Dataset Information

Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.

ABSTRACT:

Purpose

The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.

Methods

We generated Bayesian penetrance models for KCNQ1-LQT1 and SCN5A-LQT3 using variant-specific features and clinical data from the literature, international arrhythmia genetic centers, and population controls. We analyzed the distribution of posterior penetrance estimates across 4 genotype-phenotype relationships and compared continuous estimates with ClinVar annotations. Posterior estimates were mapped onto protein structure.

Results

Bayesian penetrance estimates of KCNQ1-LQT1 and SCN5A-LQT3 are empirically equivalent to 10 and 5 clinically phenotype heterozygotes, respectively. Posterior penetrance estimates were bimodal for KCNQ1-LQT1 and KCNH2-LQT2, with a higher fraction of missense variants with high penetrance among KCNQ1 variants. There was a wide distribution of variant penetrance estimates among identical ClinVar categories. Structural mapping revealed heterogeneity among "hot spot" regions and featured high penetrance estimates for KCNQ1 variants in contact with calmodulin and the S6 domain.

Conclusions

Bayesian penetrance estimates provide a continuous framework for variant interpretation.

SUBMITTER: O'Neill MJ

PROVIDER: S-EPMC9992222 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.

O'Neill Matthew J MJ Sala Luca L Denjoy Isabelle I Wada Yuko Y Kozek Krystian K Crotti Lia L Dagradi Federica F Kotta Maria-Christina MC Spazzolini Carla C Leenhardt Antoine A Salem Joe-Elie JE Kashiwa Asami A Ohno Seiko S Tao Ran R Roden Dan M DM Horie Minoru M Extramiana Fabrice F Schwartz Peter J PJ Kroncke Brett M BM

Genetics in medicine : official journal of the American College of Medical Genetics 20221207 3

<h4>Purpose</h4>The congenital Long QT Syndrome (LQTS) and Brugada Syndrome (BrS) are Mendelian autosomal dominant diseases that frequently precipitate fatal cardiac arrhythmias. Incomplete penetrance is a barrier to clinical management of heterozygotes harboring variants in the major implicated disease genes KCNQ1, KCNH2, and SCN5A. We apply and evaluate a Bayesian penetrance estimation strategy that accounts for this phenomenon.<h4>Methods</h4>We generated Bayesian penetrance models for KCNQ1- ...[more]

PMID: 36496179

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Project description:BackgroundSyndactyly (SD) refers to a deformity caused by the fusion and limb differentiation disorder of soft tissues and/or skeletons to varying extents between adjacent fingers (toes). The main features of this disease are phenotypic heterogeneity and genetic heterogeneity. In this study, we examined four generations of a Chinese Mongolian with different phenotypes of syndactylia and analysed and identified the pathogenic genetic variants of SD by exon sequencing.MethodsThe clinical phenotypes of patients were analysed, and the hands and feet were examined by X-ray. The pedigree was drawn, and the family data were analysed. Peripheral blood was collected from the family members, and genomic DNA was extracted. The candidate genes of SD were identified by exon sequencing, and the mutation sites of the captured candidate genes were amplified by PCR and verified by Sanger sequencing.ResultsThe family has congenital syndactyly, which is an autosomal dominant disease. At present, this condition has been passed down for 4 generations and was identified in 9 patients, including 4 males and 5 females. Five patients, I2, II4, III5, III,7 and III10, had unilateral syndactyly, and four patients, III16, IV3, IV6 and IV7, had bilateral finger syndactyly. All of their toes were unaffected. The proband and the other patients in this family had a c.917G > A (p.R306Q) mutation, which is located at position 917 of the second exon of the HOXD13 gene. This mutation results in a change in the amino acid at position 306, in which arginine is changed to glutamine. This mutation cosegregates in unaffected individuals and affected patients in this family. Moreover, 201 Mongolian genome databases and a thousand human genome databases were referenced to further confirm that the pathogenic genetic variant that causes syndactyly in this family is found in HOXD13.ConclusionThis study found that the mutation site of the pathogenic gene in this family was HOXD13, c.917G > A (p.R306Q). The phenotype of the family member III12 was normal, but this member was also a carrier of the pathogenic genetic variant. This indicates that the disease of this family has incomplete penetrance characteristics. Our results further enrich the expression profile of the HOXD13 gene.

Dataset Information

Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.

Purpose

Methods

Results

Conclusions

Publications

Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.

Similar Datasets

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