Genotipe-phenotype correlation in alpk3 null variants. an extended analysis

Abstract Introduction ALPK3 null variants (ALPK3nv) in simple heterozygosis represent an established and emerging genetic cause for hypertrophic cardiomyopathy. Some studies have indicated that this genetic substrate would be associated with a disease of late-onset disease and incomplete penetrance. Purpose To perform an extended genotype-phenotype correlation analysis with respect to simple heterozygous ALPK3nv carriers, focusing on age at diagnosis, maximum wall thickness and survival analysis, performed on the largest available released cohort to date. Methods ALPK3 gene was included in an extended NGS panel in 16,780 probands from a reference multicentric genetic laboratory, of whom 6,505 were referred with a HCM phenotype. We collected a composite cohort of ALPK3nv (considering frameshift, nonsense and splice-site predicted frameshift variants), including index and familial cases referred to this laboratory, but also cases reported in the literature. Phenotypic behavior was analyzed, mainly considering age at diagnosis, maximum LV wall thickness, and a composite of events (heart failure and arrhythmia-related endpoints). Results A heterozygous ALPK3 null variant was identified in 110 probands out of 6,505 index cases diagnosed with HCM in our center (1.7% of HCM cases). For genotype-phenotype analysis, in total 189 heterozygous carriers were included, considering relatives and cases from the literature; 21 carriers had biallelic involvement (were homozygous or compound heterozygous for two ALPK3Knv). Among ALPK3nv heterozygous carriers, mean age at diagnosis was 53.4 (±15.2) years; mean left ventricular thickness was 17.7 (±4.9) mm, and morphological profile was mainly apical (42%) and/or concentric (26%). Males tended to be diagnosed at an earlier age than females (median age of diagnosis was 56 vs 71 years, respectively, p