TY - JOUR
T1 - Cadherin 2-Related Arrhythmogenic Cardiomyopathy
T2 - Prevalence and Clinical Features
AU - Ghidoni, Alice
AU - Elliott, Perry M.
AU - Syrris, Petros
AU - Calkins, Hugh
AU - James, Cynthia A.
AU - Judge, Daniel P.
AU - Murray, Brittney
AU - Barc, Julien
AU - Probst, Vincent
AU - Schott, Jean Jacques
AU - Song, Jiang Ping
AU - Hauer, Richard N.W.
AU - Hoorntje, Edgar T.
AU - Van Tintelen, J. Peter
AU - Schulze-Bahr, Eric
AU - Hamilton, Robert M.
AU - Mittal, Kirti
AU - Semsarian, Christopher
AU - Behr, Elijah R.
AU - Ackerman, Michael J.
AU - Basso, Cristina
AU - Parati, Gianfranco
AU - Gentilini, Davide
AU - Kotta, Maria Christina
AU - Mayosi, Bongani M.
AU - Schwartz, Peter J.
AU - Crotti, Lia
N1 - Publisher Copyright:
© 2021 American Heart Association, Inc.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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.
AB - 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.
KW - Cadherins
KW - Cardiomyopathy
KW - Mutation
KW - Sudden cardiac death
KW - Tachycardia
UR - https://www.scopus.com/pages/publications/85104674276
UR - https://www.scopus.com/pages/publications/85104674276#tab=citedBy
U2 - 10.1161/CIRCGEN.120.003097
DO - 10.1161/CIRCGEN.120.003097
M3 - Article
C2 - 33566628
AN - SCOPUS:85104674276
SN - 1942-325X
VL - 14
SP - E003097
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 2
ER -