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PubMed2026

Exome sequencing and large-scale analysis of electronic medical record-linked biobank data identify candidate deafness genes.

INTRODUCTION: Rapid advances in whole-exome sequencing (WES) have enabled large-scale detection of pathogenic variants. Although hundreds of genes are implicated in hearing loss, up to half of inherited cases remain unsolved, limiting eligibility for gene therapy trials that require genetic diagnosis. Biobanks and electronic medical records (EMRs) offer opportunities to integrate genomic and clinical data at scale and expand the spectrum of hearing loss genes. Despite clinical value, EMRs often lack key information such as inheritance patterns, posing challenges for accurate interpretation. METHODS: WES was performed on DNA samples from 1038 hearing-impaired patients enrolled in the Maccabi Research and Innovation Center Tipa Biobank. Clinical data were extracted from EMRs. Audiograms were available for all cases, although data on age of onset, family history and mode of inheritance were mostly unavailable. We applied a scalable bioinformatics analysis strategy for high-throughput annotation, filtering and prioritisation of WES variants across more than 1000 patients, designed to accommodate incomplete and heterogeneous clinical records. RESULTS: Using this approach, 15% of cases were solved or potentially solved through known or novel variants in established deafness genes. Homozygous variants in novel candidate genes were identified in 3% of cases. Functional characterisation was performed for promising candidate genes to validate their role in the ear. CONCLUSION: These findings demonstrate that WES can determine disease aetiology in large, genetically heterogeneous populations, even in the context of incomplete clinical data. This approach supports large-scale genetic screening and provides a framework for identifying patients who may benefit from emerging gene-based therapies.

Genetic Testing↗

PubMed1998

Telomere variation in Xenopus laevis.

Eukaryotic telomeres are variable at several levels, from the length of the simple sequence telomeric repeat tract in different cell types to the presence or number of telomere-adjacent DNA sequence elements in different strains or individuals. We have investigated the sequence organization of Xenopus laevis telomeres by use of the vertebrate telomeric repeat (TTAGGG)n and blot hybridization analysis. The (TTAGGG)n-hybridizing fragments, which ranged from less than 10 to over 50 kb with frequently cutting enzymes, defined a pattern that was polymorphic between individuals. BAL 31 exonuclease treatment confirmed that these fragments were telomeric. The polymorphic fragments analyzed did not hybridize to 5S RNA sequences, which are telomeric according to in situ hybridization. When telomeric fragments from offspring (whole embryos) were compared to those from the spleens of the parents, the inheritance pattern of some bands was found to be unusual. Furthermore, in one cross, the telomeres of the embryo were shorter than the telomeres of the parents' spleen, and in another, the male's testis telomeres were shorter than those of the male's spleen. Our data are consistent with a model for chromosome behavior that involves a significant amount of DNA rearrangement at telomeres and suggest that length regulation of Xenopus telomeres is different from that observed for Mus spretus and human telomeres.

Animals↗

PubMed2004

Characterization of mutator phenotype in familial colorectal cancer patients not fulfilling amsterdam criteria.

PURPOSE: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria. EXPERIMENTAL DESIGN: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2). RESULTS: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P=0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P=0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors. CONCLUSION: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2003

X chromosome inactivation patterns in Russell-Silver syndrome patients and their mothers.

Russell-Silver syndrome (RSS) is a disorder characterized by pre- and post-natal growth deficiency, triangular facies, relative macrocephaly, and body asymmetry. Maternal uniparental disomy for chromosome 7 has been found in approximately 10% of RSS cases, while the cause in the remaining cases is unknown. Although most cases of RSS are sporadic, at least 25 families have been reported with familial RSS and inheritance patterns of RSS consistent with an X-linked dominant mutation. Thus, we hypothesized that skewed X-chromosome inactivation (XCI) could be increased in some females with RSS as a consequence of a tendency to have the mutant allele on the predominantly active chromosome. Alternatively, unaffected mothers of children with RSS may tend to be skewed due to preferential inactivation of the mutant allele. In support of this last hypothesis, a significant increase in extremely skewed XCI (>95%) was found in mothers of children with RSS (4 of 21, 19%) compared to controls (2 of 101, 2%) (P = 0.008). However, an increase in skewed XCI was also observed in female patients who had unexplained short stature but did not fulfill the criteria for RSS (3 of 17, 18%) (P = 0.02), but not in those diagnosed as RSS (0 of 7, n.s.). Different mechanisms may underlie the increase in skewing in each group, possibly being due to different X-linked mutations or growth restriction during very early in utero development.

Abnormalities, Multiple↗

PubMed1995

Evidence against unusual sex concordance and pseudoautosomal inheritance in the catatonic subtype of schizophrenia.

The study is based on sibships with multiply afflicted members derived from a family study of consecutively admitted probands with catatonic schizophrenia. As shown recently, the clinical subtype of periodic catatonia, as defined by Leonhard, is compatible with a major gene effect and genetic anticipation; that is, the age of illness onset of the probands is significantly earlier than that of their parents. In the present study, 83 probands with the clinical subtype of periodic catatonia had 26 afflicted siblings that were distributed among 23 families. We analyzed sex-concordance and pseudoautosomal inheritance patterns. Stratifying the 26 afflicted siblings by sibship size and by the proband's sex, we did not find unusual sex-concordance rates in sibships afflicted with periodic catatonia. Further, there was no association between sex concordance and maternal or paternal origin of the disease. Thus, our results provide strong evidence against pseudoautosomal inheritance or sex-linked transmission in affected sibships in the obviously familial schizophrenic subtype of periodic catatonia.

Adult↗

PubMed1994

Genetics of the Costello syndrome.

Although Costello syndrome is considered to be an autosomal recessive disorder, review of 20 families demonstrated that the 37 sibs of the probands were all normal. In 6 families on whom pedigrees were not available, 2 affected sib-pairs were born. Even if there were no normal offspring in these latter families, the occurrence of the Costello syndrome in only 2 of 39 sibs virtually excludes an autosomal recessive inheritance pattern (P = 0.999). Moreover, a significant increase of mean paternal age (38.0 yr) and paternal-maternal age difference (7.36 yr) suggests sporadic autosomal dominant mutations as a likely cause. The 2 reported cases of affected sibs born to healthy parents may be explained by gonadal mosaicism, although heterogeneity with a small proportion of recessively inherited cases cannot be excluded.

Abnormalities, Multiple↗

PubMed1986

Genetic polymorphism of IgG in mink. II. A genetic analysis of allotypes.

Population distribution and inheritance pattern were analyzed in mink IgG allotypes: L1 (L chains), H2, H3, H4, H6, H7, and H8 (the constant region of the H chains, i.e. C gamma-allotypes) and conformational allotype 5 with unknown chain localization. Contrary to expectation, neither allelism, nor close linkage were demonstrated for these allotypes. The major feature of the inheritance of H2, H3, and H4 C gamma-allotypes, as well as allotype 5, was significant excess of negative (without these allotypes) progeny in the F1 generation from monohybrid cross. The explanation offered for this departure of the C gamma-allotypes from normal Mendelian genetics suggests widespread latencies of their expression in mink.

Animals↗

PubMed1991

Jarcho-Levin syndrome: four new cases and classification of subtypes.

The Jarcho-Levin syndrome is a condition manifested by vertebral body and related rib malformations. We report on four new cases and review 57 cases from the literature. Analysis of the 61 cases suggests that there are two major subtypes (spondylocostal dysostosis and spondylothoracic dysostosis) with different survival rates, associated malformations, and inheritance patterns. Individuals with spondylothoracic dysostosis have vertebral body malformations and ribs which flare in a fanlike pattern but which are not significantly malformed. This is an autosomal recessive trait, and the patients have a higher mortality rate and greater incidence of neural tube defects. Individuals with spondylocostal dysostosis have vertebral malformations, frequent dramatic rib malformations, and short stature, but do not have a fanlike thoracic configuration. Most cases of spondylocostal dysostosis are inherited in an autosomal recessive fashion, although in a few families it is a dominant trait which is correlated with better survival. Respiratory compromise previously accounted for the high mortality in these conditions, but improvements in respiratory technology have increased survival. Appropriate classification of these similar phenotypes will improve counseling concerning recurrence risk, management, and prognosis.

Abnormalities, Multiple↗

PubMed1998

Familial megacecum and colon in the rat: a new model of gastrointestinal neuromuscular dysfunction.

Gastrointestinal motility disorders are of considerable clinical importance in humans and animals. Abnormalities of smooth muscle and the enteric nervous system have been described. We have identified and characterized a new mutant stock of rats that develops severe megacecum and colon with pseudo-obstruction, Familial Megacecum and Colon (FMC). The inheritance pattern of FMC was characterized by selective breeding. Gastrointestinal motility was evaluated radiographically. Complete pathologic evaluations, including ultrastructural examination and staining of colonic segments for acetylcholinesterase, peripherin, vasoactive intestinal peptide, substance P, nitric oxide synthase, and somatostatin, were performed. Spontaneous contractility and contractile force in isolated colonic muscle strips were examined. Familial megacecum and colon is inherited as an autosomal recessive trait. The markedly dilated cecum and proximal portion of the colon are followed by a short, funnel-shaped segment and distal portion of the colon with normal or slightly reduced lumen. Although clinical features and gross anatomic changes of the colon resemble those of Hirschsprung's disease in humans and animals, aganglionosis is not a feature of FMC. An increase in somatostatin staining was observed in dilated regions of bowel. The spontaneous contractile frequency and contractile force were diminished in the affected colon. Familial megacecum and colon is a new mutant, distinct from previously described hereditary and targeted mutant rodent models that develop megacecum and colon as a result of distal colonic dysfunction. The functional or morphologic defect(s) that result in colonic dysfunction in rats with FMC was not determined. The disease may result from an absence or overexpression of a single or group of neurotransmitters or their respective neurons, receptor abnormalities, or defects in the intestinal pacemaker system.

Animals↗

PubMed2000

Familial temporal lobe epilepsy autosomal dominant inheritance in a large pedigree from southern Italy.

To further elucidate the inheritance pattern and range of phenotypic manifestations of benign familial temporal lobe epilepsy (FTLE), we report a large family recently identified in southern Italy. There were 8 patients (4 men), ranging in age from 31 to 68 years in three generations. One affected patient was deceased at the time of the study. Genealogical study strongly supported autosomal dominant inheritance with incomplete penetrance, as three unaffected individuals transmitted the disease. Clinical anticipation could not be assessed because of the ascertainment method. Male to male transmission occurred. Identifiable antecedents for seizures were present in only two patients, who had a simple febrile convulsion and a closed head trauma, respectively. Migraine was overrepresented in this family. Onset of seizures ranged from 17 to 52 years (mean: 27 years). All patients had weekly simple partial seizures suggestive of temporal origin with vegetative or experiential phenomena. Very rare partial complex seizures occurred in 6/7 patients. One had two generalized nocturnal seizures as well. Two had previously been misdiagnosed as having gastritis or panic attacks, and one had not been diagnosed. Interictal anteromesiotemporal spiking was seen in 5/7 patients, and occurred mostly during NREM sleep. Neurological examination, brain CT or MR scans were normal. Antiepileptic medication always controlled the seizures.

Adult↗

PubMed2025

Exploring the c.406 C > T variant in TNNI3 gene: pathogenic insights into restrictive cardiomyopathy.

BACKGROUND: Restrictive cardiomyopathy (RCM) is a rare cardiac disorder characterized by diastolic dysfunction and myocardial stiffness, frequently associated with genetic variants. We aimed to explore the genetic basis of RCM in a diagnosed patient through comprehensive genetic analysis. METHODS: Whole exome sequencing (WES) was conducted on the proband, followed by Sanger sequencing for variant confirmation and familial segregation analysis. In silico tools and structural protein modeling were employed to assess the functional impact of the identified variant. RESULTS: The c.406 C > T variant, classified as likely pathogenic, results in a truncated TNNI3 protein. Bioinformatics analysis highlighted significant structural disruptions, likely impairing sarcomere function. The patient presented with growth retardation, progressive dyspnea, and echocardiographic findings consistent with RCM. Both parents were heterozygous carriers, supporting an autosomal recessive inheritance pattern. The homozygosity of the novel variant identified in this study is a critical factor in the genotype-phenotype correlation observed in this case. CONCLUSION: This study identified the novel c.406 C > T variant in TNNI3 as a potential pathogenic driver of RCM, emphasizing the critical role of genetic evaluations in early diagnosis and management of inherited cardiomyopathies. Further studies are warranted to explore therapeutic interventions targeting TNNI3-related pathologies.

Humans↗

PubMed1990

Pattern dystrophy of the retinal pigment epithelium.

The authors describe a family in which one member had pattern dystrophy of the retinal pigment epithelium. The proband also had neovascular membranes which resulted in decreased visual acuity. Two other family members had abnormal electro-oculographic findings, but a clinical normal-appearing fundus that could represent an early stage of the disease. The incidence of this condition in this family indicates autosomal dominance as the inheritance pattern of this dystrophy.

Adult↗

PubMed1991

Complex segregation analysis of nonsyndromic cleft lip and palate.

This study was undertaken to examine the inheritance pattern of nonsyndromic cleft lip with or without cleft palate (CL/P). Complex segregation analysis using the unified model as in POINTER and the regressive model as in REGD programs were applied to analyze a midwestern U.S. Caucasian population of 79 families ascertained through a proband with CL/F. In REGD, the dominant or codominant Mendelian major locus models of inheritance were the most parsimonious fit. In POINTER, besides the Mendelian major locus model, the multifactorial threshold (MF/T) model and the mixed model were also consistent with the observed data. However, the high heritability parameter of .93 (SD .063) in the MF/T model suggests that any random exogenous factors are unlikely to be the underlying mechanisms, and the mixed model indicates that this high heritability is accounted for by a major dominant locus component. These findings indicate that the best explanation for the etiology of CL/P in this study population is a putative major locus associated with markedly decreased penetrance. Molecular studies may provide further insight into the genetic mechanism underlying CL/P.

Cleft Lip↗

PubMed1995

Autosomal dominant pattern dystrophy of the retina associated with a 4-base pair insertion at codon 140 in the peripherin/RDS gene.

OBJECTIVE: To define the phenotype of a retinal dystrophy associated with a 4-base pair insertion at codon 140 of the peripherin/RDS gene. PATIENTS: Six affected members spanning two generations of a single family were examined. Five were studied in detail electrophysiologically and psychophysically. METHODS: Psychophysical testing included color vision testing, photopic and scotopic static threshold perimetry, and dark adaptometry. Electrophysiological testing included flash and pattern electroretinography, as well as electrooculography. RESULTS: Clinical findings ranged from subtle pigmentary changes at the level of the retinal pigment epithelium to more widespread pigmentary changes associated with choroidal neovascularization. Those with severe fundus changes exhibited greater abnormalities in psychophysical and electrophysiological testing than those with minimal fundus changes. CONCLUSIONS: This particular peripherin/RDS gene mutation is associated with dominantly inherited pattern dystrophy of the retina. The phenotypic expression is variable in a manner not explained by age.

Aged↗

PubMed2006

Role of peripherin/rds in vertebrate photoreceptor architecture and inherited retinal degenerations.

The vertebrate photoreceptor outer segment (OS) is a highly structured and dynamic organelle specialized to transduce light signals. The elaborate membranous architecture of the OS requires peripherin/rds (P/rds), an integral membrane protein and tetraspanin protein family member. Gene-level defects in P/rds cause a broad variety of late-onset progressive retinal degenerations in humans and dysmorphic photoreceptors in murine and Xenopus models. Although proposed to fulfill numerous roles related to OS structural stability and renewal, P/rds molecular function remains uncertain. An increasingly resolved model of this protein's oligomeric structure can account for disease inheritance patterns and severity in some instances. Nonetheless, the pathogenic mechanisms underlying the uniquely broad spectrum of retinal diseases associated with P/rds defects are not currently well understood. Recent findings point to the possibility that P/rds acts as a multifunctional scaffolding protein for OS architecture and that partial-loss-of-function mutations contribute to the hallmark phenotypic heterogeneity associated with inherited defects in RDS.

Amino Acid Sequence↗

PubMed1999

Genetic linkage study of family members of a patient with adult polycystic kidney disease.

OBJECTIVE: To study the feasibility of making an early diagnosis of adult polycystic kidney disease by using genetic linkage analysis in Hong Kong. DESIGN: Genetic linkage study. SETTING: University teaching hospital, Hong Kong. PARTICIPANTS: Six members of a Chinese family with a history of adult polycystic kidney disease. MAIN OUTCOME MEASURES: The inheritance pattern of adult polycystic kidney disease, as detected by polyacrylamide gel electrophoresis of polymerase chain reaction products using radioactively labelled primers specific to six microsatellite DNA markers that are closely linked to the PKD1 gene on chromosome 16. RESULTS: Four of the six members of the family studied were shown to be positive for disease-linked markers, and the inheritance of adult polycystic kidney disease could be traced in this family with a higher degree of precision (93.7%) using genetic linkage analysis, than could be predicted otherwise. CONCLUSION: The success of genetic linkage analysis in providing an early diagnosis of adult polycystic kidney disease is dependent on having a sufficient number of family members whose disease status has been established by imaging methods to allow the disease-linked marker haplotype to be determined. The establishment of a genetic data bank for families with adult polycystic kidney disease should be considered to maximise the effectiveness of this diagnostic approach.

Journal Article↗

PubMed2003

Familial eccrine spiradenoma: a case report and review of the literature.

BACKGROUND: Familial eccrine spiradenoma is a rare autosomal dominant condition that is characterized by slow-growing, benign adnexal tumors. OBJECTIVE: We investigated a case of familial eccrine spiradenoma displaying an autosomal dominant inheritance pattern. To our knowledge, only two previously reported cases of familial eccrine spiradenoma exist in the literature. METHODS: A case report and review of the literature are given. RESULTS: We report a case of familial eccrine spiradenoma in a mother and daughter and present successful treatment using surgical extirpation and CO2 laser ablation. CONCLUSION: Familial eccrine spiradenoma is a benign autosomal dominantly inherited condition that is characterized by tender, slow-growing, adnexal tumors of the head and neck. Surgical tumor extirpation and CO2 laser ablation offer both an effective symptomatic and cosmetically elegant treatment option.

Adenoma, Sweat Gland↗

PubMed1999

The molecular basis for apoptotic defects in patients with CD95 (Fas/Apo-1) mutations.

Heterozygous mutations of the receptor CD95 (Fas/Apo-1) are associated with defective lymphocyte apoptosis and a clinical disease characterized by lymphadenopathy, splenomegaly, and systemic autoimmunity. From our cohort of 11 families, we studied eight patients to define the mechanisms responsible for defective CD95-mediated apoptosis. Mutations in and around the death domain of CD95 had a dominant-negative effect that was explained by interference with the recruitment of the signal adapter protein, FADD, to the death domain. The intracellular domain (ICD) mutations were associated with a highly penetrant Canale-Smith syndrome (CSS) phenotype and an autosomal dominant inheritance pattern. In contrast, mutations affecting the CD95 extracellular domain (ECD) resulted in failure of extracellular expression of the mutant protein or impaired binding to CD95 ligand. They did not have a dominant-negative effect. In each of the families with an ECD mutation, only a single individual was affected. These observations were consistent with differing mechanisms of action and modes of inheritance of ICD and ECD mutations, suggesting that individuals with an ECD mutation may require additional defect(s) for expression of CSS.

Apoptosis↗