Whole Exome Sequencing versus Target Gene Panels for Evaluation of Isolated CaseProbands with Dilated and Hypertrophic Cardiomyopathy

Abstract

Background: Targeted Next Generation Sequencing of gene panels has become a popular tool for the genetic diagnosis of hypertrophic (HCM) and dilated cardiomyopathy (DCM). As the number of genes associated with HCM and DCM grows, however, Whole Exome Sequencing (WES) may become a suitable alternative. The coverage of WES on genes and variants related to HCM and DCM is unknown, however. Objective: We aimed to assess the coverage of WES on genes and variants related to HCM and DCM, as compared to several commercial gene panels used for HCM and DCM diagnosis. We also reported on a case study of using WES for genetic diagnosis in a group of 40 HCM and DCM patients. Methods: We followed current standards in carrying out WES on 40 HCM and DCM patients recruited locally, and examined their coverage of genes and a set of potentially pathogenic variants curated from Clinvar. Genetic diagnosis of the 40 patients was carried out using a procedure developed based on the ACMG guidelines. Results: Although the coverage of WES on genes and potentially pathogenic variants were high for most genes and variants, the coverage appeared inadequate for a number of genes included in target gene panels forclosely related to HCM and DCM, including TNNT2 and TNNI3. Within our study, 6 pathogenic or likely pathogenic variants were found among 14 HCM patients, and 4 pathogenic or likely pathogenic variants were found among the 26 DCM patients. Conclusion: Our study highlighted potential inadequacy in the coverage of current WES on variants and genes related to HCM and DCM.