Abstract
BACKGROUND: Primary hypertrophic cardiomyopathy (HCM) is predominantly a genetic disease causing left ventricular hypertrophy in the absence of other cardiac and systemic metabolic diseases. Currently, limited data exist on the prevalence of clinically actionable gene variants for primary HCM in South Asian Indian (SAI) patients, which are necessary for minimizing disparities in interpreting ancestry-specific variants. The ClinGen Hereditary Cardiovascular Disorders Gene Curation Expert Panel categorized HCM-causing genes into 5 categories according to their clinical relevance: definitive, strong, moderate, limited, and disputed. However, comprehensive studies examining this classification in SAI patients are lacking. METHODS: Whole-exome sequencing was performed for 335 primary SAI patients with HCM, including all known cardiovascular genes and clinically actionable gene categories to determine their allele frequencies. RESULTS: SAI HCM exomes revealed a total of 193 pathogenic/likely pathogenic variants and variants of uncertain significance across 26 clinically actionable genes in 119 (35.52%) of 335 cases. The SAI HCM exhibited significantly fewer variants in the 12 definitive category genes compared with other global HCM cohorts (15.77% versus 43.23%; P<0.0001). For the 5 strong/moderate genes, no significant difference was observed between the SAI HCM and other global HCM cohorts (3.28% versus 2.73%; P=0.3499). Among the 21 limited and disputed genes, MYH6 showed a significantly higher prevalence of pathogenic/likely pathogenic variants in the SAI HCM than in the other global HCM cohorts (0.897% versus 0%; P=0.0287). CONCLUSIONS: The clinically actionable gene variants in SAI HCM differed significantly from other global HCM cohorts, specifically MYBPC3, MYH7, and MYH6.