Association of cardiomyopathy with MYBPC3 D389V and MYBPC3 ^Δ25bp intronic deletion in south asian descendants

IMPORTANCE The genetic variant MYBPC3 ^Δ25bp occurs in 4%of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 ^Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3 ^Δ25bp suggests that other stressors act in concert with MYBPC3 ^Δ25bp . OBJECTIVE To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3 ^Δ25bp . DESIGN, SETTING, ANDPARTICIPANTS South Asian individuals living in the United States were screened for MYBPC3 ^Δ25bp , and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016. MAIN OUTCOMES AND MEASURES Next-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3 ^Δ25bp . RESULTS In this genotype-phenotype study, individuals of South Asian descent living in the United States from both sexes (36.23%female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Genetic screening of 2401 US South Asian individuals found an MYBPC3 ^Δ25bp carrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3 ^Δ25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3 ^Δ25bp carrier group. Strikingly, 9.6%of MYBPC3 ^Δ25bp carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3 ^Δ25bp , and D389V was only seen in the presence of MYBPC3 ^Δ25bp . In contrast to MYBPC3 ^Δ25bp , MYBPC3 ^Δ25bp/D389V was associated with hyperdynamic left ventricular performance (mean [SEM] left ventricular ejection fraction, 66.7 [0.7%]; left ventricular fractional shortening, 36.6 [0.6%]; P < .03) and stem cell-derived cardiomyocytes exhibited cellular hypertrophy with abnormal Ca2+ transients. CONCLUSIONS AND RELEVANCE MYBPC3 ^Δ25bp/D389V is associated with hyperdynamic features, which are an early finding in hypertrophic cardiomyopathy and thought to reflect an unfavorable energetic state. These findings support that a subset of MYBPC3 ^Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3 ^Δ25bp .