Produção Nacional
Revisado por pares
Alpha-protein kinase 3 ( ALPK3 ) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy
2021; Oxford University Press; Volume: 42; Issue: 32 Linguagem: Inglês
10.1093/eurheartj/ehab424
ISSN1522-9645
AutoresLuís R. Lopes, Soledad García-Hernández, Massimiliano Lorenzini, Marta Futema, О. С. Чумакова, D. A. Zateyshchikov, María Isidoro‐García, Eduardo Villacorta, Luis Escobar-López, Pablo García‐Pavía, R.M. Bilbao, David Dobarro, María Sandín‐Fuentes, Claudio Catalli, Blanca Gener Querol, Ainhoa Robles Mezcua, Jose Garcia Pinilla, Torsten B. Rasmussen, Ana Ferreira-Aguar, Pablo Revilla-Martí, María Teresa Basurte Elorz, Alicia Bautista Pavés, Juan R. Gimeno, Ana Virginia Figueroa, Raúl Franco‐Gutiérrez, María Eugenia Fuentes‐Cañamero, Marina Martínez Moreno, Martín Ortiz-Genga, Jesús Piqueras‐Flores, Karina Analía Ramos, Ainārs Rudzītis, Luis Ruiz‐Guerrero, Ricardo Stein, Mayte Triguero-Bocharán, Luis de la Higuera, Juan Pablo Ochoa, Dad Abu-Bonsrah, Cecilia Y T Kwok, Jacob Smith, Enzo R. Porrello, Mohammed Akhtar, Joanna Jager, Michael Ashworth, Petros Syrris, David A. Elliott, Lorenzo Monserrat, Perry Elliott,
Tópico(s)Viral Infections and Immunology Research
ResumoAbstract Aims The 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.
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