Key result
Heterozygous ALPK3 truncating variants in patients with hypertrophic cardiomyopathy were associated with a higher incidence of apical aneurysms compared to those with sarcomeric variants.
Why the study?
Recent studies have associated heterozygous truncating variants in ALPK3 with milder adult-onset HCM, but their clinical phenotype required comprehensive characterization.
Do heterozygous ALPK3 truncating variants cause a distinct clinical phenotype compared to sarcomeric hypertrophic cardiomyopathy?
Cohort (n=153)
Yes
Do heterozygous ALPK3 truncating variants cause a distinct clinical phenotype compared to sarcomeric hypertrophic cardiomyopathy?
Answers are grounded in this paper and cite their sources.
Heterozygous ALPK3 truncating variants cause a distinct, late-onset form of hypertrophic cardiomyopathy with milder hypertrophy but a significantly higher risk of apical aneurysms, highlighting the potential need for cardiac MRI in risk stratification.
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.
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Huth et al. (2024) conducted a cohort in Hypertrophic cardiomyopathy (n=153). Heterozygous ALPK3 truncating variants vs. Sarcomeric gene variants was evaluated on Incidence of apical aneurysm (p=0.005). Heterozygous ALPK3 truncating variants in patients with hypertrophic cardiomyopathy were associated with a higher incidence of apical aneurysms compared to those with sarcomeric variants.
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