The Dilemma of Genotype Positive-Phenotype Negative Hypertrophic Cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and the leading cause of sudden death in athletes. An autosomal dominant disorder affecting approximately 1 in 500 individuals, HCM has been linked to multiple mutations and exhibits variable phenotypic expression. The utility of cardiovascular screening in diagnosing risk factors for sudden cardiac death continues to be debated intensely. Genetic testing has been employed increasingly in diagnosing HCM, resulting in a subset of patients with genotype positive-phenotype negative disease; these patients carry the mutation for HCM but lack pathologic evidence of disease. These individuals pose a dilemma in the clinical management of HCM: should treatment guidelines for phenotypically normal HCM patients be the same as that of symptomatic patients? Governing bodies continue to disagree, providing conflicting guidelines for sports participation. This review examines the current fund of knowledge regarding HCM and the debate regarding screening.

Hypertrophic Cardiomyopathy from A to Z: Genetics, Pathophysiology, Imaging, and Management

“…Cardiomyocyte disarray and increased extracellular fibrosis contribute to higher passive chamber stiffness, and increasing hypertrophy leads to distortion in LV chamber shape, which further hampers diastolic filling (68). These diastolic abnormalities are highly prevalent and can be detected in genotype-positive individuals before significant hypertrophy or symptoms appear (69). Cardiac MR imaging is increasingly being used to assess diastolic function by means of velocity encoding and spatial modulation of magnetization (SPAMM) sequences (24).…”

Sports and Exercise in Athletes with Hypertrophic Cardiomyopathy

“…[69][70][71] However, this once promising approach has ultimately been thwarted by an unanticipated volume of unique mutations as well as the inconsistent correlation between genotype and Alpert et al phenotype. 10,70,72 At least for the time being, genetics does not typically affect risk stratification for athletes with HCM.…”

“…Furthermore, the widespread availability of clinical genetic testing has revealed a new cohort of individuals who carry a gene mutation yet lack any evidence of clinical disease (referred to as genotype positive-phenotype negative). 9,10 Diagnosis of HCM relies on history, physical examination, electrocardiography (ECG), imaging, and sometimes genetic testing. A personal or family history of either syncope or SCD can be informative.…”

Screening program in the athlete in the suspicion of HCM

“…Genetic testing has been employed increasingly in diagnosing HCM, resulting in a subset of patients with genotype positivephenotype negative disease; these patients carry the mutation for HCM but lack pathological evidence of disease [10]. Thus, a growing body of evidence continues to disagree, in regard to the treatment for phenotypically normal HCM.…”