%0 Journal Article
%T Compound Heterozygosity for Late-Onset Cardiomyopathy-Causative ALPK3 Coding Variant and Novel Intronic Variant Cause Infantile Hypertrophic Cardiomyopathy.
%A Poleg T
%A Eskin-Schwartz M
%A Proskorovski-Ohayon R
%A Aminov I
%A Dolgin V
%A Agam N
%A Jean M
%A Safran A
%A Freund O
%A Levitas A
%A Konstantino Y
%A Birk OS
%A Westreich R
%A Haim M
%J J Cardiovasc Transl Res
%V 16
%N 6
%D 2023 12
%M 37973666
%F 3.216
%R 10.1007/s12265-023-10461-y
%X 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.