Whole Genome Sequencing in Hypertrophic Cardiomyopathy

Study Questions:

What is the additional yield of whole genome sequencing (WGS) over targeted gene sequencing for identifying disease-related sequence variation in patients with hypertrophic cardiomyopathy (HCM)?


A total of 58 unrelated HCM patients along with 14 affected family members underwent WGS. Authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes, intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. Splice-altering variants were confirmed with RNA analysis.


Plausible pathogenic variants were found in 9 of 46 families (20%) who had undergone prior genetic testing that was inconclusive. Four families had variants in genes not included (or filtered out) in prior testing and five families had variants in noncoding regions, including four that activate novel splicing, and one mitochondrial genome variant. In families without prior genetic testing, WGS identified a pathogenic variant in 5 of 12 families (42%).


WGS identifies additional genetic causes of HCM over targeted gene sequencing approaches.


Low-cost WGS is enabling greatly expanded genetic analysis of diseases in which targeted gene panels fail to identify a pathogenic variant. As sequencing methods and interpretation of these large data sets improve, WGS may become the standard for genetic analysis of HCM. This may lead to improved diagnosis, family screening, and management of HCM patients, and may contribute to further understanding of HCM pathogenesis.

Keywords: Cardiomegaly, Cardiomyopathy, Hypertrophic, Genetic Testing, Genome, Mitochondrial, Genome-Wide Association Study, Genomics, Heart Defects, Congenital, Heart Failure, Introns, Nucleotides, Primary Prevention, RNA, RNA Splicing

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