AUTHOR=Chen Yuanying , Sun Qiqing , Hao Chanjuan , Guo Ruolan , Wang Chentong , Yang Weili , Zhang Yaodong , Wang Fangjie , Li Wei , Guo Jun 

TITLE=Identification of a novel variant in N-cadherin associated with dilated cardiomyopathy

JOURNAL=Frontiers in Medicine

VOLUME=Volume 9 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2022.944950

DOI=10.3389/fmed.2022.944950

ISSN=2296-858X

ABSTRACT=Background: Dilated cardiomyopathy (DCM), which is a major cause of heart failure, is a primary cardiac muscle disease with high morbidity and mortality rates. DCM is a genetically heritable disease and more than 10 gene ontologies have been implicated in DCM. CDH2 encodes N-cadherin and belongs to a superfamily of transmembrane proteins that mediate cell-cell adhesion in a calcium-dependent manner. There have been no reports of isolated DCM associated with CDH2 deficiency. 
Methods: We performed whole-exome sequencing in a 12-year-old girl with non-syndromic DCM and her unaffected parents. Variants in both known DCM-related genes and novel candidate genes were analyzed and pathogenicity confirmation experiments were performed.
Results: No pathogenic/likely pathogenic variant in known DCM-related genes was identified in the patient. We found a de novo variant in a candidate gene CDH2 in the patient, namely, NC_000018.9(NM_001792.5):c.474G>C, NP_001783.2:p.(Lys158Asn). CDH2 p.Lys158Asn was found in the conserved domain of N-cadherin, which is associated with hydrolysis of the precursor segment and interference with adhesiveness. Furthermore, we tested the expression and efficiency of cell-cell adhesion while overexpressing the CDH2 Lys158Asn mutant. The adhesion efficiency was considerably reduced in the presence of the mutated CDH2 protein compared with wild-type CDH2 protein, which suggested that the mutated CDH2 protein’s adhesion capacity was impaired. The variant was probably pathogenic after integrating clinical manifestations, genetic analysis, and functional tests. 
Conclusion: We identified a CDH2 variant in DCM. We observed a new clinical symptom associated with N-cadherin deficiency, and broadened the genetic spectra of DCM.