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Original Investigation
June 2018

Association of Cardiomyopathy With MYBPC3 D389V and MYBPC3Δ25bpIntronic Deletion in South Asian Descendants

Author Affiliations
  • 1Heart, Lung and Vascular Institute, Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio
  • 2Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, Illinois
  • 3Center for Genetic Medicine, Northwestern University, Chicago, Illinois
  • 4National Heart Research Institute Singapore
  • 5Cardiovascular Academic Clinical Program, DUKE-NUS Medical School, Singapore
  • 6PSC and Phenotyping Laboratory, Victor Chang Cardiac Research Institute, Sydney, Australia
  • 7Cardiovascular and Metabolic Disease Innovative Medicines and Early Development Unit, AstraZeneca Research and Development, Gothenburg, Sweden
  • 8Cardiovascular and Metabolic Disorders Program, DUKE-NUS Medical School, Singapore
  • 9Department of Cardiology, National Heart Centre Singapore, Singapore
  • 10Department of Biotechnology, Indian Institute of Technology Madras, Chennai, Tamilnadu, India
  • 11Department of Public Health Sciences, Loyola University Chicago, Maywood, Illinois
  • 12Computation Institute, The University of Chicago, Chicago, Illinois
  • 13Divison of Hematology and Oncology, University of Illinois at Chicago
  • 14St Elizabeth Physicians Heart and Vascular, Florence, Kentucky
  • 15Heart Institute, Cincinnati Children’s Hospital, Cincinnati, Ohio
  • 16Marcella Niehoff School of Nursing, Loyola University Chicago, Maywood, Illinois
  • 17Department of Cardiology and Echocardiography and Cardiographics, Loyola University Chicago, Maywood, Illinois
  • 18Integrated Cardio-Metabolic Centre, Myocardial Genetics, Karolinska Institutet, University Hospital, Heart and Vascular Theme, Stockholm, Sweden
  • 19Associate Editor for Translational Science, JAMA Cardiology
JAMA Cardiol. 2018;3(6):481-488. doi:10.1001/jamacardio.2018.0618
Key Points

Question  Are there additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3Δ25bp variant, which is found in nearly 100 million individuals worldwide?

Findings  In this genotype-phenotype study, MYBPC3Δ25bp was found in 6% of 2401 South Asian individuals living in the United States, and genetic and phenotypic characterization of a subset identified distinct populations within this heterogeneous group. Specifically, 9.6% of MYBPC3Δ25bp carriers also had a novel MYBPC3 variant, D389V, on the same single allele, and this subset had hyperdynamic findings on echocardiogram.

Meaning  Additional genetic variants, specifically D389V, were associated with the variable cardiomyopathic findings linked to MYBPC3Δ25bp.


Importance  The genetic variant MYBPC3Δ25bp 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 MYBPC3Δ25bp suggests that other stressors act in concert with MYBPC3Δ25bp.

Objective  To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3Δ25bp.

Design, Setting, andParticipants  South Asian individuals living in the United States were screened for MYBPC3Δ25bp, 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 MYBPC3Δ25bp.

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 MYBPC3Δ25bpcarrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3Δ25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3Δ25bp carrier group. Strikingly, 9.6% of MYBPC3Δ25bp carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3Δ25bp, and D389V was only seen in the presence of MYBPC3Δ25bp. In contrast to MYBPC3Δ25bp, MYBPC3Δ25bp/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  MYBPC3Δ25bp/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 MYBPC3Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3Δ25bp.