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Whole exome sequencing with genomic triangulation implicates CDH2-encoded N-cadherin as a novel pathogenic substrate for arrhythmogenic cardiomyopathy

Kari L. Turkowski1, David J. Tester2,3, J. Martijn Bos2,4, Kristina H. Haugaa5, Michael J. Ackerman2,3,4

1 Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Rochester, Minnesota, USA
2 Department of Molecular Pharmacology & Experimental Therapeutics; Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota, USA
3 Department of Cardiovascular Diseases, Division of Heart Rhythm Services, Mayo Clinic, Rochester, Minnesota, USA
4 Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota, USA
5 Center for Cardiological Innovation, Department of Cardiology, Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo Norway and University of Oslo, Oslo, Norway

* Corresponding Author:Michael J. Ackerman, M.D., Ph.D., Windland Smith Rice Sudden Death Genomics Laboratory, Guggenheim 501, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Email: email

Congenital Heart Disease 2017, 12(2), 226-235.


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, CDH2 emerged as a novel, autosomal dominant, ACM-susceptibility gene. The CDH2-encoded N-cadherin is a cell-cell adhesion protein predominately expressed in the heart. Cardiac dysfunction has been demonstrated in prior CDH2 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 CDH2-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.


Cite This Article

Turkowski, K. L., Tester, D. J., Bos, J. M., Haugaa, K. H., Ackerman, M. J. (2017). Whole exome sequencing with genomic triangulation implicates CDH2-encoded N-cadherin as a novel pathogenic substrate for arrhythmogenic cardiomyopathy. Congenital Heart Disease, 12(2), 226–235.

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