ALPK3 heterozygous truncating variants cause late-onset hypertrophic cardiomyopathy with frequent apical involvement and apical aneurysm

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder with several established genotype-phenotype relationships. While biallelic truncating variants in the ALPK3 gene cause severe congenital HCM, recent studies have associated heterozygous truncating variants (ALPK3tv) with milder adult-onset HCM. Here we describe a multicenter cohort of 21 individuals with heterozygous ALPK3tv from 10 institutions in the United States, highlighting distinctive clinical characteristics compared to a control group of 132 patients with HCM caused by deleterious variants in sarcomeric genes. As compared to other HCM genotypes, ALPK3tv patients present at an older age (mean 57.25 years) with significantly lower left ventricular wall thickness (14.09 vs 19.78 mm with echocardiogram and 16.13 vs 21.13 mm with cardiac MRI), a lower prevalence of obstructive HCM (15% of ALPK3tv vs 45% of controls), and a strikingly higher incidence of apical aneurysm (22.22% vs. 2.40% in the control group). These results suggest a milder degree of hypertrophy in heterozygous ALPK3-related HCM as compared to other Mendelian causes of HCM, although the increased occurrence of apical aneurysms could have implications for ventricular arrhythmia risk. Our study underscores the importance of recognizing heterozygous ALPK3tv as a cause of adult-onset HCM and provides a comprehensive characterization of its clinical phenotype.