Am J Med Genet A. 2026 Mar 11. doi: 10.1002/ajmg.a.70120. Online ahead of print.
ABSTRACT
The key diagnostic criterion for hypertrophic cardiomyopathy is the presence of otherwise unexplained hypertrophy. Current definitions of HCM rely on specific thresholds to establish a diagnosis, while guideline directed risk stratification algorithms take its magnitude into consideration. Presently, secondary features such as myocardial crypts and valve abnormalities in the absence of hypertrophy are solely considered as markers of preclinical disease in variant carriers, with no perceptible excess risk for arrhythmic events. Strictly adhering to hypertrophy as the sole criterion for a diagnosis may at times result in delays in diagnosis of the condition in the proband and consequently initiation of family screening. At the same time, arrhythmic risk in individuals with minimal or no hypertrophy may be underestimated. In this study, we describe a novel ACTC1 variant expressed with arrhythmic instability in the proband, closely segregating in family members. The presenting phenotype is characterized by frank secondary abnormalities related to HCM in the absence of conventional wall thickness criteria to establish a formal diagnosis. Thereby, the description of this phenotype may challenge the established perception that hypertrophy is a prerequisite for establishing an HCM diagnosis.
PMID:41813625 | DOI:10.1002/ajmg.a.70120