Clinically actionable hypertrophic cardiomyopathy genes in South Asian Indians

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 exists on the prevalence of clinically actionable gene variants for primary HCM in South Asian Indians (SAI), that is necessary for minimizing disparities in interpreting ancestry-specific variants. Objectives The ClinGen Hereditary Cardiovascular Disorders (HCVD) Gene Curation Expert Panel categorized HCM-causing genes into five categories according to their clinical relevance: definitive, strong, moderate, limited, and disputed. However, comprehensive studies examining this classification in SAI are lacking. Methods Whole-exome sequencing was performed for 335 primary SAI-HCM patients, including all known cardiovascular genes and clinically actionable gene categories to determine their allele frequencies. Results SAI-HCM exomes revealed a total of 194 P/LP and VUS across 26 clinically actionable genes in 119 (35.52%) of the 335 cases. The SAI-HCM cohort exhibited significantly fewer variants in the 12 definitive category genes compared to other global HCM cohorts (17.33% vs. 41.21%, P = 0.0003). For the five strong/moderate genes, no significant difference was observed between the SAI-HCM cohort and other global HCM cohorts (2.59% vs. 2.49%, P = 1). Among the 21 limited and disputed genes, MYH6 showed a significantly higher prevalence of variants in the SAI-HCM cohort than in the other global HCM cohorts (5.07% vs. 1.67%, P = 0.0408). Conclusions The clinically actionable gene variants in SAI-HCM cohort differed significantly from other global HCM cohorts, specifically MYBPC3 , MYH7 , and MYH6 .