title: Identification of Cadherin 2 (CDH2) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy.
abstract: 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.
  
  
  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 inCDH2(c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. TheCDH2c.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 inCDH2(c.1219G>A, p.Asp407Asn).CDH2encodes 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 implicateCDH2mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.
authors.forename: Bongani M
authors.initials: BM
authors.lastname: Mayosi
authors.forename: Maryam
authors.initials: M
authors.lastname: Fish
authors.forename: Gasnat
authors.initials: G
authors.lastname: Shaboodien
authors.forename: Elisa
authors.initials: E
authors.lastname: Mastantuono
authors.forename: Sarah
authors.initials: S
authors.lastname: Kraus
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieland
authors.forename: Maria-Christina
authors.initials: MC
authors.lastname: Kotta
authors.forename: Ashley
authors.initials: A
authors.lastname: Chin
authors.forename: Nakita
authors.initials: N
authors.lastname: Laing
authors.forename: Ntobeko B A
authors.initials: NB
authors.lastname: Ntusi
authors.forename: Michael
authors.initials: M
authors.lastname: Chong
authors.forename: Christopher
authors.initials: C
authors.lastname: Horsfall
authors.forename: Simon N
authors.initials: SN
authors.lastname: Pimstone
authors.forename: Davide
authors.initials: D
authors.lastname: Gentilini
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Parati
authors.forename: Tim-Matthias
authors.initials: TM
authors.lastname: Strom
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pare
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Schwartz
authors.forename: Lia
authors.initials: L
authors.lastname: Crotti
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D015703:Antigens, CD / Q000235:genetics*; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins
keywords: arrhythmogenic right ventricular dysplasia; cadherins; cardiomyopathies; genetics; mutation