Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy. (15th July 2021)

• Record Type: Journal Article
• Authors: 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;
• Is Part Of: European heart journal. Volume 42:Number 32(2021)
• Page Start: 3063
• Page End: 3073
• Publication Date: 2021-07-15
• Subjects: ALPK3 -- Hypertrophic cardiomyopathy -- Genetics; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehab424
• Languages: English
• ISSNs: 0195-668X

Abstract

Abstract: Aims: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants ( ALPK3 tv) 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 ALPK3 tv [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 ALPK3 tv (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 ALPK3 tv 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−), ALPK3 tv 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 ALPK3 tv 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 ALPK3 tv are pathogenic and segregate with a characteristic HCM phenotype. Graphical Abstract: