Abstract

Background Primary hypertrophic cardiomyopathy (HCM) is predominantly a genetic disease causing left ventricular hypertrophy in the absence of other cardiac and systemic metabolic diseases. Currently, limited data exists on the prevalence of clinically actionable gene variants for primary HCM in South Asian Indians (SAI), that is necessary for minimizing disparities in interpreting ancestry-specific variants.

Objectives The ClinGen Hereditary Cardiovascular Disorders (HCVD) Gene Curation Expert Panel categorized HCM-causing genes into five categories according to their clinical relevance: definitive, strong, moderate, limited, and disputed. However, comprehensive studies examining this classification in SAI are lacking.

Methods Whole-exome sequencing was performed for 335 primary SAI-HCM patients, including all known cardiovascular genes and clinically actionable gene categories to determine their allele frequencies.

Results SAI-HCM exomes revealed a total of 194 P/LP and VUS across 26 clinically actionable genes in 119 (35.52%) of the 335 cases. The SAI-HCM cohort exhibited significantly fewer variants in the 12 definitive category genes compared to other global HCM cohorts (17.33% vs. 41.21%, P = 0.0003). For the five strong/moderate genes, no significant difference was observed between the SAI-HCM cohort and other global HCM cohorts (2.59% vs. 2.49%, P = 1). Among the 21 limited and disputed genes, MYH6 showed a significantly higher prevalence of variants in the SAI-HCM cohort than in the other global HCM cohorts (5.07% vs. 1.67%, P = 0.0408).

Conclusions The clinically actionable gene variants in SAI-HCM cohort differed significantly from other global HCM cohorts, specifically MYBPC3, MYH7, and MYH6.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

PSD is supported by the DBT/Wellcome Trust Indian Alliance (IA/I/16/1/502367), Department of Science and Technology (DST/CRG/2019/005401), Biotechnology Industry Research Assistance Council (BT/AIR01350/PACE-22/20), Department of Biotechnology (BT/PR45262/MED/12/955/2022), Scientist Development Grant (SDG) from American Heart Association (AHA), ICMR, and inStem core funding. VJR is supported by ICMR-SRF (3/1/1 (8)/CVD/2020-NCD-1).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Institutional Ethical Committee of Institute for Stem Cell Science and Regenerative Medicine, Bangalore (Reference number: inStem/IEC-10/001).

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations and AcronymsHCMHypertrophic cardiomyopathySAISouth Asian IndianP/LPPathogenic or likely pathogenicVUSVariant of uncertain significanceECGElectrocardiogramLGELate gadolinium enhancementACMGAmerican College of Medical GeneticsLVIDdLeft ventricular internal diameter at diastoleLVIDsLeft ventricular internal diameter at end-systoleEFEjection fraction