Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.
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Lopes Luis R, Garcia-Hernández Soledad, Lorenzini Massimiliano, Futema Marta, Chumakova Olga, Zateyshchikov Dmitry, Isidoro-Garcia Maria, Villacorta Eduardo, Escobar-Lopez Luis, Garcia-Pavia Pablo, Bilbao Raquel, Dobarro David, Sandin-Fuentes Maria, Catalli Claudio, Gener Querol Blanca, Mezcua Ainhoa, Garcia Pinilla Jose, Bloch Rasmussen Torsten, Ferreira-Aguar Ana, Revilla-Martí Pablo, Basurte Elorz Maria Teresa, Bautista Paves Alicia, Ramon Gimeno Juan, Figueroa Ana Virginia, Franco-Gutierrez Raul, Fuentes-Cañamero Maria Eugenia, Martinez Moreno Marina, Ortiz-Genga Martin, Piqueras-Flores Jesus, Analia Ramos Karina, Rudzitis Ainars, Ruiz-Guerrero Luis, Stein Ricardo, Triguero-Bocharán Mayte, de la Higuera Luis, Ochoa Juan Pablo, Abu-Bonsrah Dad, Kwok Cecilia Y T, Smith Jacob B, Porrello Enzo R, Akhtar Mohammed M, Jager Joanna, Ashworth Michael, Syrris Petros, Elliott David A, Monserrat Lorenzo, Elliott Perry M
Аннотация
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.