Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy-Reference-Cited by-同舟云学术

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy

Published:2021-07-15 Issue:32 Volume:42 Page:3063-3073
ISSN:0195-668X
Container-title:European Heart Journal
language:en
Short-container-title:

Author:

Lopes Luis R¹²^ORCID,Garcia-Hernández Soledad³,Lorenzini Massimiliano¹²^ORCID,Futema Marta¹,Chumakova Olga⁴⁵,Zateyshchikov Dmitry⁶^ORCID,Isidoro-Garcia Maria⁷,Villacorta Eduardo⁸^ORCID,Escobar-Lopez Luis⁹¹⁰^ORCID,Garcia-Pavia Pablo⁹¹⁰¹¹,Bilbao Raquel¹²,Dobarro David¹²,Sandin-Fuentes Maria¹³,Catalli Claudio¹⁴,Gener Querol Blanca¹⁴,Mezcua Ainhoa¹⁵¹⁶^ORCID,Garcia Pinilla Jose¹⁵¹⁶,Bloch Rasmussen Torsten¹⁷^ORCID,Ferreira-Aguar Ana¹⁸,Revilla-Martí Pablo¹⁸^ORCID,Basurte Elorz Maria Teresa¹⁹,Bautista Paves Alicia²⁰,Ramon Gimeno Juan¹⁰²¹,Figueroa Ana Virginia²²,Franco-Gutierrez Raul²³^ORCID,Fuentes-Cañamero Maria Eugenia²⁴,Martinez Moreno Marina²⁵^ORCID,Ortiz-Genga Martin²⁶^ORCID,Piqueras-Flores Jesus²⁷,Analia Ramos Karina²⁸,Rudzitis Ainars²⁹,Ruiz-Guerrero Luis³⁰,Stein Ricardo³¹,Triguero-Bocharán Mayte²⁷,de la Higuera Luis²⁶,Ochoa Juan Pablo⁹¹⁰,Abu-Bonsrah Dad³²^ORCID,Kwok Cecilia Y T³²,Smith Jacob B³²,Porrello Enzo R³²³³^ORCID,Akhtar Mohammed M¹²^ORCID,Jager Joanna¹^ORCID,Ashworth Michael³⁴,Syrris Petros¹^ORCID,Elliott David A³²³³,Monserrat Lorenzo²⁶^ORCID,Elliott Perry M¹²^ORCID

Affiliation:

1. Centre for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, 62 Huntley St, London WC1E 6DD, UK

2. Barts Heart Centre, St. Bartholomew’s Hospital, Barts Health NHS Trust, West Smithfield, London EC1A 7BE, UK

3. Health in Code S.L., Cardiology and Scientific Department, As Xubias, s/n Edificio O Fortín, 15006 A Coruña, Spain

4. Federal Scientific Clinical Centre of Federal Medical and Biological Agency, 30, Volokolamskoe Shosse, Moscow, Russia

5. Department of Cardiology, City Clinical Hospital, #17, Volynska st., 7, Moscow, Russia

6. Federal Scientific Clinical Centre of Federal Medical and Biological Agency, Genetic Laboratory, Moscow, Russia

7. Inherited Cardiac Disease Unit (CSUR), Biochemistry Department, Instituto de Investigación Biomédica de Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), Medicine Department, Facultad de Medicina, Universidad de Salamanca, Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Paseo de San Vicen

8. Inherited Cardiac Disease Unit (CSUR), Cardiology Department, Instituto de Investigación Biomédica de Salamanca (IBSAL), Complejo Asistencial Universitario de Salamanca, Gerencia Regional de Salud de Castilla y León (SACYL), Medicine Department, Facultad de Medicina, Universidad de Salamanca, Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Paseo de San Vicente

9. Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, CIBERCV, Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0 28029 and Calle Joaquín Rodrigo, 1, 28222 Majadahonda, Madrid, Spain

10. European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN-GUARDHEART)

11. Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcón, Carretera Pozuelo a Majadahonda, Km 1.800, 28223 Madrid, Spain

12. Heart Failure and Pulmonary Hypertension Unit, Hospital Alvaro Cunqueiro, Complexo Hospitalario Universitario de Vigo, Estrada de Clara Campoamor, 341, 36213 Vigo, Pontevedra, Spain

13. Hospital Clínico Universitario de Valladolid, Cardiology, Av. Ramón y Cajal, 3, 47003 Valladolid, Spain

14. Osakidetza Basque Health Service, Cruces University Hospital, Department of Genetics, Biocruces Bizkaia Health Research Institute, Cruces Plaza, 48903 Barakaldo, Bizkaia, Spain

15. Heart Failure and Familial Heart Diseases Unit, Cardiology Service, Hospital Universitario Virgen de la Victoria, IBIMA, Campus de Teatinos, S/N, 29010 Málaga, Spain

16. Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Av. Monforte de Lemos, 3-5. Pabellón 11. Planta 0 28029 Madrid, Spain

17. Department of Cardiology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99 DK-8200 Aarhus, Denmark

18. Inherited Cardiac Diseases Unit, Cardiology Department, Hospital Clínico Universitario Lozano Blesa, Avda, Calle de San Juan Bosco, 15, 50009 Zaragoza, Spain

19. Complejo Hospitalario de Navarra, Calle de Irunlarrea, 3, 31008 Pamplona, Navarra, Spain

20. Hospital Universitario San Cecilio Granada, Av. del Conocimiento, s/n, 18016 Granada, Cardiology

21. Hospital Clínico Universitario Virgen de la Arrixaca, Inherited Cardiac Diseases Unit, Department of Cardiology, Ctra. Madrid-Cartagena, s/n, 30120 El Palmar, Murcia, Spain

22. Hospital Privado Universitario de Córdoba, Naciones Unidas 346, Córdoba, Argentina

23. Cardiology Department, Hospital Universitario Lucus Augusti, Lugo Biodiscovery HULA-USC Research Group, Institute for Health Research of Santiago de Compostela IDIS, s/n A, Travesía da Choupana, 15706 Santiago de Compostela, A Coruña

24. Hospital Universitario Infanta Cristina, Cardiology, Av. de Elvas, s/n, 06080 Badajoz, Spain

25. Hospital General Elche, Carrer Almazara, 11, 03203 Elche, Alicante

26. Health in Code S.L., Scientific Department, As Xubias, s/n Edificio O Fortín, 15006 A Coruña, Spain

27. Cardiology Department, Inherited Cardiovascular Diseases Unit, Hospital General Universitario de Ciudad Real, Calle Obispo Rafael Torija, s/n, 13005 Ciudad Real, Spain

28. Hospital Centenario, Urquiza 3101, S2002 KDT, Santa Fe, Rosario, Argentina

29. Pauls Stradins Clinical University Hospital, Pilsoņu iela 13, Zemgales priekšpilsēta, Rīga, LV-1002, Latvia

30. Hospital Universitario Marqués de Valdecilla (IDIVAL), Av. de Valdecilla, 25, 39008 Santander, Spain

31. School of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Av. Paulo Gama, 110 Secretaria de Comunicação Social – 8º andar – Reitoria – Farroupilha, Porto Alegre – RS 90040-060, Brazil

32. Murdoch Research Childrens Research Institute, Royal Melbourne Hospital, Parkville, VIC 3052, Australia

33. Dept. of Physiology, University of Melbourne, Parkville, VIC 3052, Australia

34. Department of Histopathology, Great Ormond St Hospital for Children, London WC1N 3NN, UK

Abstract

Abstract 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.

Funder

Medical Research Council

Clinical Academic Research Partnership

British Heart Foundation Program

National Institute for Health Research University College London Hospitals Biomedical Research Centre

National Health and Medical Research Council of Australia

Australian Research Council

Heart Foundation of Australia

The Stafford Fox Medical Research Foundation

Royal Children’s Hospital Foundation

Publisher

Oxford University Press (OUP)