Predictors for increasing genetic testing yields in hypertrophic cardiomyopathy

Area of Science:

• Cardiology
• Genetics
• Inherited Diseases

Background:

• Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, affecting approximately 1 in 500 individuals.
• Genetic testing is increasingly used for HCM diagnosis and management.
• Identifying phenotypic predictors of HCM genotype is crucial for targeted genetic counseling and cascade testing.

Purpose of the Study:

• To identify phenotypic predictors of hypertrophic cardiomyopathy (HCM) genotype.
• To improve genetic targeting, counseling, and cascade testing for first-degree relatives of HCM patients.

Main Methods:

• Retrospective analysis of 166 adult patients undergoing HCM gene panel testing.
• Classification of left ventricular hypertrophy (LVH) patterns using trans-thoracic echocardiography (TTE).
• Classification of variant pathogenicity according to American College of Medical Genetics (ACMG) criteria.

Main Results:

• The overall genetic testing yield for pathogenic or likely pathogenic variants was 28.9%.
• Concentric HCM was the most frequent pattern (31.9%).
• Younger age, female sex, and a reverse curve LVH pattern were significant predictors of identifying pathogenic variants, particularly sarcomere gene variants (p < 0.001).

Conclusions:

• Phenotypic features like younger age, female sex, family history of sudden cardiac death, normal blood pressure, and reverse curve LVH on TTE predict a higher yield of pathogenic variants in HCM.
• These findings support phenotype-based genetic counseling and optimized resource allocation for HCM patients.
• Reverse curve morphology is a significant predictor for sarcomere variants in HCM.