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.

Ghidoni, A., Elliott, P., Syrris, P., Calkins, H., James, C., Judge, D., et al. (2021). Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features. CIRCULATION, 14(2), 159-169 [10.1161/CIRCGEN.120.003097].

Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features

Parati G.;Crotti L.
Ultimo
2021

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.
Articolo in rivista - Articolo scientifico
cadherins; cardiomyopathy; mutation; sudden cardiac death; tachycardia;
English
159
169
11
Ghidoni, A., Elliott, P., Syrris, P., Calkins, H., James, C., Judge, D., et al. (2021). Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features. CIRCULATION, 14(2), 159-169 [10.1161/CIRCGEN.120.003097].
Ghidoni, A; Elliott, P; Syrris, P; Calkins, H; James, C; Judge, D; Murray, B; Barc, J; Probst, V; Schott, J; Song, J; Hauer, R; Hoorntje, E; Van Tintelen, J; Schulze-Bahr, E; Hamilton, R; Mittal, K; Semsarian, C; Behr, E; Ackerman, M; Basso, C; Parati, G; Gentilini, D; Kotta, M; Mayosi, B; Schwartz, P; Crotti, L
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/354087
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