraging the wider use of this method in low- and middle-income primary care settings. PMID:27275666

  12. Self-reported cancer family history is a useful tool for identification of individuals at risk of hereditary cancer predisposition syndrome at primary care centers in middle-income settings: a longitudinal study.

    PubMed

    Flória-Santos, Milena; Lopes-Júnior, Luís Carlos; Alvarenga, Larissa de Melo; Ribeiro, Mayara Segundo; Ferraz, Victor Evangelista de Faria; Nascimento, Lucila Castanheira; Pereira-da-Silva, Gabriela

    2016-06-01

    Analysis of cancer family history (CFH) offers a low-cost genetic tool to identify familial cancer predisposition. In middle-income settings, the scarcity of individual records and database-linked records hinders the assessment of self-reported CFH consistency as an indicator of familial cancer predisposition. We used self-reported CFH to identify those families at risk for hereditary cancer syndromes in community-based primary care centers of a low-income Brazilian area. We also evaluated the consistency of the information collected by reassessing CFH five years later. We interviewed 390 families and constructed their pedigrees for genetic cancer risk assessment. We found 125 families affected by cancer, 35.2% with moderate to high risk of familial susceptibility to cancer, a number that represents a relatively high prevalence of potential hereditary cancer syndromes in the overall study sample. Upon reassessment of CFH in 14/20 families that were previously identified as having at least one first-degree and one second-degree relative affected by cancer, and presented moderate to high risk for developing cancer, 90% of initial pedigrees were confirmed. These results demonstrate the reliability of self-reports as a means of early identification of healthy individuals at risk, encouraging the wider use of this method in low- and middle-income primary care settings. PMID:27275666

  13. Abnormal pattern of post-gamma-ray DNA replication in radioresistant fibroblast strains from affected members of a cancer-prone family with Li-Fraumeni syndrome.

    PubMed Central

    Mirzayans, R.; Aubin, R. A.; Bosnich, W.; Blattner, W. A.; Paterson, M. C.

    1995-01-01

    Non-malignant dermal fibroblast strains, cultured from affected members of a Li-Fraumeni syndrome (LFS) family with diverse neoplasms associated with radiation exposure, display a unique increased resistance to the lethal effects of gamma-radiation. In the studies reported here, this radioresistance (RR) trait has been found to correlate strongly with an abnormal pattern of post-gamma-ray DNA replicative synthesis, as monitored by radiolabelled thymidine incorporation and S-phase cell autoradiography. In particular, the time interval between the gamma-ray-induced shutdown of DNA synthesis and its subsequent recovery was greater in all four RR strains examined and the post-recovery replication rate was much higher and was maintained longer than in normal and spousal controls. Alkaline sucrose sedimentation profiles of pulse-labelled cellular DNA indicated that the unusual pattern of DNA replication in irradiated RR strains may be ascribed to anomalies in both replicon initiation and DNA chain elongation processes. Moreover, the RR strain which had previously displayed the highest post-gamma-ray clonogenic survival was found to harbour a somatic (codon 234) mutation (presumably acquired during culture in vitro) in the same conserved region of the p53 tumour-suppressor gene as the germline (codon 245) mutation in the remaining three RR strains from other family members, thus coupling the RR phenotype and abnormal post-gamma-ray DNA synthesis pattern with faulty p53 expression. Significantly, these two aberrant radioresponse end points, along with documented anomalies in c-myc and c-raf-1 proto-oncogenes, are unprecedented among other LFS families carrying p53 germline mutations. We thus speculate that this peculiar cancer-prone family may possess in its germ line a second, as yet unidentified, genetic defect in addition to the p53 mutation. Images Figure 8 PMID:7779715

  14. Family-focused cognitive behaviour therapy versus psycho-education for adolescents with chronic fatigue syndrome: long-term follow-up of an RCT.

    PubMed

    Lloyd, Samantha; Chalder, Trudie; Rimes, Katharine A

    2012-11-01

    The aim of this study was to investigate the long term efficacy of family-focused cognitive behaviour therapy (CBT) compared with psycho-education in improving school attendance and other secondary outcomes in adolescents with chronic fatigue syndrome (CFS). A 24 month follow-up of a randomised controlled trial was carried out. Participants received either 13 one-hour sessions of family-focused CBT or four one-hour sessions of psycho-education. Forty-four participants took part in the follow-up study. The proportion of participants reporting at least 70% school attendance (the primary outcome) at 24 months was 90% in CBT group and 84% in psycho-education group; the difference between the groups was not statistically significant (OR = 1.29, p = 0.80). The proportion of adolescents who had recovered in the family-focused CBT group was 79% compared with 64% in the psycho-education, according to a definition including fatigue and school attendance. This difference was not statistically significant (Fisher's exact test, p = 0.34). Family-focused CBT was associated with significantly better emotional and behavioural adjustment at 24 month follow-up compared to psycho-education, as reported by both adolescents (F = 6.49, p = 0.02) and parents (F = 4.52, P = 0.04). Impairment significantly decreased in both groups between six and 24 month follow-ups, with no significant group difference in improvement over this period. Gains previously observed for other secondary outcomes at six month follow-up were maintained at 24 month follow-up with no further significant improvement or group differences in improvement. In conclusion, gains achieved by adolescents with CFS who had undertaken family-focused CBT and psycho-education generally continued or were maintained at two-year follow-up. The exception was that family-focused CBT was associated with maintained improvements in emotional and behavioural difficulties whereas psycho-education was associated with

  15. Two families with quadrupedalism, mental retardation, no speech, and infantile hypotonia (Uner Tan Syndrome Type-II); a novel theory for the evolutionary emergence of human bipedalism.

    PubMed

    Tan, Uner

    2014-01-01

    Two consanguineous families with Uner Tan Syndrome (UTS) were analyzed in relation to self-organizing processes in complex systems, and the evolutionary emergence of human bipedalism. The cases had the key symptoms of previously reported cases of UTS, such as quadrupedalism, mental retardation, and dysarthric or no speech, but the new cases also exhibited infantile hypotonia and are designated UTS Type-II. There were 10 siblings in Branch I and 12 siblings in Branch II. Of these, there were seven cases exhibiting habitual quadrupedal locomotion (QL): four deceased and three living. The infantile hypotonia in the surviving cases gradually disappeared over a period of years, so that they could sit by about 10 years, crawl on hands and knees by about 12 years. They began walking on all fours around 14 years, habitually using QL. Neurological examinations showed normal tonus in their arms and legs, no Babinski sign, brisk tendon reflexes especially in the legs, and mild tremor. The patients could not walk in a straight line, but (except in one case) could stand up and maintain upright posture with truncal ataxia. Cerebello-vermial hypoplasia and mild gyral simplification were noted in their MRIs. The results of the genetic analysis were inconclusive: no genetic code could be identified as the triggering factor for the syndrome in these families. Instead, the extremely low socio-economic status of the patients was thought to play a role in the emergence of UTS, possibly by epigenetically changing the brain structure and function, with a consequent selection of ancestral neural networks for QL during locomotor development. It was suggested that UTS may be regarded as one of the unpredictable outcomes of self-organization within a complex system. It was also noted that the prominent feature of this syndrome, the diagonal-sequence habitual QL, generated an interference between ipsilateral hands and feet, as in non-human primates. It was suggested that this may have been

  16. 22q11.2 duplication syndrome: two new familial cases with some overlapping features with DiGeorge/velocardiofacial syndromes.

    PubMed

    Portnoï, Marie-France; Lebas, Fanny; Gruchy, Nicolas; Ardalan, Azarnouche; Biran-Mucignat, Valérie; Malan, Valérie; Finkel, Lina; Roger, Gilles; Ducrocq, Sarah; Gold, Francis; Taillemite, Jean-Louis; Marlin, Sandrine

    2005-08-15

    Twenty-one patients, including our two cases, with variable clinical phenotype, ranging from mild learning disability to severe congenital malformations or overlapping features with DiGeorge/velocardiofacial syndromes (DG/VCFS), have been shown to have a chromosome duplication 22q11 of the region that is deleted in patients with DG/VCFS. The reported cases have been identified primarily by interphase FISH and could have escaped identification and been missed by routine cytogenetic analysis. Here we report on two inherited cases, referred to us, to rule out 22q11 microdeletion diagnosis of VCFS. The first patient was a 2-month-old girl, who presented with cleft palate, minor dysmorphic features including short palpebral fissures, widely spaced eyes, long fingers, and hearing loss. Her affected mother had mild mental retardation and learning disabilities. The second patient was a 7(1/2)-year-old boy with velopharyngeal insufficiency and mild developmental delay. He had a left preauricular tag, bifida uvula, bilateral fifth finger clinodactyly, and bilateral cryptorchidism. His facial features appeared mildly dysmorphic with hypertelorism, large nose, and micro/retrognathia. The affected father had mild mental retardation and had similar facial features. FISH analysis of interphase cells showed three TUPLE1-probe signals with two chromosome-specific identification probes in each cell. FISH analysis did not show the duplication on the initial testing of metaphase chromosomes. On review, band q11.2 was brighter on one chromosome 22 in some metaphase spreads. The paucity of reported cases of 22q11.2 microduplication likely reflects a combination of phenotypic diversity and the difficulty of diagnosis by FISH analysis on metaphase spreads. These findings illustrate the importance of scanning interphase nuclei when performing FISH analysis for any of the genomic disorders. PMID:16007629

  17. Trisomy 1q41-qter and monosomy 3p26.3-pter in a family with a translocation (1;3): further delineation of the syndromes

    PubMed Central

    2014-01-01

    Background Trisomy 1q and monosomy 3p deriving from a t(1;3) is an infrequent event. The clinical characteristics of trisomy 1q41-qter have been described but there is not a delineation of the syndrome. The 3p25.3-pter monosomy syndrome (MIM 613792) characteristics include low birth weight, microcephaly, psychomotor and growth retardation and abnormal facies. Case presentation A 2 years 8 months Mexican mestizo male patient was evaluated due to a trisomy 1q and monosomy 3p derived from a familial t(1;3)(q41;q26.3). Four female carriers of the balanced translocation and one relative that may have been similarly affected as the proband were identified. The implicated chromosomal regions were defined by microarray analysis, the patient had a trisomy 1q41-qter of 30.3 Mb in extension comprising about 240 protein coding genes and a monosomy 3p26.3-pter of 1.7 Mb including only the genes CNTN6 (MIM 607220) and CHL1 (MIM 607416), which have been implicated in dendrite development. Their contribution to the phenotype, regarding the definition of trisomy 1q41-qter and monosomy 3p26.3-pter syndromes are discussed. Conclusion We propose that a trisomy 1q41-qter syndrome should be considered in particular when the following characteristics are present: postnatal growth delay, macrocephaly, wide fontanelle, triangular facies, frontal bossing, thick eye brows, down slanting palpebral fissures, hypertelorism, flat nasal bridge, hypoplasic nostrils, long filtrum, high palate, microretrognathia, ear abnormalities, neural abnormalities (in particular ventricular dilatation), psychomotor developmental delay and mental retardation. Our patient showed most of these clinical characteristics with exception of macrocephaly, possibly due to a compensatory effect by haploinsufficiency of the two genes lost from 3p. The identification of carriers has important implications for genetic counseling as the risk of a new born with either a der(3) or der(1) resulting from an adjacent-1

  18. Gastrointestinal permeability (GIPerm) is increased in family members of children with functional abdominal pain (FAP) and irritable bowel syndrome (IBS)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Increased GIPerm has been described in children with FAP/IBS and adults with IBS. We sought to determine if baseline GIPerm is increased and if ibuprofen induces a greater increase in GIPerm in parents and siblings of children with FAP/IBS vs. control families without children with FAP/IBS. Site spe...

  19. Multiple recurrent de novo copy number variations (CNVs), including duplications of the 7q11.23 Williams-Beuren syndrome region, are strongly associated with autism

    PubMed Central

    Sanders, Stephan J.; Ercan-Sencicek, A. Gulhan; Hus, Vanessa; Luo, Rui; Murtha, Michael T.; Moreno-De-Luca, Daniel; Chu, Su H.; Moreau, Michael P.; Gupta, Abha R.; Thomson, Susanne A.; Mason, Christopher E.; Bilguvar, Kaya; Celestino-Soper, Patricia B. S.; Choi, Murim; Crawford, Emily L.; Davis, Lea; Wright, Nicole R. Davis; Dhodapkar, Rahul M.; DiCola, Michael; DiLullo, Nicholas M.; Fernandez, Thomas V.; Fielding-Singh, Vikram; Fishman, Daniel O.; Frahm, Stephanie; Garagaloyan, Rouben; Goh, Gerald S.; Kammela, Sindhuja; Klei, Lambertus; Lowe, Jennifer K.; Lund, Sabata C.; McGrew, Anna D.; Meyer, Kyle A.; Moffat, William J.; Murdoch, John D.; O'Roak, Brian J.; Ober, Gordon T.; Pottenger, Rebecca S.; Raubeson, Melanie J.; Song, Youeun; Wang, Qi; Yaspan, Brian L.; Yu, Timothy W.; Yurkiewicz, Ilana R.; Beaudet, Arthur L.; Cantor, Rita M.; Curland, Martin; Grice, Dorothy E.; Günel, Murat; Lifton, Richard P.; Mane, Shrikant M.; Martin, Donna M.; Shaw, Chad A.; Sheldon, Michael; Tischfield, Jay A.; Walsh, Christopher A.; Morrow, Eric M.; Ledbetter, David H.; Fombonne, Eric; Lord, Catherine; Martin, Christa Lese; Brooks, Andrew I.; Sutcliffe, James S.; Cook, Edwin H.; Geschwind, Daniel; Roeder, Kathryn; Devlin, Bernie; State, Matthew W.

    2014-01-01

    Summary Given prior evidence for the contribution of rare copy number variations (CNVs) to autism spectrum disorders (ASD), we studied these events in 4,457 individuals from 1,174 simplex families, composed of parents, a proband and, in most kindreds, an unaffected sibling. We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, featuring a highly social personality. We identify rare recurrent de novo CNVs at five additional regions including two novel ASD loci, 16p13.2 (including the genes USP7 and C16orf72) and Cadherin13, and implement a rigorous new approach to evaluating the statistical significance of these observations. Overall, we find large de novo CNVs carry substantial risk (OR=3.55; CI =2.16-7.46, p=6.9 × 10−6); estimate the presence of 130-234 distinct ASD-related CNV intervals across the genome; and, based on data from multiple studies, present compelling evidence for the association of rare de novo events at 7q11.23, 15q11.2-13.1, 16p11.2, and Neurexin1. PMID:21658581

  20. Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13

    SciTech Connect

    Gong, Yaoqin; Liu, Jin; Warman, M.L.

    1996-07-01

    Osteoporosis-pseudoglioma syndrome (OPS) is an autosomal recessive disorder characterized by severe juvenile-onset osteoporosis and congenital or juvenile-onset blindness. The pathogenic mechanism is not known. Clinical, biochemical, and microscopic analyses suggest that OPS may be a disorder of matrix homeostasis rather than a disorder of matrix structure. Consequently, identification of the OPS gene and its protein product could provide insights regarding common osteoporotic conditions, such as postmenopausal and senile osteoporosis. As a first step toward determining the cause of OPS, we utilized a combination of traditional linkage analysis and homozygosity mapping to assign the OPS locus to chromosome region 11q12-13. Mapping was accomplished by analyzing 16 DNA samples (seven affected individuals) from three different consanguineous kindreds. Studies in 10 additional families narrowed the candidate region, supported locus homogeneity, and did not detect founder effects. The OPS locus maps to a 13-cM interval between D11S1298 and D11S971 and most likely lies in a 3-cM region between GSTP1 and D11S1296. At present, no strong candidate genes colocalize with OPS. 33 refs., 2 figs., 1 tab.