Abstract
Hypertrophic and dilated cardiomyopathy (HCM, DCM) are leading causes of cardiovascular morbidity and mortality in children. The pseudokinase alpha-protein kinase 3 (ALPK3) plays an essential role in sarcomere organization and cardiomyocyte differentiation. ALPK3 coding mutations are causative of recessively inherited pediatric-onset DCM and HCM with variable expression of facial dysmorphism and skeletal abnormalities and implicated in dominantly inherited adult-onset cardiomyopathy. We now report two variants in ALPK3—a coding variant and a novel intronic variant affecting splicing. We demonstrate that compound heterozygosity for both variants is highly suggestive to be causative of infantile-onset HCM with webbed neck, and heterozygosity for the coding variant presents with adult-onset HCM. Our data validate partial penetrance of heterozygous loss-of-function ALPK3 mutations in late-onset hypertrophic cardiomyopathy and expand the genotypic spectrum of autosomal recessive ALPK3-related cardiac disease with Noonan-like features.
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Data Availability
Data supporting the findings of this study, including the WES raw data, are available from the corresponding author (O.S.B) upon request.
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Funding
The study was funded by the Morris Kahn Family Foundation, the Israel Science Foundation (grant no. 2034/18) awarded to OSB, and the National Knowledge Center for Rare/Orphan Diseases sponsored by the Israel Ministry of Science, Technology and Space, at Ben-Gurion University of the Negev and Soroka Medical Center, Beer Sheva, Israel.
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YK, MH, MES, and OSB initiated the studies. TP designed molecular experiments; data analyzed by TP, MES, and OSB. TP, RPO, IA, VD, NA, MJ, AS, and OF performed the molecular experiments. RW, MH, YK, AL, and MES performed clinical phenoty**. TP drafted the manuscript with MES and OSB, revised and approved by all authors.
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The participants of this study provided written informed consent according to a protocol approved by the Soroka Medical Center institutional review board (ID5071G) and by the Israel National Committee for Human Genetic Studies, in adherence with the Helsinki principles.
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Poleg, T., Eskin-Schwartz, M., Proskorovski-Ohayon, R. et al. Compound Heterozygosity for Late-Onset Cardiomyopathy-Causative ALPK3 Coding Variant and Novel Intronic Variant Cause Infantile Hypertrophic Cardiomyopathy. J. of Cardiovasc. Trans. Res. 16, 1325–1331 (2023). https://doi.org/10.1007/s12265-023-10461-y
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DOI: https://doi.org/10.1007/s12265-023-10461-y