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

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.

New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis

“…In accordance with previous studies [ 9 ], the majority of VOIs were detected in disease-specific core gene panels (28/39 VOIs; 71%). However, 21% of VOIs (8/39 VOIs) were detected only after the extension of the analysis to genes not directly associated with the patient phenotype.…”

“…It is important to emphasize here that the diagnostic benefit of the second step of our analysis mainly concerned genes with established pathogenic relevance that are primarily associated with a different clinical cardiac phenotype than the original clinical diagnosis. Though some studies have questioned the benefit of broad genetic diagnostics in inherited heart diseases [ 9 ] and have suggested limiting genetic testing to the core genes associated with a given phenotype [ 11 ], the extensive phenotypic variability of inherited cardiac diseases supports the requirement of at least an extended gene panel in routine diagnostics.…”

“…These methods offer the possibility of analyzing more genes than the ones included in routine gene panels. However, there is an ongoing debate in the literature regarding the utility of whole exome/genome sequencing [ 9 ]. Among the expressed considerations are difficulties in the interpretation of numerous variants of uncertain significance, as well as secondary findings [ 10 ].…”

Clinical Implications of the Genetic Architecture of Dilated Cardiomyopathy

“…Many genetic testing laboratories offer WES as an alternative approach [84]. However, whole-exome sequencing (WES) may not provide sufficient coverage for all genes; TNNI3 and PLN were reported to have insufficient coverage for complete variant interpretation [85]. By contrast, results from whole-genome sequencing (WGS) correlated well with panel-based sequencing, and WGS performed better than WES: WES covered only 69% of panel sequence targets, most likely due to capture bias during sample preparation and use of predefined target regions that may miss isoforms [86].…”

Exome Sequencing in Gastrointestinal Food Allergy Induced by Multiple Food Protein

“…Detection of associations with low frequency and rare variants will be facilitated by the comprehensive catalogue of variants with MAF $ 1% being generated by the 1,000 Genomes Project (http:// www.1000genomes.org/page.php), which will also identify many variants at lower allele frequencies. The pilot effort of that program has already identified more than 11 million new SNPs in initially lowdepth coverage of 172 individuals 44 .…”