Ethnicity, consanguinity, and genetic architecture of hypertrophic cardiomyopathy

Area of Science:

• Cardiovascular Genetics
• Human Genetics
• Population Genetics

Background:

• Hypertrophic cardiomyopathy (HCM) exhibits significant phenotypic heterogeneity, influenced by diverse genetic variants.
• Interpreting genetic variants for HCM diagnosis and precision medicine is challenging, especially in understudied populations.
• North African populations, characterized by high consanguinity, present a unique context for studying HCM genetics.

Purpose of the Study:

• To define the genetic architecture of HCM in North African cohorts.
• To investigate the role of genetic variant homozygosity and recessive inheritance in HCM within these populations.
• To improve variant classification and diagnostic yield by utilizing ancestry-matched controls.

Main Methods:

• Clinical phenotyping and genetic testing of prospective Egyptian patients (n=514) and controls (n=400).
• Classification of rare variants in 13 validated HCM genes using standard clinical guidelines.
• Comparison with a European HCM cohort (n=684) and incorporation of novel ancestry-matched controls.

Main Results:

• Egyptian HCM patients showed a significantly higher prevalence of homozygous variants (4.1% vs. 0.1%).
• Recessive inheritance, particularly biallelic variants in TRIM63, was more prevalent in Egyptian patients (2.1%).
• Fewer variants in Egyptian HCM patients were classified as pathogenic compared to Europeans (40.8% vs. 61.6%) before incorporating new controls.

Conclusions:

• Consanguinity in North African populations influences HCM's genetic architecture, emphasizing homozygous and recessive variants.
• The study underscores the need for ancestry-matched reference resources to accurately interpret genetic variants in diverse populations.
• Findings provide critical insights for genetic testing and advancing precision medicine for HCM globally.