Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features

Alice Ghidoni, Perry M. Elliott, Petros Syrris, Hugh Calkins, Cynthia A. James, Daniel P. Judge, Brittney Murray, Julien Barc, Vincent Probst, Jean Jacques Schott, Jiang Ping Song, Richard N.W. Hauer, Edgar T. Hoorntje, J. Peter Van Tintelen, Eric Schulze-Bahr, Robert M. Hamilton, Kirti Mittal, Christopher Semsarian, Elijah R. Behr, Michael J. AckermanCristina Basso, Gianfranco Parati, Davide Gentilini, Maria Christina Kotta, Bongani M. Mayosi, Peter J. Schwartz, Lia Crotti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number003097
Pages (from-to)159-169
Number of pages11
JournalCirculation: Genomic and Precision Medicine
DOIs
StateAccepted/In press - 2021

Keywords

  • cadherins
  • cardiomyopathy
  • mutation
  • sudden cardiac death
  • tachycardia

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

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