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Identification of a novel variant in N-cadherin associated with dilated cardiomyopathy
Yuanying Chen1,2, Qiqing Sun3, Chanjuan Hao1,2
1Beijing 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.
Insights
Dilated cardiomyopathy (DCM) can be caused by genetic mutations. Researchers identified a novel CDH2 gene variant in a young patient with DCM, expanding the known genetic causes of this heart condition.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Dilated cardiomyopathy (DCM) is a primary cardiac muscle disease causing heart failure with high morbidity and mortality.
- DCM is genetically heritable, with over 10 implicated gene ontologies.
- CDH2 encodes N-cadherin, a transmembrane protein crucial for cell-cell adhesion; its deficiency is linked to other heart conditions, but not isolated DCM.
Purpose of the Study:
- To investigate the genetic basis of non-syndromic DCM in a 12-year-old girl.
- To identify novel gene variants associated with DCM through whole exome sequencing.
- To confirm the pathogenicity of identified variants through functional experiments.
Main Methods:
- Whole exome sequencing was performed on a patient with non-syndromic DCM and her unaffected parents.
- Analysis of variants in known DCM-related genes and novel candidate genes.
- Pathogenicity confirmation experiments, including cell-cell adhesion assays for CDH2 variants.
Main Results:
- No pathogenic variants were found in known DCM-related genes.
- A de novo CDH2 variant (c.474G>C/p.Lys158Asn) was identified in the patient.
- Functional studies showed impaired cell-cell adhesion with the mutated CDH2 protein, suggesting pathogenicity.
Conclusions:
- A CDH2 variant was identified as a cause of DCM in this patient.
- This finding reveals a new clinical manifestation associated with N-cadherin deficiency.
- The study broadens the genetic spectrum of DCM and highlights CDH2 as a potential causative gene.
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.
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