Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1). Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular etiology, and guide screening and management. The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy. Genetic testing remains challenging in the interpretation of results and classification of variants. Therefore, in 2015 the American College of Medical Genetics and Genomics (ACMG) established guidelines to classify and interpret the variants with an emphasis on the necessity of periodic reassessment of variant classification as genetic knowledge rapidly expands. The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband. Genetic test results in family members guide longitudinal clinical surveillance. At present, there is emerging evidence for genetic test application in risk stratification and management but its implementation into clinical practice needs further study. Promising fields such as gene therapy and implementation of artificial intelligence in the diagnosis of HCM are emerging and paving the way for more effective screening and management, but many challenges and obstacles need to be overcome before establishing the practical implications of these new methods.

Keywords: cascade testing; gene therapy; hypertrophic cardiomyopathy; longitudinal surveillance; next-generation sequencing; phenocopies; sarcomeric genes; whole exome sequencing.

Figure 1

Flowchart illustrates genetic testing and screening in HCM. HCM: Hypertrophic cardiomyopathy; LPV/PV: likely pathogenic variant/pathogenic variant; VUS: variant of unknown significance; LBV/BV: likely benign variant/benign variant.

Figure 2

Cardiovascular imaging revealing hypertrophic cardiomyopathy (HCM) and phenocopies. Panel A and B show apical 4-chamber (A) and parasternal long axis (B) transthoracic echocardiography (TTE) views demonstrating asymmetric septal hypertrophy (reverse curve morphology, maximal wall thickness 19 mm) in a patient with confirmed typical HCM. Panel C and D depict apical 4-chamber (C) and parasternal long axis (D) TTE views showing increased wall thickness of the left and right ventricle and enlarged left atrium in a patient with light chain (AL) amyloidosis. Panel E and F show images from a patient initially diagnosed with HCM; however, genetic testing confirmed the diagnosis of Fabry’s disease in the absence of any other clue for Fabry; magnetic resonance imaging coronal section (E) reveals diffuse left ventricular hypertrophy and parasternal long axis TTE view (F) shows increased wall thickness.

Figure 3

Illustration of future directives and evolving fields in employing genetics in HCM management. HCM: hypertrophic cardiomyopathy; AI: artificial intelligence; WES/WGS: whole exome sequencing/whole genome sequencing.