A novel polymorphic MYBPC3 variant causes hypertrophic cardiomyopathy in US-South Asian descendants
Description: Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people, translating into approximately 600,000 people with HCM in the United States. HCM is associated with thickening of the heart muscle to the point of causing left ventricular outflow obstruction symptoms. Many different genes have been linked to HCM, and morbidity and mortality are highly variable and dependent on the particular gene mutation. Therefore, functional characterization of frequent mutations would help bring to light the more common mechanisms of pathogenesis. Our long-term goal is to understand how gene mutations lead to cardiomyopathy, thereby laying a foundation for the development of novel therapeutic strategies. The previous CVGPS proposal performed genotype-phenotype correlation in the presence of a polymorphic MYBPC3-DeltaInt32 variant that is exclusively present in 4% of South Asian descendants, with an estimated 80 million carriers worldwide. Results indicated that MYBPC3-DeltaInt32 was found in 5.84% of US-South Asians with incomplete penetrance. Strikingly, a novel MYBPC3 variant, D389V, was only identified in MYBPC3-DeltaInt32 variant carriers with a definite HCM phenotype. Out of 47 MYBPC3-DeltaInt32 carriers, 11 (23%) were positive for the D389V variant and abnormal cardiac function. This variant changed the native aspartic acid (D) to valine (V), amino acid position 389, in the C2 domain of MYBPC3, which is expected to reduce actomyosin interaction and contractility. However, the sufficiency of D389V variant to cause HCM, its ancestry, and its allele frequency are all factors to be determined. We hypothesize that the MYBPC3-D389V variant is pathogenic and sufficient to cause HCM. The primary objectives of this genome-phenome study are to (i) elucidate the presence of HCM in D389V variant carriers co-segregating with MYBPC3-DeltaInt32 variant, (ii) determine the presence of additional modifying gene mutations in MYBPC3-DeltaInt32 variant carriers, (iii) define the haplotype and evolutionary age of the D389V variant, and (iv) recapitulate HCM phenotype in vitro using iPSC-derived cardiomyocytes from D389V carriers. The phenotypic and genotypic characterization of D389V variant carriers is consistent with AHA requirements for a genome-phenome study and proposes precision medicine for the D389V carriers.
Funder: American Heart Association
Amount: $250,000
Funding type: research
Funder scheme: Institute - Catalyst Renewal Grant
Start date: 2017-05-01
End date: 2018-04-30
Investigators: Sakthivel Sadayappan, Sakthivel Sadayappan
Institution: University of Cincinnati
Funded outputs count: 13
Funder award ID: 17CCRG33671128
OpenAlex ID: G5658387178