Key result
Heterozygous loss-of-function ALPK3 variants are strongly associated with autosomal dominant hypertrophic cardiomyopathy, though they exhibit reduced penetrance compared to other HCM genes.
Why the study?
Bi-allelic ALPK3 variants cause severe paediatric cardiomyopathy, but whether heterozygous loss-of-function ALPK3 variants cause autosomal dominant HCM required clinical validity assessment.
Heterozygous loss-of-function ALPK3 variants have strong clinical validity as a cause of autosomal dominant hypertrophic cardiomyopathy, though reduced penetrance and transcript versioning require careful clinical interpretation.
Heterozygous ALPK3 variants may rarely cause cardiomyopathy; leaves open their contribution to adult-onset disease.
ALPK3 encodes the protein α-kinase 3, an essential cardiac-enriched atypical a-kinase that inserts in the nuclear envelope and the sarcomere M-band of cardiac myocytes, functioning to aid in myosin-mediated force buffering and sarcomere proteostasis. Previously, bi-allelic loss-of-function ALPK3 variants have been reported causative in a severe paediatric phenotype including hypertrophic (HCM) and dilated cardiomyopathy (DCM). Very few heterozygous carries in these cases express any cardiac phenotype. However, recently studies have reported heterozygous loss-of-function ALPK3 variants causative of HCM. In this research letter we present a patient series of 29 cardiac patients (26 probands) with heterozygous putative loss-of-function ALPK3 variants without another causative variant in other definitive HCM genes. As well as, a ClinGen gene curation assessing the clinical validity of the gene-disease association of ALPK3 for autosomal dominant HCM, which was evaluated to be strong. With reduced penetrance compared to other HCM genes and issues with historic genetic reports using a superseded transcript care needs to be taken when interpreting these variants to account for these nuances.
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Hespe et al. (2025) conducted a letter in Hypertrophic Cardiomyopathy (n=29). Heterozygous loss-of-function ALPK3 variants was evaluated on Clinical diagnosis and gene-disease clinical validity. Heterozygous loss-of-function ALPK3 variants are strongly associated with autosomal dominant hypertrophic cardiomyopathy, though they exhibit reduced penetrance compared to other HCM genes.
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