De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects.

Journal Article (Journal Article)

Cadherins constitute a family of transmembrane proteins that mediate calcium-dependent cell-cell adhesion. The extracellular domain of cadherins consists of extracellular cadherin (EC) domains, separated by calcium binding sites. The EC interacts with other cadherin molecules in cis and in trans to mechanically hold apposing cell surfaces together. CDH2 encodes N-cadherin, whose essential roles in neural development include neuronal migration and axon pathfinding. However, CDH2 has not yet been linked to a Mendelian neurodevelopmental disorder. Here, we report de novo heterozygous pathogenic variants (seven missense, two frameshift) in CDH2 in nine individuals with a syndromic neurodevelopmental disorder characterized by global developmental delay and/or intellectual disability, variable axon pathfinding defects (corpus callosum agenesis or hypoplasia, mirror movements, Duane anomaly), and ocular, cardiac, and genital anomalies. All seven missense variants (c.1057G>A [p.Asp353Asn]; c.1789G>A [p.Asp597Asn]; c.1789G>T [p.Asp597Tyr]; c.1802A>C [p.Asn601Thr]; c.1839C>G [p.Cys613Trp]; c.1880A>G [p.Asp627Gly]; c.2027A>G [p.Tyr676Cys]) result in substitution of highly conserved residues, and six of seven cluster within EC domains 4 and 5. Four of the substitutions affect the calcium-binding site in the EC4-EC5 interdomain. We show that cells expressing these variants in the EC4-EC5 domains have a defect in cell-cell adhesion; this defect includes impaired binding in trans with N-cadherin-WT expressed on apposing cells. The two frameshift variants (c.2563_2564delCT [p.Leu855Valfs∗4]; c.2564_2567dupTGTT [p.Leu856Phefs∗5]) are predicted to lead to a truncated cytoplasmic domain. Our study demonstrates that de novo heterozygous variants in CDH2 impair the adhesive activity of N-cadherin, resulting in a multisystemic developmental disorder, that could be named ACOG syndrome (agenesis of corpus callosum, axon pathfinding, cardiac, ocular, and genital defects).

Full Text

Duke Authors

Cited Authors

  • Accogli, A; Calabretta, S; St-Onge, J; Boudrahem-Addour, N; Dionne-Laporte, A; Joset, P; Azzarello-Burri, S; Rauch, A; Krier, J; Fieg, E; Pallais, JC; Undiagnosed Diseases Network, ; McConkie-Rosell, A; McDonald, M; Freedman, SF; Rivière, J-B; Lafond-Lapalme, J; Simpson, BN; Hopkin, RJ; Trimouille, A; Van-Gils, J; Begtrup, A; McWalter, K; Delphine, H; Keren, B; Genevieve, D; Argilli, E; Sherr, EH; Severino, M; Rouleau, GA; Yam, PT; Charron, F; Srour, M

Published Date

  • October 3, 2019

Published In

Volume / Issue

  • 105 / 4

Start / End Page

  • 854 - 868

PubMed ID

  • 31585109

Pubmed Central ID

  • PMC6817525

Electronic International Standard Serial Number (EISSN)

  • 1537-6605

Digital Object Identifier (DOI)

  • 10.1016/j.ajhg.2019.09.005


  • eng

Conference Location

  • United States