Influence of ethnicity and consanguinity on the genetic architecture of Hypertrophic Cardiomyopathy: insights from an understudied population

Abstract

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition characterized by phenotypic heterogeneity that could partly be explained by the variability in genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. Here, we leverage ancestry-matched Egyptian patients (n=514) and deeply-phenotyped controls (n=400) to accurately define the genetic architecture of HCM. We also compare HCM variation between Egyptian and predominantly European patients to identify genetic features unique to consanguineous populations in Middle East and North Africa (MENA), which are likely to represent important contributors to disease. We report a higher prevalence of homozygous variants in Egyptian patients (4.1% vs 0.1%, p-value=2x10-7), with variants in the minor HCM genes MYL2, MYL3 and CSRP3 more likely to present in homozygosity than the major genes (MYH7, MYBPC3), suggesting that these variants are less penetrant in heterozygosity. Biallelic variants in the recessive HCM gene TRIM63 were detected in 2.1% of patients (5-fold greater than European patients), highlighting the importance of recessive inheritance/genes in consanguineous populations. Finally, significantly fewer rare variants detected in Egyptian HCM patients could be classified as (likely) pathogenic compared to Europeans (40.8% vs. 61.6%, p-value=1.6x10-5) due to the underrepresentation of MENA populations in current HCM databases. This proportion increased to 53.8% after incorporating methods that compare variant frequencies between Egyptian patients and controls. Together, our findings demonstrate that studying consanguineous populations reveals novel insights with relevance to genetic testing and our understanding of the genetic architecture of HCM.