Clinical Validity of Autosomal Dominant ALPK3 Loss-of-Function Variants as a Cause of Hypertrophic Cardiomyopathy

Sophie Hespe^{1

2}, Emma S Singer^{2

3}, Chloe Reuter⁴, Brittney Murray⁵, Elizabeth Jordan⁶, Jessica Chowns⁷, Stacey Peters⁸, Megan Mayers⁹, Belinda Gray^{2

10}, Ray E Hershberger⁶, Anjali T Owens⁷, Christopher Semsarian^{2

3

10}, Amber Waddell⁹, Babken Asatryan⁵, Emma Owens⁹, Courtney Thaxton⁹, Mhy-Lanie Adduru¹¹, Kailyn Anderson¹², Emily E Brown⁵, Lily Hoffman-Andrews⁷, Fergus Stafford¹, Richard D Bagnall^{2

3}, Lucas Bronicki^{13

14}, Bert Callewaert^{15

16}, C Anwar A Chahal^{17

18

19}, Cynthia A James⁵, Olga Jarinova^{20

14}, Andrew P Landstrom²¹, Elizabeth M McNally²², Laura Muiño-Mosquera^{16

23}, Victoria Parikh⁴, Roddy Walsh²⁴, Bess Wayburn²⁵, James S Ware^{26

27}, Benjamin L Parker²⁸, Enzo R Porrello²⁹, David A Elliott²⁹, James W McNamara²⁹, Jodie Ingles^{1

30}

Affiliations

¹ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia (S.H., F.S., J.I.).
² Faculty of Medicine and Health (S.H., E.S.S., B.G., C.S., R.D.B.), The University of Sydney, New South Wales, Australia.
³ Centenary Institute (E.S.S., C.S., R.D.B.), The University of Sydney, New South Wales, Australia.
⁴ Division of Cardiovascular Medicine, Department of Medicine, Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, CA (C.R., V.P.).
⁵ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (B.M., B.A., E.E.B., C.A.J.).
⁶ Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus (E.J., R.E.H.).
⁷ Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (J.C., A.O., L.H.-A.).
⁸ Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Victoria, Australia (S.P.).
⁹ Department of Genetics, University of North Carolina at Chapel Hill (M.M., A.W., E.O., C.T.).
¹⁰ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (B.G., C.S.).
¹¹ Predictiv Care, San Francisco, CA (M.-L.A.).
¹² Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle (K.A.).
¹³ Department of Pathology and Laboratory Medicine (L.B.), University of Ottawa, Canada.
¹⁴ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada (L.B., O.J.).
¹⁵ Department of Biomolecular Medicine, Ghent University, Belgium (B.C.).
¹⁶ Center for Medical Genetics (B.C., L.M.-M.), Ghent University Hospital, Belgium.
¹⁷ Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, PA (C.A.A.C.).
¹⁸ Mayo Clinic, Rochester, MN (C.A.A.C.).
¹⁹ Barts Heart Centre and William Harvey Research Institute, Queen Mary University of London, United Kingdom (C.A.A.C.).
²⁰ Children's Hospital of Eastern Ontario Research Institute (O.J.), University of Ottawa, Canada.
²¹ Division of Cardiology, Department of Pediatrics, Duke University School of Medicine, Durham, NC (A.P.L.).
²² Department of Medicine (Cardiology), Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.).
²³ Division of Pediatric Cardiology, Department of Pediatrics (L.M.-M.), Ghent University Hospital, Belgium.
²⁴ Heart Center and Department of Experimental Cardiology, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, the Netherlands (R.W.).
²⁵ Clinical Genomics, Ambry Genetics, Aliso Viejo, CA (B.W.).
²⁶ National Heart and Lung Institute and Medical Research Council (MRC) Laboratory of Medical Science, Imperial College London, United Kingdom (J.S.W.).
²⁷ Royal Brompton, Harefield Hospitals, Guy's & St Thomas' National Health Service (NHS) Foundation Trust, London, United Kingdom (J.S.W.).
²⁸ Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia (B.L.P.).
²⁹ Murdoch Children's Research Institute and Melbourne Center for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Parkville, Victoria, Australia (E.R.P., D.A.E., J.W.M.).
³⁰ Faculty of Medicine and Health, School of Clinical Medicine, University of New South Wales Sydney, Sydney, Australia (J.I.).

PMID: 40255155
DOI: 10.1161/CIRCGEN.124.004976

Clinical Validity of Autosomal Dominant ALPK3 Loss-of-Function Variants as a Cause of Hypertrophic Cardiomyopathy

Sophie Hespe et al. Circ Genom Precis Med. 2025 Jun.

. 2025 Jun;18(3):e004976.

doi: 10.1161/CIRCGEN.124.004976. Epub 2025 Apr 21.

Authors

Affiliations

¹ Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia (S.H., F.S., J.I.).
² Faculty of Medicine and Health (S.H., E.S.S., B.G., C.S., R.D.B.), The University of Sydney, New South Wales, Australia.
³ Centenary Institute (E.S.S., C.S., R.D.B.), The University of Sydney, New South Wales, Australia.
⁴ Division of Cardiovascular Medicine, Department of Medicine, Stanford Center for Inherited Cardiovascular Disease, Stanford University School of Medicine, CA (C.R., V.P.).
⁵ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (B.M., B.A., E.E.B., C.A.J.).
⁶ Division of Human Genetics, Department of Internal Medicine, Ohio State University, Columbus (E.J., R.E.H.).
⁷ Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia (J.C., A.O., L.H.-A.).
⁸ Department of Cardiology and Genomic Medicine, Royal Melbourne Hospital, Victoria, Australia (S.P.).
⁹ Department of Genetics, University of North Carolina at Chapel Hill (M.M., A.W., E.O., C.T.).
¹⁰ Department of Cardiology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (B.G., C.S.).
¹¹ Predictiv Care, San Francisco, CA (M.-L.A.).
¹² Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle (K.A.).
¹³ Department of Pathology and Laboratory Medicine (L.B.), University of Ottawa, Canada.
¹⁴ Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada (L.B., O.J.).
¹⁵ Department of Biomolecular Medicine, Ghent University, Belgium (B.C.).
¹⁶ Center for Medical Genetics (B.C., L.M.-M.), Ghent University Hospital, Belgium.
¹⁷ Center for Inherited Cardiovascular Diseases, WellSpan Health, Lancaster, PA (C.A.A.C.).
¹⁸ Mayo Clinic, Rochester, MN (C.A.A.C.).
¹⁹ Barts Heart Centre and William Harvey Research Institute, Queen Mary University of London, United Kingdom (C.A.A.C.).
²⁰ Children's Hospital of Eastern Ontario Research Institute (O.J.), University of Ottawa, Canada.
²¹ Division of Cardiology, Department of Pediatrics, Duke University School of Medicine, Durham, NC (A.P.L.).
²² Department of Medicine (Cardiology), Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.).
²³ Division of Pediatric Cardiology, Department of Pediatrics (L.M.-M.), Ghent University Hospital, Belgium.
²⁴ Heart Center and Department of Experimental Cardiology, Amsterdam University Medical Center, Amsterdam Cardiovascular Sciences, University of Amsterdam, the Netherlands (R.W.).
²⁵ Clinical Genomics, Ambry Genetics, Aliso Viejo, CA (B.W.).
²⁶ National Heart and Lung Institute and Medical Research Council (MRC) Laboratory of Medical Science, Imperial College London, United Kingdom (J.S.W.).
²⁷ Royal Brompton, Harefield Hospitals, Guy's & St Thomas' National Health Service (NHS) Foundation Trust, London, United Kingdom (J.S.W.).
²⁸ Department of Anatomy and Physiology, University of Melbourne, Victoria, Australia (B.L.P.).
²⁹ Murdoch Children's Research Institute and Melbourne Center for Cardiovascular Genomics and Regenerative Medicine, The Royal Children's Hospital, Parkville, Victoria, Australia (E.R.P., D.A.E., J.W.M.).
³⁰ Faculty of Medicine and Health, School of Clinical Medicine, University of New South Wales Sydney, Sydney, Australia (J.I.).

PMID: 40255155
DOI: 10.1161/CIRCGEN.124.004976

No abstract available

Keywords: cardiomyopathy, hypertrophic; exons; myocytes, cardiac; phenotype; protein kinases.

PubMed Disclaimer

Conflict of interest statement

Dr McNally consults for Amgen, Cytokinetics, PepGen, and Tenaya Therapeutics and is a founder of Ikaika Therapeutics and EnCarda. Dr Ware has consulted for MyoKardia, Inc, Pfizer, Foresite Labs, Health Lumen, and Tenaya Therapeutics and receives research support from Bristol Myers Squibb. Dr Ingles receives research grant support from Bristol Myers Squibb, unrelated to this work. Dr James receives research funding from Lexeo Therapeutics, Arvada Therapeutics, EicOsis, and StrideBio, Inc, and has consulted for Pfizer and Lexeo Therapeutics. Dr Porrello is a cofounder and a scientific advisor and holds equity in Dynomics, a biotechnology company focused on the development of heart failure therapeutics. The other authors report no conflicts.

Publication types

Actions

LinkOut - more resources

Full Text Sources
- Atypon

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Clinical Validity of Autosomal Dominant ALPK3 Loss-of-Function Variants as a Cause of Hypertrophic Cardiomyopathy

Affiliations

Clinical Validity of Autosomal Dominant ALPK3 Loss-of-Function Variants as a Cause of Hypertrophic Cardiomyopathy

Authors

Affiliations

Conflict of interest statement

Publication types

LinkOut - more resources

Full Text Sources