Coverage and diagnostic yield of Whole Exome Sequencing for the Evaluation of Cases with Dilated and Hypertrophic Cardiomyopathy

Timothy Shin Heng Mak,Xinru Ran,Hung-Fat Tse,Yee-Ki Lee,Jojo S H Hai,Clara S Tang,Pak-Chung Sham

doi:10.1038/s41598-018-29263-3

Abstract

Targeted next generation sequencing of gene panels has become a popular tool for the genetic diagnosis of hypertrophic (HCM) and dilated cardiomyopathy (DCM). However, it is uncertain whether the use of Whole Exome Sequencing (WES) represents a more effective approach for diagnosis of cases with HCM and DCM. In this study, we performed indirect comparisons of the coverage and diagnostic yield of WES on genes and variants related to HCM and DCM versus 4 different commercial gene panels using 40 HCM and DCM patients, assuming perfect coverage in those panels. We identified 6 pathogenic or likely pathogenic among 14 HCM patients (diagnostic yield 43%). 3 pathogenic or likely pathogenic were found among the 26 DCM patients (diagnostic yield 12%). The coverage was similar to that of four existing commercial gene panels due to the clustering of mutation within MYH7, MYBPC3, TPM1, TNT2, and TTN. Moreover, the coverage of WES appeared inadequate for TNNI3 and PLN. We conclude that most of the pathogenic variants for HCM and DCM can be found within a small number of genes which were covered by all the commercial gene panels, and the application of WES did not increase diagnostic yield.

Highlights

NGS can be applied in three ways: targeted sequencing for a number of genes, whole-exome sequencing (WES), and whole-genome sequencing (WGS)[8]
Whole Exome Sequencing (WES) may be sufficient for the genetic diagnosis of cardiomyopathy if the majority of the associated mutations are found in protein coding regions
Cirino et al.[9] compared the use of WGS and target sequencing in genetic tests of HCM. They found that WGS was able to identify most of the pathogenic or likely pathogenic variants identified using a targeted HCM panel, and a number not included in the gene panel

Summary

Introduction

NGS can be applied in three ways: targeted sequencing for a number of genes, whole-exome sequencing (WES), and whole-genome sequencing (WGS)[8]. WES attempts to capture and sequence all protein-coding regions in the genome, the capture regions being predesigned through commercial capture kits. The advantage of this approach is that it covers the entire exome and can be used for discovery purposes. Cirino et al.[9] compared the use of WGS and target sequencing in genetic tests of HCM They found that WGS was able to identify most of the pathogenic or likely pathogenic variants identified using a targeted HCM panel, and a number not included in the gene panel. For diseases other than cardiomyopathies, a number of studies recently found that targeted sequencing provided a better coverage than WES for genetic diagnosis[10,11]. We add to this literature by comparing between WES and targeted sequencing used by 4 commercial panels for genetic diagnosis of HCM and DCM

Methods

Results

Discussion

Conclusion