Clinical Validity of Autosomal Dominant ALPK3 Loss-of-function Variants as a Cause of Hypertrophic Cardiomyopathy
Hespe, S.; Singer, E. S.; Reuter, C.; Murray, B.; Jordan, E.; Chowns, J.; Peters, S.; Mayers, M.; Gray, B.; Hershberger, R. E.; Owens, A.; Semsarian, C.; Waddell, A.; Asatryan, B.; Owens, E.; Thaxton, C.; Adduru, M.-L.; Anderson, K.; Brown, E. E.; Hoffman-Andrews, L.; Stafford, F.; Bagnall, R. D.; Bronicki, L.; Callewaert, B.; Chahal, C. A. A.; James, C. A.; Jarinova, O.; Landstrom, A. P.; McNally, E. M.; Muino-Mosquera, L.; Parikh, V.; Walsh, R.; Wayburn, B.; Ware, J. S.; Parker, B. L.; Porrello, E. R.; Elliott, D. A.; McNamara, J. W.; Ingles, J.
Show abstract
ALPK3 encodes the protein -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 With reduced penetrance compared to other HCM genes and issues with historic genetic reports using a superseded transcript care needs to be taken when interpreting these variants to account for these nuances.
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