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Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy
Insights
Mutations in the CDH2 gene are identified as a novel genetic cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). This discovery helps identify more disease genes for ARVC, improving genetic diagnosis for affected families.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Cardiomyopathies
Background:
- Arrhythmogenic right ventricular cardiomyopathy (ARVC) is genetically diverse, with mutations in desmosomal genes identified in 60% of cases.
- A significant proportion of ARVC cases (40%) remain genotype-negative, necessitating the identification of novel genetic contributors.
- Studying genotype-negative ARVC families is crucial for uncovering new genetic substrates of the disease.
Purpose of the Study:
- To identify novel genetic causes of arrhythmogenic right ventricular cardiomyopathy (ARVC) in genotype-negative families.
- To investigate the role of the cadherin 2 (CDH2) gene in ARVC pathogenesis.
- To expand the spectrum of known genetic factors implicated in cardiomyopathies.
Main Methods:
- Whole exome sequencing was employed to analyze genetic variations in ARVC patients.
- Sanger sequencing and high-resolution melting analysis were used for variant validation and mutation screening in the CDH2 gene.
- Genotype-phenotype cosegregation analysis was performed within affected families to confirm causality.
Main Results:
- A novel mutation (c.686A>C, p.Gln229Pro) in the CDH2 gene was identified in a 3-generation family with ARVC, cosegregating with the disease.
- The identified CDH2 variant was absent in large population databases and altered a conserved amino acid, supported by linkage analysis.
- An additional likely pathogenic variant in CDH2 (c.1219G>A, p.Asp407Asn) was found in 73 genotype-negative ARVC probands.
Conclusions:
- Mutations in the CDH2 gene are implicated as novel genetic causes of arrhythmogenic right ventricular cardiomyopathy (ARVC).
- These findings contribute to a more comprehensive understanding of the genetic landscape of ARVC.
- The study highlights CDH2's role in cell adhesion as a plausible mechanism in ARVC pathogenesis.
Background:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families.
Methods And Results:
Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype-phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 (CDH2) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in CDH2 (c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The CDH2 c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in CDH2 (c.1219G>A, p.Asp407Asn). CDH2 encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis.
Conclusions:
These data implicate CDH2 mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.
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