Clinical Validity of Autosomal DominantALPK3Loss-of-function Variants as a Cause of Hypertrophic Cardiomyopathy

• DOI: 10.1101/2025.03.27.25324722
• Publication Date: 2025-03-31T05:11:50Z
• Authors: Sophie Hespe; Emma S. Singer; Chloe Reuter; Brittney Murray; Elizabeth Jordan; Jessica Chowns; Stacey Peters; Megan Mayers; Belinda Gray; Ray E. Hershberger; Anjali Owens; Christopher Semsa...; Amber Waddell; Babken Asatryan; Emma Owens; Courtney Thaxton; Mhy-Lanie Adduru; Kailyn Anderson; Emily E. Brown; Lily Hoffman-Andrews; Fergus Stafford; Richard D. Bagnall; Lucas Bronicki; Bert Callewaert; C. Anwar A. Chahal; Cynthia A. James; Olga Jarinova; Andrew P. Landstrom; Elizabeth M. McNally; Laura Muiño-Mosquera; Victoria Parikh; Roddy Walsh; Bess Wayburn; James S. Ware; Benjamin L. Parker; Enzo R. Porrello; David A. Elliott; James W. McNamara; Jodie Ingles

AbstractALPK3encodes 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-functionALPK3variants 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-functionALPK3variants causative of HCM. In this research letter we present a patient series of 29 cardiac patients (26 probands) with heterozygous putative loss-of-functionALPK3variants 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 ofALPK3for 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 With reduced penetrance compared to other HCM genes and issues with historic genetic reports using a superseded transcript care needs to be taken when interpreting these variants to account for these nuances.