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

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

  • Am J Hum Genet. 2019 Oct 3;105(4):854-868. doi: 10.1016/j.ajhg.2019.09.005.
Andrea Accogli 1,  Sara Calabretta 2,  Judith St-Onge 3,  Nassima Boudrahem-Addour 3,  Alexandre Dionne-Laporte 4,  Pascal Joset 5,  Silvia Azzarello-Burri 5,  Anita Rauch 5,  Joel Krier 6,  Elizabeth Fieg 6,  Juan C Pallais 6,  Undiagnosed Diseases Network,  Allyn McConkie-Rosell 7,  Marie McDonald 7,  Sharon F Freedman 8,  Jean-Baptiste Rivière 3,  Joël Lafond-Lapalme 3,  Brittany N Simpson 9,  Robert J Hopkin 9,  Aurélien Trimouille 10,  Julien Van-Gils 10,  Amber Begtrup 11,  Kirsty McWalter 11,  Heron Delphine 12,  Boris Keren 12,  David Genevieve 13,  Emanuela Argilli 14,  Elliott H Sherr 14,  Mariasavina Severino 15,  Guy A Rouleau 16,  Patricia T Yam 2,  Frédéric Charron 17,  Myriam Srour 18
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Pediatric Neurology, McGill University, H4A 3J1, Montreal, QC, Canada; Medical Genetics Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genova, Italy; Dipartimento di Neuroscienze, Reabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili, Università degli Studi di Genova, 16132 Genova Italy.
  • 2 Montreal Clinical Research Institute, H2W 1R7 Montreal, QC, Canada.
  • 3 McGill University Health Center Research Institute, H4A 3J1, Montreal, QC, Canada.
  • 4 Montreal Neurological Institute, McGill University, H3A 2B4, Montreal, QC, Canada.
  • 5 Institute of Medical Genetics, University of Zurich, CH-8952 Schlieren, Switzerland.
  • 6 Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 7 Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27707, USA.
  • 8 Department of Ophthalmology, Duke University Medical Center, Durham, NC 27710, USA.
  • 9 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
  • 10 Centre Hospitalier Universitaire Bordeaux, Service de Génétique Médicale, 33076 Bordeaux, France; Laboratoire Maladies Rares: Génétique et Métabolisme, Inserm U1211, Université de Bordeaux, 33076 Bordeaux, France.
  • 11 GeneDx, Gaithersburg, MD 20877, USA.
  • 12 Département de Génétique, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 75013 Paris.
  • 13 Département de Genetique Médicale, Maladies Rares et Médecine Personnalisée, Centre de Référence Anomalies du Développement, Université Montpellier, Unité Inserm U1183, Centre Hospitalier Universitaire Montpellier, 34000 Montpellier, France.
  • 14 Departments of Neurology and Pediatrics, Weill Institute of Neuroscience and Institute of Human Genetics, University of California, CA 94143 San Francisco.
  • 15 Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Giannina Gaslini, 16147 Genova, Italy.
  • 16 Montreal Neurological Institute, McGill University, H3A 2B4, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, H3A 2B4, Montreal, QC, Canada.
  • 17 Montreal Clinical Research Institute, H2W 1R7 Montreal, QC, Canada; Department of Medicine, University of Montreal, H3C 3J7, Montreal, QC, Canada; Department of Anatomy and Cell Biology, McGill University, H4A 3J1, Montreal, QC, Canada; Department of Experimental Medicine, McGill University, H4A 3J1, Montreal, QC, Canada. Electronic address: frederic.charron@ircm.qc.ca.
  • 18 Department of Pediatrics, Division of Pediatric Neurology, McGill University, H4A 3J1, Montreal, QC, Canada; McGill University Health Center Research Institute, H4A 3J1, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, H3A 2B4, Montreal, QC, Canada. Electronic address: myriam.srour@mcgill.ca.
PMID: 31585109 DOI: 10.1016/j.ajhg.2019.09.005
Abstract

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).

Keywords

ACOG; CDH2; N-cadherin; cardiac defects; cell-cell adhesion; corpus callosum; eye defects; genital defects; intellectual disability.

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