Submission Details

CDH2 was evaluated for autosomal dominant dilated cardiomyopathy (DCM). In addition to DCM, CDH2 has also been reported with arrhythmogenic right ventricular cardiomyopathy (ARVC) in the literature and curated by the Arrhythmogenic Right Ventricular Cardiomyopathy Gene Curation Expert Panel for autosomal dominant ARVC (Limited evidence, July 2018). This was considered in accordance with ClinGen lumping and splitting criteria. Due to distinct phenotypic variability (left-sided findings specifically and not meeting clinical criteria for classical ARVC, as previously defined), the curation was split and curated for autosomal dominant DCM.

Human genetic evidence supporting this gene-disease relationship includes case level evidence was reviewed across 7 primary publications, with scorable evidence present in 1 primary publication. In brief, Chen et al. reported a DCM case of a 12-year-old female of Chinese ancestry identified to harbor a rare CDH2 heterozygous, de novo variant via whole exome trio sequencing (Chen et al. 2022, PMID: 36111109) with functional variant level evidence showing significantly decreased cell-cell adhesion in vitro and no other variants identified in 51 DCM-associated genes. While additional probands were reported across 6 additional publications reviewed, evidence was limited and not scored due to limited clinical details to confirm a DCM phenotype, presence of additional cardiovascular disease such as congenital heart defects, or due to unknown investigation and exclusion of additional variants in high-evidence DCM associated genes (Mayosi et al. 2017, PMID: 28280076; Ghidoni et al 2021, PMID: 33566628; Turkoswki et al 2016, PMID: 26753747; Marinas et al 2024, PMID: 38892455; Li et al 2023, PMID: 38075981; Luo et al 2023, PMID: 36961336).

In addition, this gene-disease assertion is supported by biochemical function, expression, non-human model organism evidence, and rescue across 4 scorable primary publications. In brief, Chaffin et al. 1995, PMID: 35732739 showed high CDH2 expression in cardiomyocytes through single-nuclear RNA sequencing of heart tissue from 11 DCM hearts, 15 HCM hearts, and 16 non-failing hearts. Yukinobu et al 2021, PMID: 34088908 identified key morphological and cellular differences between 5 DCM hearts, 9 chronic heart failure samples, and 8 control hearts revealing intercalated discs disruption in DCM compared to control and decreased N-cadherin staining. Kostetskii et al 2005, PMID: 15662031 investigated a conditional knock-out of CDH2 in myocardium in mice via a Cre/loxP tamoxifen-induced model. Loss of CDH2 compared to controls revealed loss of sarcomere structure, intercalated disc proteins and structure, and mice developed a cardiomyopathy phenotype (increased LVEDV, LVESV, and reduced LVEF and cardiac output) consistent with a non-human DCM model. Tsai et al 2025, PMID: 39837836 investigated overexpression of CDH2 via AAV9-based models in mice with ischemia induced via LAD ligation. Overexpression of CDH2 after ischemia showed improved recovery of LVEF and decrease in LV enlargement suggestive of rescue of this cardiomyopathy phenotype.

In summary, there is limited evidence to support this gene-disease relationship. More evidence is needed to support the relationship of CDH2 with autosomal dominant DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 16th, 2025 (SOP Version 10).