Correction: Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment.

When this article was published, the Supplementary Material was omitted. The files are now provided in the online version of the article. The publisher regrets the error.

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment.

PURPOSE: Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. METHODS: Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current population-based allele frequencies. RESULTS: From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. CONCLUSION: Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.

Exome analysis-based molecular autopsy in cases of sudden unexplained death in the young.

BACKGROUND: Postmortem genetic testing (molecular autopsy) for the common long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) genes reveals a pathogenic mutation in up to 30% of sudden unexplained death (SUD). The role of additional cardiac arrhythmia and cardiomyopathy genes in SUD is largely unknown. OBJECTIVE: The purpose of this study was to investigate the feasibility and outcomes of performing exome sequencing-based molecular autopsies in a cohort of consecutive SUD cases. METHODS: Autopsies performed from 2005 to 2009 were reviewed for SUD. Postmortem blood was collected, DNA was isolated, and whole exome sequencing was performed. Rare sequence variants in cardiac arrhythmia and cardiomyopathy genes were sought. RESULTS: There were 50 SUD cases aged 1 to 40 years (mean 21.7 ± 12 years) in the 5-year period, with a male predominance of 1.9:1. The most common event at death was "sleep" (48%). Exome sequencing in a subgroup of 28 SUD cases revealed 3 rare variations in 3 SUD cases (10%; 2 from exome sequencing and 1 from previous Sanger sequencing) in the common LQTS genes: a splice site variation and a single base deletion in KCNH2, and a missense variation in KCNQ1. Six rare variations in an additional 25 common genes of cardiac arrhythmias and cardiomyopathies were identified in 6 SUD (21%). CONCLUSION: Exome sequencing-based molecular autopsy is a useful strategy as part of the investigation of SUD cases. The findings further expand the role of the molecular autopsy in both identifying a cause of death in the decedent and evaluating at-risk family relatives.