Structured Graphical Abstract.

The genetic architecture of hypertrophic cardiomyopathy (HCM) in the Egyptian population was assessed by comparing the frequency of rare variation in HCM genes with Egyptian controls as well as with a UK HCM cohort (left). HCM minor genes MYL2, MYL3 and CSRP3 were more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity (top right). Integrating methods that leverage Egyptian controls increased the yield of clinically actionable variants (pathogenic, likely pathogenic) from 19% (initial analysis) to 29.6% (cohort-informed analysis) (bottom right). HCM: Hypertrophic Cardiomyopathy; ACMG/AMP: American College of Medical Genetics and Genomics/Association of Molecular Pathology. Created with BioRender.com.