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 With reduced penetrance compared to other HCM genes and issues with historic genetic reports using a superseded transcript care needs to be taken when interpreting these variants to account for these nuances.

EMM consults for Amgen, Cytokinetics, PepGen, Tenaya Therapeutics and is a founder of Ikaika Therapeutics and EnCarda. JW has consulted for MyoKardia, Inc., Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics, and receives research support from Bristol Myers-Squibb. JI receives research grant support from Bristol Myers Squibb unrelated to this work. CAJ receives research funding from Lexeo Therapeutics, Arvada Therapeutics, EicOsis, and StrideBio Inc and has consulted for Pfizer and Lexeo Therapeutics. E.R.P. are cofounders, scientific advisors and hold equity in Dynomics, a biotechnology company focused on the development of heart failure therapeutics. All other authors declare no competing interests.

JI is the recipient of a National Heart Foundation of Australia Future Leader Fellowship (#106732). CS is the recipient of a National Health and Medical Research Council (NHMRC) Investigator Grant (#2016822) and a New South Wales Health Cardiovascular Disease Clinician Scientist Grant. RDB is the recipient of a New South Wales Cardiovascular Disease Senior Scientist Grant. JSW is supported by Medical Research Council (UK), Sir Jules Thorn Charitable Trust (JTA1), British Heart Foundation (RE/18/4/34215), and the NIHR Imperial College Biomedical Research Centre. JWM is the recipient of a National Heart Foundation of Australia Future Leader Fellowship (#107192) and Medical Research Future Fund Stem Cell Mission (MRF2024440).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Each participating site has received ethics approval in accordance with local policies, as per the following: ethical approval requiring informed consent was obtained from Childrens Hospital of Philadelphia USA, Yale Medical USA, Royal Brompton Hospital United Kingdom, Melbourne Health Human Research Australia, and Sydney Local Health District Royal Prince Alfred Hospital Australia ethics committees. Waiver of consent was granted by Stanford School of Medicine USA, Pennsylvania University Medical Center USA, Johns Hopkins University USA, and Sydney Local Health District Royal Prince Alfred Hospital Australia ethics committees.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

COMPETING INTERESTS EMM consults for Amgen, Cytokinetics, PepGen, Tenaya Therapeutics and is a founder of Ikaika Therapeutics and EnCarda. JW has consulted for MyoKardia, Inc., Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics, and receives research support from Bristol Myers-Squibb. JI receives research grant support from Bristol Myers Squibb unrelated to this work. CAJ receives research funding from Lexeo Therapeutics, Arvada Therapeutics, EicOsis, and StrideBio Inc and has consulted for Pfizer and Lexeo Therapeutics. E.R.P. are cofounders, scientific advisors and hold equity in Dynomics, a biotechnology company focused on the development of heart failure therapeutics. All other authors declare no competing interests.

All data produced in the present study are available upon reasonable request to the authors