Defining the genetic architecture of hypertrophic cardiomyopathy in Egypt

Abstract

Hypertrophic Cardiomyopathy (HCM) is an inherited disease of the myocardium characterised by genetic and phenotypic heterogeneity. Despite the substantial progress made in understanding the genetic basis of HCM, several populations remain understudied, which hampers the progression of precision medicine and exacerbates health inequalities.

This research study represents the largest and most comprehensive analysis of HCM in the Middle East and North Africa (MENA) region to date: It includes an ethnically-matched cohort of deeply-phenotyped healthy volunteers (n=400), allowing the genetic architecture of HCM in prospective Egyptian patients enrolled at the Aswan Heart Centre (n=514) to be accurately defined against an appropriate control group. Analysis of genetic variation in well-characterised HCM genes revealed interesting findings. For example, it demonstrated a relatively higher burden of rare homozygous variants in Egyptian patients compared to other well-studied populations, owing to the issue of consanguinity. This opens new avenues for further characterising the effect of homozygosity in HCM-related genes on disease pathogenesis and for identifying novel recessive genes unique to consanguineous populations of MENA ancestry.

In addition, a highly prevalent frameshift variant (c.5769delG) in MYH7 was identified in the Egyptian HCM cohort. According to the current clinical variant classification guidelines, c.5769delG would be considered a “variant of uncertain significance”. However, it was found to be significantly enriched in Egyptian patients compared to controls (3.31% vs. 0%, p=0.0004) and to co-segregate with HCM in a large family (LOD score: 3.01), thereby supporting disease-causality. RNA sequencing analysis confirmed the expression of the variant MYH7 transcript suggesting a new mechanism of pathogenicity whereby distal MYH7 truncations cause HCM by escaping nonsense-mediated decay.

Overall, these findings facilitate the implementation of precision medicine by enhancing our understanding of disease mechanisms involved in HCM and improving the utility of clinical genetic testing in the region.