Second mutation in MYBPC3 gene increases cardiomyopathy risk in South Asians

A novel genetic variant that occurs with a known mutation in the MYBPC3 gene increases the risk of cardiomyopathy and heart failure in South Asians, an international research team reported in JAMA Cardiology.

The finding could open the door to tailored drugs that focus on mutations in the MYBPC3 gene.

Four percent of South Asians, or approximately 100 million individuals worldwide, are thought to carry a deletion in MYBPC3. This deletion, MYBPC3^Δ25bp, is already known to be associated with an increased risk for cardiomyopathy and heart failure, but to varying degrees. The researchers, led by Shiv Kumar Viswanathan, PhD, postdoctoral fellow, Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, OH, sought to determine if additional genetic variants could account for this risk variability.

To better define the cardiovascular findings associated with MYBPC3^Δ25bp, they conducted clinical and genetic screening over 2 years to find MYBPC3^Δ25bp carriers among South Asians who migrated to the United States. Over this time, 2,401 South Asian participants from several US cities were evaluated.

Using a polymerase chain reaction-based assay, the researchers found that the frequency of the MYBPC3^Δ25bp mutation was 6% in this population, which was slightly more than the previously reported prevalence of 4%. Because this percentage exceeds the incidence of heart failure, the researchers suspected that other factors were contributing to the risk associated with MYBPC3^Δ25bp.

The possibility of other cardiomyopathy variants in MYBPC3^Δ25bp carriers was evaluated using targeted sequencing. A panel of 174 cardiovascular disease-associated genes was sequenced and evaluated, of which 46 genes were specifically linked to cardiomyopathy. Protein-altering variants were analyzed in these 46 cardiomyopathy genes. MYBPC3^Δ25bp carriers had 4.8 rare protein-altering variants per individual compared with 3.4 in noncarriers, consistent with a distinct genetic background between MYBPC3^Δ25bp carriers and noncarriers. MYBPC3^Δ25bp carriers also had an excess of rare TTN variants compared with noncarriers (3.2 vs 2.4 counts per participant).

Notably, 9.6% of MYBPC3^Δ25bp carriers had a novel MYBPC3 variant, D389V. The D389V variant was found on the same single allele as MYBPC3^Δ25bp, but was not identified in noncarriers. This combination of mutations was associated with an increase in left ventricular ejection fraction (LVEF) and left ventricular fractional shortening compared with MYBPC3^Δ25bp carriers and noncarriers, similar to what has been described in early hypertrophic cardiomyopathy (HCM).

“MYBPC3^Δ25bp in the context of D389V may be an important marker of cardiac health,” the investigators wrote. “MYBPC3^Δ25bp/D389V, especially when combined with additional cardiac stressors, could prove suitable substrate for cardiomyopathy development and heart failure. Specifically, those with single MYBPC3^Δ25bp/D389V allele had increased LVEF. The hyperdynamic phase of HCM is recognized as an early feature of HCM, and despite an appearance of hyperperformance is one that is deceivingly energetically unfavorable.”

Human cardiomyocytes derived from human-induced pluripotent stem cells (iPSC) were examined to understand the cellular phenotype associated with MYBPC3^Δ25bp/D389V. The researchers found that iPSC-derived cardiomyocytes with MYBPC3^Δ25bp/D389V had hypertrophy and increased frequency of abnormal Ca²⁺ transients. Ca²⁺ hypersensitivity and hyperdynamic ventricles “are viewed as an early compensation or adaptation for the unfavorable energetic state and altered myocyte signaling,” according to the authors.

“Importantly, this hyperdynamic state in HCM is viewed as a target for drug development and intervention,” they predicted.