A genetic study of Hirschsprung disease.
427
Citation
43
Reference
10
Related Paper
Citation Trend
Keywords:
Penetrance
Proband
Hirschsprung's disease
Megacolon
Expressivity
Cite
Abstract Ten families in which there were 79 individuals affected by Waardenburg's syndrome were examined for penetrance of sensorineural hearing loss and expressivity of the gene. There were 47 with Waardenburg syndrome Type 1 and 32 with Waardenburg syndrome Type II. Penetrance of senorineural hearing loss was calculated after exclusion of the probands and was found not to be significantly different between each syndrome type but to show marked interfamilial variation. A bilateral sensorineural hearing loss was present more frequently than unilateral with the proportion varying between families. Certain audiometric shapes were found to recur in the syndrome but, apart from possibly one asymmetric configuration, seem to have been described also in other conditions. The degree of hearing loss was very variable within and between families. The implications for genetic counselling are discussed and the advantages of basing risk factors upon individual families rather than syndrome types emphasized.
Penetrance
Waardenburg syndrome
Proband
Expressivity
Cite
Citations (66)
Abstract Background Previous studies of individuals with hereditary or sporadic congenital heart disease (CHD) have provided strong evidence for a genetic basis for CHD. The aim of this study was to identify novel pathogenic genes and variants in a Chinese CHD family. Methods Three generations of a family with CHD were recruited. We performed whole exome sequencing for the affected individuals and the proband's unaffected aunt to investigate the genetic causes of CHD in this family. Heterozygous variants carried by the proband and her maternal grandmother, but not the proband's aunt, were selected. The frequencies of the variants detected were assessed using public databases, and their influences on protein function were predicted using online prediction software. The candidate variant was further confirmed by Sanger sequencing of other members of the family. Results On the basis of the family's pedigree, the mode of inheritance was speculated to be autosomal dominant with incomplete penetrance. We identified a novel heterozygous missense variant in SOX9 in all affected individuals and one asymptomatic family member, suggesting an inheritance pattern with incomplete penetrance. The variant was not found in any public database. In addition, the variant was highly conserved among mammals, and was predicted to be deleterious by online software programs. Conclusions We report for the first time a novel heterozygous missense variant in SOX9 (NM_000346:c.931G>T:p.Gly311Cys) in a Chinese CHD family. Our results provide further evidence supporting a causative role for SOX9 variants in CHD.
Proband
Penetrance
Sanger sequencing
Aunt
Cite
Citations (5)
Penetrance
Proto-Oncogene Proteins c-ret
Heterozygote advantage
Expressivity
Cite
Citations (11)
This study examines the association of Hirschsprung disease with Down syndrome and calculates the recurrence risk for families of Hirschsprung patients. Information was collected from 134 histologically diagnosed patients with Hirschsprung disease, from Children's Hospital in Pittsburgh, PA between 1950 and 1977. One hundred and three patients had short segment Hirschsprung disease which is defined as involvement up to and including the sigmoid colon. Thirty-one patients had the long segment type with aganglionosis extending in some cases to the small intestine. As in other studies, we found a significant association between Hirschsprung disease and Down syndrome in that 5.9% of probands had both. Mean maternal age of cases with both Hirschsprung disease and Down syndrome (33.5 years) was significantly different from controls (26.7 years) and non-Down syndrome Hirschsprung patients (26.6 years). The overall sex ratio for Hirschsprung disease was 3.6. Recurrence risks were dependent on proband sex and the degree of aganglionic involvement.
Proband
Hirschsprung's disease
Megacolon
Cite
Citations (84)
Abstract The 3p deletion syndrome is a rare disorder caused by deletions of different sizes in the 3p25‐pter region. It is characterized by growth retardation, developmental delay, mental retardation, dysmorphism, microcephaly, and ptosis. The phenotype of individuals with deletions varies from normal to severe. Most cases occur de novo, but a few familial cases have been reported. We describe two families with terminal 3p deletions and extremely variable clinical features. In family A, the mother and daughter were extremely mildly affected whereas the son had more severe clinical features. In family B, the mother was normal and her son was affected, having some symptoms that had not been described in the 3p deletion syndrome before. The deletions were characterized by genome‐wide SNP array analysis and were 9 and 1.1 Mb in size. Sequencing analysis of the CHL1 , CNTN4 , and CRBN genes did not reveal any masked recessive alleles that might explain the more severe phenotypes in the probands. In family A, the 9 Mb deletion can be considered causal for the 3p deletion syndrome in the proband, but the extremely mild phenotype in the other family members remains unexplained. In family B, the 1.1 Mb terminal deletion encompasses only the CHL1 gene, which is insufficient to cause 3p deletion symptoms; thus the clinical features observed in this family may have a different cause. The variable penetrance of 3p deletions creates challenges in genetic counseling, as the phenotype of the offspring cannot be predicted based on chromosomal and/or genome‐wide array analytical findings. © 2010 Wiley‐Liss, Inc.
Proband
Penetrance
Microcephaly
SNP array
Subtelomere
Cite
Citations (51)
Hirschsprung disease (HSCR) is a complex disorder that exhibits incomplete penetrance and variable expressivity due to interactions among multiple susceptibility genes. Studies in HSCR families have identified RET-dependent modifiers for short-segment HSCR (S-HSCR), but epistatic effects in long-segment (L-HSCR) and syndromic cases have not been fully explained. SOX10 mutations contribute to syndromic HSCR cases and Sox10 alleles in mice exhibit aganglionosis and pigmentary anomalies typical of a subset of HSCR patients categorized as Waardenburg–Shah syndrome (WS4, OMIM 277580). Sox10 mutant alleles in mice exhibit strain-dependent variation in penetrance and expressivity of aganglionic megacolon analogous to the variation observed in patients with aganglionosis. In this study, we focused on enteric ganglia deficits in Sox10Dom mice and defined aganglionosis as a quantitative trait in Sox10Dom intercross progeny to investigate the contribution of strain background to variation in enteric nervous system deficits. We observe that the phenotype of Sox10Dom/+ mutants ranges over a continuum from severe aganglionosis to no detectable phenotype in the gut. To systematically identify genes that modulate Sox10-dependent aganglionosis, we performed a single nucleotide polymorphism-based genome scan in Sox10Dom/+ F1 intercross progeny. Our analysis reveals modifier loci on mouse chromosomes 3, 5, 8, 11 and 14 with distinct effects on penetrance and severity of aganglionosis. Three of these loci on chromosomes 3, 8 and 11 do not coincide with previously known aganglionosis susceptibility genes or modifier loci and offer new avenues for elucidating the genetic network that modulates this complex neurocristopathy.
Penetrance
Expressivity
SOX10
Waardenburg syndrome
Genetic linkage
Megacolon
Epistasis
Hirschsprung's disease
Enteric Nervous System
Cite
Citations (38)
Penetrance
Proband
Hirschsprung's disease
Megacolon
Expressivity
Cite
Citations (427)
The recurrent microduplication of 16p11.2 (dup16p11.2) is associated with a broad spectrum of neurodevelopmental disorders (NDD) confounded by incomplete penetrance and variable expressivity. This inter- and intra-familial clinical variability highlights the importance of personalized genetic counselling in individuals at-risk. In this study, we performed whole exome sequencing (WES) to look for other genomic alterations that could explain the clinical variability in a family with a boy presenting with NDD who inherited the dup16p11.2 from his apparently healthy mother. We identified novel splicing variants of VPS13B (8q22.2) in the proband with compound heterozygous inheritance. Two VPS13B mutations abolished the canonical splice sites resulting in low RNA expression in transformed lymphoblasts of the proband. VPS13B mutation causes Cohen syndrome (CS) consistent with the proband's phenotype (intellectual disability (ID), microcephaly, facial gestalt, retinal dystrophy, joint hypermobility and neutropenia). The new diagnosis of CS has important health implication for the proband, provides the opportunity for more meaningful and accurate genetic counselling for the family; and underscores the importance of longitudinally following patients for evolving phenotypic features. This is the first report of a co-occurrence of pathogenic variants with familial dup16p11.2. Our finding suggests that the variable expressivity among carriers of rare putatively pathogenic CNVs such as dup16p11.2 warrants further study by WES and individualized genetic counselling of families with such CNVs.
Human genetics
Exome
Cite
Citations (18)
Abstract Introduction: Diagnostic yield of the genetic testing in search for the molecular basis of neurodevelopmental diseases remains low due to incomplete knowledge of the phenotypic spectrum of pathogenic variants in a specific gene. Recently the MED13 gene was linked to neurodevelopmental disease. Methods: Four families with children affected by autism spectrum disorder (ASD) were recruited to the study. Extensive genetic testing was performed for each proband: CGG repeat expansion analysis in FMR1 gene; whole exome sequencing (WES); array comparative genomic hybridization (aCGH); maternity and paternity confirmation. Genetic variants which were revealed by WES were verified with Sanger sequencing or aCGH in probands and their relatives. Results: Four rare heterozygous genetic variants in MED13 gene were identified in four unrelated patients with clinical features matching MED13 -associated phenotype: intellectual disability (ID) of various degrees, speech delay, ASD and mild facial dysmorphisms. Three of the variants occurred de novo , while one was inherited maternally, in accordance with previous findings, suggesting incomplete penetrance. A patient with a de novo missense mutation in the intrinsic disordered region of MED13 developed seizures similarly to the only other reported patient with a pathogenic missense variant in this region. Limitations: Additional functional studies are needed to elucidate molecular mechanisms of the disease and distinguish between pathogenic and non-pathogenic variation. Conclusion: Our data strongly support the role of MED13 in neurodevelopmental disease by eliminating other common genetic defects. We expand the phenotypic spectrum of the disease causing variants: pathogenic missense variants in the intrinsic disordered region of MED13 may lead to a phenotype with seizures and incomplete penetrance of the maternally inherited variants may occur.
Proband
Sanger sequencing
Penetrance
Comparative genomic hybridization
Cite
Citations (1)