Whole genome sequencing (WGS) is a comprehensive genetic testing approach that reports most types of nucleotide variants.

This study sought to assess WGS for hypertrophic cardiomyopathy (HCM) in which prior genetic testing did not establish a molecular diagnosis, and as a first-line genetic test.

WGS was performed on 58 unrelated patients with HCM, 14 affected family members, and 2 unaffected parents of a severely affected proband. The authors searched for nucleotide variants in coding regions of 184 candidate cardiac hypertrophy genes. They also searched for nucleotide variants in deep intronic regions that alter RNA splicing, large genomic rearrangements, and mitochondrial genome variants. RNA analysis was performed to validate splice-altering variants.

The authors found a pathogenic or likely pathogenic variant in 9 of 46 families (20%) for which prior genetic testing was inconclusive. Three families had variants in genes not included in prior genetic testing. One family had a pathogenic variant that was filtered out with prior exome sequencing. Five families had pathogenic variants in noncoding regions, including 4 with deep intronic variants that activate novel splicing, and 1 mitochondrial genome variant. As a first-line genetic test, WGS identified a pathogenic variant in 5 of 12 families (42%) that had never received prior genetic testing.

WGS identified additional genetic causes of HCM over targeted gene sequencing approaches. Extending genetic screening to deep intronic regions identified pathogenic variants in 9% of gene-elusive HCM. These findings translate to more accurate diagnosis and management in HCM families.