Association of Cardiomyopathy With <i>MYBPC3</i> D389V and <i>MYBPC3<sup>Δ25bp</sup></i>Intronic Deletion in South Asian Descendants
Authors: Shiv Kumar Viswanathan, Megan J. Puckelwartz, Ashish Mehta, Chrishan J. A. Ramachandra, Aravindakshan Jagadeesan, Regina Fritsche-Danielson, Ratan V. Bhat, Philip Wong, Sangeetha Kandoi, Jennifer A. Schwanekamp, Gina Kuffel, Lorenzo L. Pesce, Michael J. Zilliox, U. Nalla B. Durai, Rama Shanker Verma, Robert E. Molokie, Domodhar P. Suresh, Philip R. Khoury, Annie Thomas, Thriveni Sanagala, Hak Chiaw Tang, Richard C. Becker, Ralph Knöll, Winston Shim, Elizabeth M. McNally, Sakthivel Sadayappan
Journal: JAMA Cardiology (2018)

<h3>Importance</h3> The genetic variant<i>MYBPC3Δ25bp</i>occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide.<i>MYBPC3 Δ25bp</i>has been linked to cardiomyopathy and heart failure. However, the high prevalence of<i>MYBPC3Δ25bp</i>suggests that other stressors act in concert with<i>MYBPC3Δ25bp</i>. <h3>Objective</h3> To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of<i>MYBPC3Δ25bp</i>. <h3>Design, Setting, andParticipants</h3> South Asian individuals living in the United States were screened for<i>MYBPC3Δ25bp</i>, and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016. <h3>Main Outcomes and Measures</h3> 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<i>MYBPC3Δ25bp</i>. <h3>Results</h3> 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<i>MYBPC3Δ25bp</i>carrier frequency of 6%. A higher frequency of missense<i>TTN</i>variation was found in<i>MYBPC3Δ25bp</i>carriers compared with noncarriers, identifying distinct genetic backgrounds within the<i>MYBPC3Δ25bp</i>carrier group. Strikingly, 9.6% of<i>MYBPC3Δ25bp</i>carriers also had a novel<i>MYBPC3</i>variant, D389V. Family studies documented D389V was in tandem on the same allele as<i>MYBPC3Δ25bp</i>, and D389V was only seen in the presence of<i>MYBPC3Δ25bp</i>. In contrast to<i>MYBPC3Δ25bp</i>,<i>MYBPC3Δ25bp/D389V</i>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%];<i>P</i> &lt; .03) and stem cell–derived cardiomyocytes exhibited cellular hypertrophy with abnormal Ca<sup>2+</sup>transients. <h3>Conclusions and Relevance</h3> <i>MYBPC3Δ25bp/D389V</i>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<i>MYBPC3Δ25bp</i>carriers, those with D389V, account for the increased risk attributed to<i>MYBPC3Δ25bp</i>.