A Comparison of Whole Genome Sequencing to Multigene Panel Testing in Hypertrophic Cardiomyopathy Patients

Abstract

Background As DNA sequencing costs decline, genetic testing options have expanded. Whole exome and whole genome sequencing (WGS) are entering clinical use, posing questions about their incremental value compared with disease-specific multi-gene panels that have been the cornerstone of genetic testing. Methods and Results Forty-one patients with hypertrophic cardiomyopathy (HCM) who had undergone targeted HCM genetic testing (either multi-gene panel or familial variant test) were recruited into the MedSeq Project, a clinical trial of WGS. Results from panel genetic testing and WGS were compared. In 20 of 41 participants panel genetic testing identified variants classified as pathogenic, likely pathogenic or uncertain significance (VUS). WGS identified 19 of these 20 variants but the variant detection algorithm missed a pathogenic 18-base pair duplication in MYBPC3 due to low coverage. In 3 individuals, WGS identified variants in genes implicated in cardiomyopathy but not included in panel testing: a pathogenic PTPN11 variant and VUSs in ILK and FLNC. WGS also identified 84 secondary findings (mean=2/person, range= 0–6), which mostly defined carrier status for recessive conditions. Conclusions WGS detected nearly all variants identified on panel testing, provided one new diagnostic finding, and allowed interrogation of posited disease genes. Several variants of uncertain clinical utility and numerous secondary genetic findings were also identified. While panel testing and WGS provided similar diagnostic yield, WGS offered the advantage of re-analysis over time to incorporate advances in knowledge, but necessitated expertise in genomic interpretation to appropriately incorporate WGS into clinical care.

Approaches to carrier testing and results disclosure in translational genomics research: The clinical sequencing exploratory research consortium experience

“…Many CSER translational research projects disclosed carrier results as a secondary result. Several projects have published outcomes that include carrier testing (Biesecker et al., ; Cirino et al., ; Lewis et al., ; Parsons et al., ; Vassy et al., ; Wynn et al., ). The Consortium's Actionability/Return of Results Working Group sought to understand the variability in CSER approaches to identifying and disclosing carrier results, including (1) selection of genes and variants; (2) choices given to research participants regarding which results to disclose; (3) results communication approaches; and (4) project outcomes, including the proportion of individuals with carrier results and which genetic variants are commonly identified.…”

Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging

“…Whole-exome or -genome sequencing (WES/WGS) has been employed as a diagnostic tool in medicine, and molecular diagnosis rates have been achieved in 17.5 to 32% of adult patients with various undiagnosed diseases (3)(4)(5). Predisposition genome sequencing in healthy adults has demonstrated medical, behavioral, and economic outcomes of using genomic sequencing information in healthy adults (6)(7)(8)(9)(10)(11). From the perspective of population-based studies, the implementation of WES in the health system with longitudinal electronic health records (EHRs) has enabled the assessment of genetic risk in a wide range of diseases.…”

Targeted panel sequencing in pediatric primary cardiomyopathy supports a critical role of TNNI3

“…It is a matter of ongoing debate whether whole genome sequencing (WGS) or whole exome sequencing (WES) in CMP would be necessary to provide more insight into the genetic disease mechanisms. 42 The incremental yield of clinically actionable variants by WGS is limited by a paucity of genetic and functional evidence. 43 In a study by Herkert et al, combining copy number variant analysis with stepwise triobased WES yielded a diagnosis in more than 50% of pediatric DCM patients.…”