Whole-Genome Sequencing as a First-Line Genetic Test in Familial Dilated Cardiomyopathy

PURPOSE: We evaluated whole-genome sequencing (WGS) as an alternative to multi-gene panel sequencing (PS) for genetic testing in dilated cardiomyopathy (DCM). METHODS: Forty-two patients with familial DCM underwent PS and WGS, and detection rates of rare single nucleotide variants and small insertions/deletions in panel genes were compared. Loss-of-function variants in 406 cardiac-enriched genes were evaluated, and an assessment of structural variation was performed. RESULTS: WGS provided broader and more uniform coverage than PS, with high concordance for rare variant detection in panel genes. WGS identified all PS-identified pathogenic or likely-pathogenic variants as well as two additional likely-pathogenic variants: one was missed by PS due to low coverage, the other was a known disease-causing variant in a gene not included on the panel. No loss-of-function variants in the extended gene set met clinical criteria for pathogenicity. One BAG3 structural variant was classified as pathogenic. CONCLUSIONS –: Our data support the use of WGS for genetic testing in DCM, with high variant detection accuracy and a capacity to identify structural variants. WGS provides an opportunity to go beyond suites of established disease genes, but the incremental yield of clinically-actionable variants is limited by a paucity of genetic and functional evidence for DCM association.