Whole exome sequencing combined with integrated variant annotation prediction identifies a causative myosin essential light chain variant in hypertrophic cardiomyopathy

Abstract

WES combined with CADD score and HHE gene data may be useful even in HCM. Furthermore, the MYL3 Arg94His variant was associated with high disease penetrance and substantial interventricular septal hypertrophy.

Identification of a mutation causing hypertrophic cardiomyopathy using whole exome sequencing: A proof-of-concept

“…In the systemic screening of mutations in these 8 sarcomere protein genes in 112 unrelated Japanese patients with familial HCM, mutations in MYBPC3, MYH7, and TNNT2 were found in 19.6%, 10.7%, and 8.9% of cases, respectively, while analysis of MYL2, MYL3, and ACTC did not reveal any mutations [8]. It can be said that a comparably rare HCM-causing mutation was successfully identified using WES in this study [5]. In hindsight, however, the same result could have been obtained even using the traditional Sanger sequencing of 8 sarcomere protein genes.…”

“…In order to efficiently and correctly define the causative mutation, the sequencing of DNA from relatives as well as the index patient is thought to be essential. Also, the prediction of in silico pathogenicity for variants using the Combined Annotation-Dependent Depletion (CADD) prediction software [13] as well as the high heart expression gene data [14] played an important role in bioinformatics filtering in this study [5]. Further improvement in prediction tools and relevant databases should contribute to the more successful identification of the causative mutation.…”

“…In this issue of the Journal of Cardiology, Nomura et al [5] performed whole exome sequencing (WES) in a large HCM family to successfully identify the previously reported Arg94His variant in MYL3 [6,7] as a definite HCM-causing mutation. HCM-causing mutations in MYL3 are very few in contrast with those in MYH7 and MYBPC3.…”

“…Most importantly, even when interpreting the WES data, segregation analysis remains the gold standard for the acquisition of robust evidence for pathogenicity/causality [12]. Actually, in this study [5], genotype-phenotype matching (cosegregation pattern) enabled the number of putative variants to be narrowed down from 3439 to only 13. In order to efficiently and correctly define the causative mutation, the sequencing of DNA from relatives as well as the index patient is thought to be essential.…”

Overview of the 81^st Annual Scientific Meeting of the Japanese Circulation Society ― Cardiovascular Medicine for the Next Generation ―

“…Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of agents that reduce LDL-C beyond the maximum achievable LDL-C reductions with statins. 13 Rare sarcomere gene variants, which were found in 0.6% in the general population, were associated with increased risk for adverse cardiovascular events even before formation of hypertrophy, suggesting that screening of these variants may improve risk stratification in the general population from the viewpoint of preemptive medicine. Dr. Teramoto (Kanazawa University) presented supportive data for detecting mutation-positive HCM patients using cardiac magnetic resonance in Symposium 14 entitled "Cardiomyopathies: A Diagnostic and Therapeutic Update".…”