Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy

Abstract

Aims: Hypertrophic cardiomyopathy (HCM) is characterized by phenotypic heterogeneity that is partly explained by the diversity of genetic variants contributing to disease. Accurate interpretation of these variants constitutes a major challenge for diagnosis and implementing precision medicine, especially in understudied populations. The aim is to define the genetic architecture of HCM in North African cohorts with high consanguinity using ancestry-matched cases and controls.

Methods and results: Prospective Egyptian patients (n = 514) and controls (n = 400) underwent clinical phenotyping and genetic testing. Rare variants in 13 validated HCM genes were classified according to standard clinical guidelines and compared with a prospective HCM cohort of majority European ancestry (n = 684). A higher prevalence of homozygous variants was observed in Egyptian patients (4.1% vs. 0.1%, P = 2 × 10-7), with variants in the minor HCM genes MYL2, MYL3, and CSRP3 more likely to present in homozygosity than the major genes, suggesting these variants are less penetrant in heterozygosity. Biallelic variants in the recessive HCM gene TRIM63 were detected in 2.1% of patients (five-fold greater than European patients), highlighting the importance of recessive inheritance in consanguineous populations. Finally, rare variants in Egyptian HCM patients were less likely to be classified as (likely) pathogenic compared with Europeans (40.8% vs. 61.6%, P = 1.6 × 10-5) due to the underrepresentation of Middle Eastern populations in current reference resources. This proportion increased to 53.3% after incorporating methods that leverage new ancestry-matched controls presented here.

Conclusion: Studying consanguineous populations reveals novel insights with relevance to genetic testing and our understanding of the genetic architecture of HCM.

Keywords: Egyptian collaborative cardiac genomics project; Homozygosity; NGS.

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.

Figure 1

Enrichment of rare variation and homozygosity in hypertrophic cardiomyopathy minor genes (MLC and CSRP3) in the Egypt hypertrophic cardiomyopathy cohort vs. UK hypertrophic cardiomyopathy. (A) The overall frequency of rare variants (gnomAD_popmax FAF ≤4 × 10⁻⁵) in 13 validated hypertrophic cardiomyopathy genes was compared between Egypt and UK hypertrophic cardiomyopathy patients and controls. A 1.6-fold greater excess burden (i.e. total case frequency − total control frequency) was observed in the Egypt hypertrophic cardiomyopathy cohort, which should be accounted for with the direct gene comparisons (B). (B) Population-matched patients vs. control comparison (Egypt HCM_Control excess and UK HCM_Control excess) of genetic variation between Egypt and UK cohorts for each hypertrophic cardiomyopathy gene/gene class. (C) Comparison of the proportion of genotype-positive patients (i.e. those carrying rare variants) per hypertrophic cardiomyopathy gene confirms the enrichment of rare variants in the hypertrophic cardiomyopathy minor genes MLC (MYL2 and MYL3) and CSRP3 in Egyptians (as observed in B). Truncating and nontruncating variants (A, B) are shown in red and grey, respectively. Thin filament: ACTC1, TNNC1, TNNI3, TNNT2, and TPM1. (D) MLC (MYL2 and MYL3) and CSRP3 genes showed a markedly higher rate of homozygosity compared with major HCM genes (MYBPC3 and MYH7) and thin filament genes (ACTC1, TNNC1, TNNI3, TNNT2, and TPM1). HCM, hypertrophic cardiomyopathy.

Figure 2

Incorporation of methods that compare frequencies between Egyptian patients and controls increases the yield of clinically actionable variants observed in the understudied population. (A) For patients with rare variants in validated hypertrophic cardiomyopathy genes, the distribution of rare variants by variant classification (pathogenic, likely pathogenic, and variant of uncertain significance) is shown. For patients with multiple hits (see Supplementary material online, Tables S8 and S9), the variant with the highest pathogenicity was prioritized (i.e. pathogenic then likely pathogenic then variant of uncertain significance). The proportion of variants of uncertain significance was significantly higher in Egypt hypertrophic cardiomyopathy patients vs. UK (59.2% vs. 38.4%, P = 1.6 × 10⁻⁵). (B) Similar distribution of rare, missense MYH7 variants between the Egypt- and large-scale hypertrophic cardiomyopathy cohort of majority European ancestry (Partners Laboratory of Molecular Medicine and Oxford Medical Genetics Laboratory, n = 6112) in the predefined hypertrophic cardiomyopathy cluster (red) (residues 167–931). Rare variants in the hypertrophic cardiomyopathy cluster were enriched in the Egypt hypertrophic cardiomyopathy cohort over Egypt controls with an etiological fraction of 0.99. (C) Application of modified variant interpretation guidelines increases the proportion of Egypt hypertrophic cardiomyopathy patients with clinically actionable variants from 19% to 29.6%. Rare variants were initially classified based on the standard American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines (initial analysis) and then reclassified after integrating ancestry-matched controls into the analysis (cohort-informed analysis). HCM, hypertrophic cardiomyopathy; P, pathogenic; LP, likely pathogenic; VUS, variant of uncertain significance; LMM/OMGL, Partners Laboratory of Molecular Medicine and Oxford Medical Genetics Laboratory; LB, likely benign.