Alice Ghidoni1, Perry M Elliott2, Petros Syrris2, Hugh Calkins3, Cynthia A James3, Daniel P Judge4, Brittney Murray3, Julien Barc5, Vincent Probst6,7, Jean Jacques Schott6, Jiang-Ping Song8, Richard N W Hauer9,10, Edgar T Hoorntje9,11, J Peter van Tintelen9,12, Eric Schulze-Bahr7,13, Robert M Hamilton14, Kirti Mittal14, Christopher Semsarian15, Elijah R Behr7,16, Michael J Ackerman17, Cristina Basso7,18, Gianfranco Parati19,20, Davide Gentilini21,22, Maria-Christina Kotta1, Bongani M Mayosi23, Peter J Schwartz1,7, Lia Crotti1,7,19,20. 1. Center for Cardiac Arrhythmias of Genetic Origin (A.G., M.-C.K., P.J.S., L.C.), Istituto Auxologico Italiano, IRCCS, Milan, Italy. 2. Center for Heart Muscle Disease, Institute of Cardiovascular Science, University College London, United Kingdom (P.M.E., P.S.). 3. Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD (H.C., C.A.J., B.M.). 4. Medical University of South Carolina, Charleston, SC (D.P.J.). 5. Université de Nantes (J.B.), CNRS, Inserm, l'Institut du Thorax, France. 6. Université de Nantes, CHU Nantes (V.P., J.J.S.), CNRS, Inserm, l'Institut du Thorax, France. 7. Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart-ERN GUARD-Heart (V.P., E.S.-B., E.R.B., C.B., P.J.S., L.C.). 8. State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China (J.-P.S.). 9. Netherlands Heart Institute (R.N.W.H., E.T.H., J.P.v.T.), University Medical Center Utrecht. 10. Department of Cardiology (R.N.W.H.), University Medical Center Utrecht. 11. Department of Genetics, University Medical Center Groningen, University of Groningen, the Netherlands (E.T.H.). 12. Department of Genetics (J.P.v.T.), University Medical Center Utrecht. 13. Institute for Genetics of Heart Diseases (IfGH), University Hospital Münster, Germany (E.S.-B.). 14. Hospital for Sick Children, Toronto, ON, Canada (R.M.H., K.M.). 15. Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, NSW, Australia (C.S.). 16. Cardiology Clinical Academic Group, Institute of Molecular and Clinical Sciences, St George's University of London, St George's University Hospitals NHS Foundation Trust, London, United Kingdom (E.R.B.). 17. Departments of Cardiovascular Medicine (Division of Heart Rhythm Services, Windland Smith Rice Genetic Heart Rhythm Clinic), Pediatric and Adolescent Medicine (Division of Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics (Windland Smith Rice Sudden Death Genomics Laboratory), Mayo Clinic, Rochester, MN (M.J.A.). 18. Cardiovascular Pathology Unit, Department of Cardiac, Thoracic and Vascular Sciences, University and Hospital of Padua, Italy (C.B.). 19. Istituto Auxologico Italiano, IRCCS, Cardiomyopathies Unit, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan (G.P., L.C.). 20. Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy (G.P., L.C.). 21. Bioinformatics and Statistical Genomics Unit (D.G.), Istituto Auxologico Italiano, IRCCS, Milan, Italy. 22. Department of Brain and Behavioural Sciences, University of Pavia, Italy (D.G.). 23. Department of Medicine, Hatter Institute for Cardiovascular Research in Africa, Groote Schuur Hospital and Division of Cardiology, Faculty of Health Sciences, University of Cape Town, South Africa (B.M.M.).
Abstract
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. METHODS: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed. RESULTS: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). CONCLUSIONS: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibrofatty replacement of the right and left ventricle, often causing ventricular dysfunction and life-threatening arrhythmias. Variants in desmosomal genes account for up to 60% of cases. Our objective was to establish the prevalence and clinical features of ACM stemming from pathogenic variants in the nondesmosomal cadherin 2 (CDH2), a novel genetic substrate of ACM. METHODS: A cohort of 500 unrelated patients with a definite diagnosis of ACM and no disease-causing variants in the main ACM genes was assembled. Genetic screening of CDH2 was performed through next-generation or Sanger sequencing. Whenever possible, cascade screening was initiated in the families of CDH2-positive probands, and clinical evaluation was performed. RESULTS: Genetic screening of CDH2 led to the identification of 7 rare variants: 5, identified in 6 probands, were classified as pathogenic or likely pathogenic. The previously established p.D407N pathogenic variant was detected in 2 additional probands. Probands and family members with pathogenic/likely pathogenic variants in CDH2 were clinically evaluated, and along with previously published cases, altogether contributed to the identification of gene-specific features (13 cases from this cohort and 11 previously published, for a total of 9 probands and 15 family members). Ventricular arrhythmic events occurred in most CDH2-positive subjects (20/24, 83%), while the occurrence of heart failure was rare (2/24, 8.3%). Among probands, sustained ventricular tachycardia and sudden cardiac death occurred in 5/9 (56%). CONCLUSIONS: In this worldwide cohort of previously genotype-negative ACM patients, the prevalence of probands with CDH2 pathogenic/likely pathogenic variants was 1.2% (6/500). Our data show that this cohort of CDH2-ACM patients has a high incidence of ventricular arrhythmias, while evolution toward heart failure is rare.
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