Dataset Information

Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3?25bp variant.

ABSTRACT: Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~?40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25-base pair deletion in intron 32 of MYBPC3 (MYBPC3?25bp) that is uniquely prevalent in South Asians and is associated with autosomal dominant cardiomyopathy. Although our studies suggest that this deletion results in left ventricular dysfunction, cardiomyopathies, and heart failure, the precise mechanism by which this variant predisposes to heart disease remains unclear. Increasingly appreciated, however, is the contribution of secondary risk factors, additional mutations, and lifestyle choices in augmenting or modifying the HCM phenotype in MYBPC3?25bp carriers. Therefore, the goal of this review article is to summarize the current research dedicated to understanding the molecular pathophysiology of HCM in South Asians with the MYBPC3?25bp variant. An emphasis is to review the latest techniques currently applied to explore the MYBPC3?25bp pathogenesis and to provide a foundation for developing new diagnostic strategies and advances in therapeutics.

SUBMITTER: Arif M

PROVIDER: S-EPMC7429610 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3<sup>Δ25bp</sup> variant.

Arif Mohammed M Nabavizadeh Pooneh P Song Taejeong T Desai Darshini D Singh Rohit R Bazrafshan Sholeh S Kumar Mohit M Wang Yigang Y Gilbert Richard J RJ Dhandapany Perundurai S PS Becker Richard C RC Kranias Evangelia G EG Sadayappan Sakthivel S

Biophysical reviews 20200712 4

Hypertrophic cardiomyopathy (HCM) is a cardiac genetic disease characterized by ventricular enlargement, diastolic dysfunction, and increased risk for sudden cardiac death. Sarcomeric genetic defects are the predominant known cause of HCM. In particular, mutations in the myosin-binding protein C gene (MYBPC3) are associated with ~ 40% of all HCM cases in which a genetic basis has been established. A decade ago, our group reported a 25-base pair deletion in intron 32 of MYBPC3 (MYBPC3<sup>Δ25bp</ ...[more]

PMID: 32656747

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Project description:ImportanceThe 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.ObjectiveTo determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3Δ25bp.Design, setting, andparticipantsSouth 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 measuresNext-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.ResultsIn 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 relevanceMYBPC3Δ25bp/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.

Dataset Information

Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3?25bp variant.

Publications

Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3<sup>Δ25bp</sup> variant.

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