Cadherin 2-Related Arrhythmogenic Cardiomyopathy: Prevalence and Clinical Features

Circ Genom Precis Med. 2021 Apr;14(2):e003097. doi: 10.1161/CIRCGEN.120.003097. Epub 2021 Feb 10.


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.

Keywords: cadherins; cardiomyopathy; mutation; sudden cardiac death; tachycardia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Arrhythmogenic Right Ventricular Dysplasia / diagnosis
  • Arrhythmogenic Right Ventricular Dysplasia / epidemiology
  • Arrhythmogenic Right Ventricular Dysplasia / genetics*
  • Cadherins / chemistry
  • Cadherins / genetics*
  • Female
  • Gene Frequency
  • Genetic Variation
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Prevalence
  • Protein Domains / genetics
  • Young Adult


  • Cadherins