TY  - EJOU
AU  - Turkowski, Kari L. 
AU  - Tester, David J. 
AU  - Bos, J. Martijn 
AU  - Haugaa, Kristina H. 
AU  - Ackerman, Michael J. 

TI  - Whole exome sequencing with genomic triangulation implicates <i>CDH2</i>-encoded N-cadherin as a novel pathogenic substrate for arrhythmogenic cardiomyopathy
T2  - Structural and Congenital Heart Disease

PY  - 2017
VL  - 12
IS  - 2
SN  - 3071-1738

AB  - Background: Arrhythmogenic cardiomyopathy (ACM) is a heritable disease characterized by fibrofatty replacement of cardiomyocytes, has a prevalence of approximately 1 in 5000 individuals, and
accounts for approximately 20% of sudden cardiac death in the young (≤35 years). ACM is most
often inherited as an autosomal dominant trait with incomplete penetrance and variable expression. While mutations in several genes that encode key desmosomal proteins underlie about half
of all ACM, the remainder is elusive genetically.
Objective: Here, whole exome sequencing (WES) was performed with genomic triangulation in an
effort to identify a novel explanation for a phenotype-positive, genotype-negative multigenerational pedigree with a presumed autosomal dominant, maternal inheritance of ACM.
Methods: WES and genomic triangulation was performed on a symptomatic 14-year-old
female proband, her affected mother and affected sister, and her unaffected father to elucidate a novel ACM-susceptibility gene for this pedigree. Following variant filtering using
Ingenuity® Variant Analysis, gene priority ranking was performed on the candidate genes using
ToppGene and Endeavour. The phylogenetic and physiochemical properties of candidate mutations were assessed further by 6 in silico prediction tools. Species alignment and amino acid
conservation analysis was performed using the Uniprot Consortium. Tissue expression data
was abstracted from Expression Atlas.
Results: Following WES and genomic triangulation, <i>CDH2</i> emerged as a novel, autosomal dominant, ACM-susceptibility gene. The <i>CDH2</i>-encoded N-cadherin is a cell-cell adhesion protein
predominately expressed in the heart. Cardiac dysfunction has been demonstrated in prior <i>CDH2</i>
knockout and over-expression animal studies. Further in silico mutation prediction, species conservation, and protein expression analysis supported the ultra-rare (minor allele frequency <0.005%)
p.Asp407Asn-CDH2 variant as a likely pathogenic variant.
Conclusions: Herein, it is demonstrated that genetic mutations in <i>CDH2</i>-encoded N-cadherin may
represent a novel pathogenetic basis for ACM in humans. The prevalence of CDH2-mediated
ACM in heretofore genetically elusive ACM remains to be determined.
KW  - area composita
KW  -  arrhythmogenic right ventricular cardiomyopathy
KW  -  desmosome
KW  -  N-cadherin
KW  -  sudden cardiac death
KW  -  ARVC

DO  - 10.1111/chd.12462