CDH2

Inheritance Pattern: AD

Disease ID:MONDO:0030065

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: ClinGen

There is moderate evidence that CDH2 is associated with ARVC. The first publication that associated TJP1 with ARVC was published in 2017 (28280076) and described two families: one family with five affected with p.Gln229Pro. The phenotype was consistent with ARVC. The second family was one proband with clear ARVC phenotype that carried p.Asp407Asn. A second publication in 2017 also identified in a Norwegian family the same variant, p.Asp407Asn in a family with biventricular ARVC phenotype. There is some experimental evidence in a KO mouse (15662031) that that CDH2 disruption leads to dissolution of desmosomes and area composite, cardiomyopathy, VT, and SCD. However, these are not missense variants as reported in the patients. There is emerging evidence that CDH2 mutations are associated with an ARVC phenotype, but additional information on mechanisms of disease, and pathogenicity of missense vs. truncating variants is still missing.

Inheritance Pattern: AD

Disease ID:MONDO:0030062

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0030065

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0030062

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

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).

Inheritance Pattern: AD

Disease ID:MONDO:0030065

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030062

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0016587

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0030065

Submitter: ClinGen

The *CDH2* gene is located on chromosome 18 at 18q12.1, and encodes cadherin-2, a calcium-dependent cell adhesion protein that mediates cell-cell adhesion. *CDH2* was first reported in relation to autosomal dominant agenesis of corpus callosum, cardiac, ocular, and genital syndrome (ACOGS) in 2019 (Accogli et al., 2019, PMID: 31585109). Features associated with ACOGS most commonly include developmental delay and/or intellectual disability, callosal malformations, cardiac abnormalities, ocular abnormalities (often Peters anomaly), genital anomalies in males, and facial dysmorphism. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic presentation. Therefore the following disease entities have been split, arrhythmogenic right ventricular dysplasia (OMIM:618920) and dilated cardiomyopathy (MONDO:0005021) have been curated separately. This curation includes 16 patients from six different publications harbouring 15 different *CDH2* variants - ten missense, two frameshift, one canonical splice-site and two stop-gain variants. The variants were confirmed to arise de novo in 14 cases (PMID: 31585109; Reis et al., Nov 2019, PMID: 31650526; Meng & Gong, 2021, PMID: 34711036; Kanjee et al., 2022, PMID: 35708058; Westenius et al., 2024, PMID: 38268232, Abdul Rahman et al., 2025, PMID: 40293216). The maximum points (12 pts) were reached for genetic evidence. This gene-disease relationship is supported by experimental data including biochemical function and model organism data. The curation includes two mouse models supportive of disease association. Mice with a conditional inactivation of N-cadherin in the cerebral cortex display cortical disorganization and lack a corpus callosum (Kadowaki et al., 2007, PMID:17222817). Conditional cdh2 knockout (Lens-Cre+,Cdh2flox/neo) mouse embryos presented with a small eye phenotype with severe lens deterioration and hyperplastic iris development. In addition, two zebrafish models were curated but not scored due to lack of controls needed for inclusion here. A cdh2 knockout zebrafish model showed early lethality, as well as several anomalies such as absence of somites, microphthalmia, malformations throughout the body and head, and cardiac deformity (Ferreira et al., 2023, PMID: 37166408). A CRISPR knockdown of cdh2 in zebrafish resulted in head and brain malformations and developmental delay (Fernandes et al., 2024, PMID: 39449741). In summary, there is definitive evidence supporting the gene-disease relationship between *CDH2* and autosomal dominant agenesis of corpus callosum, cardiac, ocular, and genital syndrome. This has been repeatedly demonstrated in literature, and has been upheld over time. This classification was approved by the ClinGen Syndromic disease GCEP on the meeting date March 20, 2026 (SOP Version 12).