Unique cardiac phenotype in ALPK3-related disease: Progression from dilated cardiomyopathy to hypertrophic cardiomyopathy

Introduction: Biallelic truncating variants in ALPK3 have recently been described to cause pediatric cardiomyopathy (CMP). Functional studies have found disorganized intercalated discs and sarcomeres and calcium mishandling in both patients and mutant stemcellderived cardiomyocytes. Objectives: To delineate the clinical and genetic spectrum of ALPK3related disease and study genotypephenotype correlations. Methods: We collected clinical and genetic data on ALPK3related CMP patients, and performed ALPK3 staining in heart and skeletal muscle of 3 individuals carrying biallelic truncating variants. Results: We report biallelic ALPK3 mutations for a total of 18 patients: 9 previously reported cases and 9 novel patients from 6 families. Nine patients had biallelic truncating variants, 7 had a truncating and a missense variant, and 1 had a homozygous missense variant in ALPK3. Nine of 16 liveborn patients showed (biventricular) DCM during neonatal life that transitioned to predominantly HCM with surveillance. Several patients showed extracardiac features, including short stature (8/13), contractures (6/15), severe scoliosis (5/12), cleft palate (CP) or velopharyngeal insufficiency (5/15), and dysmorphic (Noonanlike) facies (8/14). Biopsy of 4 patients showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis