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

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

doi:10.3389/fmed.2022.944950

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

Front Med (Lausanne). 2022 Aug 30:9:944950. doi: 10.3389/fmed.2022.944950. eCollection 2022.

Authors

Yuanying Chen^{1

2}, Qiqing Sun³, Chanjuan Hao^{1

2}, Ruolan Guo^{1

2}, Chentong Wang^{1

2}, Weili Yang², Yaodong Zhang², Fangjie Wang³, Wei Li^{1

2}, Jun Guo^{1

2}

Affiliations

¹ Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Capital Medical University, Center of Rare Diseases, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China.
² Henan Key Laboratory of Pediatric Inherited and Metabolic Diseases, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Hospital of Beijing Children's Hospital, Zhengzhou, China.
³ Department of Cardiology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou Hospital of Beijing Children's Hospital, Zhengzhou, China.

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. Deficiency of CDH2 is associated with arrhythmogenic right ventricular cardiomyopathy (OMIM: 618920) and agenesis of the corpus callosum, cardiac, ocular, and genital syndrome (OMIM: 618929). However, 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, c.474G>C/p.Lys158Asn (NM_001792.5). This variant has not been reported in the ClinVar or Human Gene Mutation Database (HGMD). CDH2 p.Lys158Asn was found in the conserved domain of N-cadherin, which is associated with the 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 and two previously reported variants in CDH2 as positive controls. 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.

Keywords: N-cadherin; cell-cell adhesion; de novo variant; dilated cardiomyopathy; whole exome sequencing.