Abstract
AimsThe aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.Methods and results In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.Conclusions Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.
Highlights
Hypertrophic cardiomyopathy (HCM)—defined as left ventricular hypertrophy (LVH) unexplained by abnormal loading conditions—is a myocardial disease affecting 1 in 500 of the general population and is a major cause of sudden cardiac death (SCD), heart failure, and stroke.[1]
Truncating variants in Alpha-protein kinase 3 (ALPK3) are a cause of 1–2% of autosomal dominant hypertrophic cardiomyopathy and are associated with a phenotype characterized by extensive fibrosis and a predominantly concentric or apical pattern of left ventricular hypertrophy without left ventricular outflow tract obstruction. (A) Main phenotype characteristics and outcomes
Bi-allelic truncating variants in ALPK3 (ALPK3tv) have been reported in small paediatric case series, presenting with a complex phenotype of dilated cardiomyopathy (DCM) often evolving into HCM with poor systolic function[3,4,5,6,7,8] and common variants in ALPK3 have been associated with DCM and more recently HCM in genome-wide approaches.[9,10,11,12,13]
Summary
Hypertrophic cardiomyopathy (HCM)—defined as left ventricular hypertrophy (LVH) unexplained by abnormal loading conditions—is a myocardial disease affecting 1 in 500 of the general population and is a major cause of sudden cardiac death (SCD), heart failure, and stroke.[1]. Bi-allelic truncating variants in ALPK3 (ALPK3tv) have been reported in small paediatric case series, presenting with a complex phenotype of dilated cardiomyopathy (DCM) often evolving into HCM with poor systolic function[3,4,5,6,7,8] and common variants in ALPK3 have been associated with DCM and more recently HCM in genome-wide approaches.[9,10,11,12,13] A case report has described a family with HCM caused by a heterozygous ALPK3 variant[14] and ALPK3tv were found to be enriched in a mixed cohort of patients with HCM and DCM.[8]
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