Ghidoni, A;
Elliott, PM;
Syrris, P;
Calkins, H;
James, CA;
Judge, DP;
Murray, B;
Barc, J;
Probst, V;
Schott, J-J;
et al.
Ghidoni, A; Elliott, PM; Syrris, P; Calkins, H; James, CA; Judge, DP; Murray, B; Barc, J; Probst, V; Schott, J-J; Song, J-P; Hauer, RNW; Hoorntje, ET; van Tintelen, JP; Schulze-Bahr, E; Hamilton, RM; Mittal, K; Semsarian, C; Behr, ER; Ackerman, MJ; Basso, C; Parati, G; Gentilini, D; Kotta, M-C; Mayosi, BM; Schwartz, PJ; Crotti, L
(2021)
Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features.
Circ Genom Precis Med, 14 (2).
e003097.
ISSN 2574-8300
https://doi.org/10.1161/CIRCGEN.120.003097
SGUL Authors: Behr, Elijah Raphael
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Abstract
Background - Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by fibro-fatty replacement of the right and/or 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 non-desmosomal 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 assessed. Results - Genetic screening of CDH2 led to the identification of 7 rare variants: five, 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/or 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.
Item Type: |
Article
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Additional Information: |
This is a non-final version of an article published in final form in Ghidoni, A; Elliott, PM; Syrris, P; Calkins, H; James, CA; Judge, DP; Murray, B; Barc, J; Probst, V; Schott, J-J; et al. (2021) Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features. Circ Genom Precis Med, 14 (2). e003097. |
Keywords: |
next generation sequencing |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Circ Genom Precis Med |
ISSN: |
2574-8300 |
Language: |
eng |
Dates: |
Date | Event |
---|
April 2021 | Published | 10 February 2021 | Published Online | 18 January 2021 | Accepted |
|
Publisher License: |
Publisher's own licence |
Projects: |
Project ID | Funder | Funder ID |
---|
2018-ATE-0359 | University of Milano Bicocca | UNSPECIFIED | JTC-2018-026 | ERA-CVD | UNSPECIFIED | 2UM1HG006542 | Baylor-Hopkins Center for Mendelian Genomics | UNSPECIFIED | Equipe FRM DEQ20140329545 | Fondation pour la Recherche Médicale | http://dx.doi.org/10.13039/501100002915 | ANR-14-CE10-0001-01 | Agence National de la Recherche | UNSPECIFIED | RISTRAD-661617 | Horizon 2020 | UNSPECIFIED | CVON2012-10 | Dutch Heart Foundation | UNSPECIFIED | CVON2018-30 PREDICT2 | Dutch Heart Foundation | UNSPECIFIED | CVON2015-12 eDETECT | Dutch Heart Foundation | UNSPECIFIED | 1154992 | National Health and Medical Research Council | http://dx.doi.org/10.13039/501100000925 |
|
PubMed ID: |
33566628 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/112972 |
Publisher's version: |
https://doi.org/10.1161/CIRCGEN.120.003097 |
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