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Am J Hum Genet. 2019 Oct 3;105(4):854-868. doi: 10.1016/j.ajhg.2019.09.005.

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

Collaborators (249)

Acosta MT, Adams DR, Agrawal P, Alejandro ME, Allard P, Alvey J, Andrews A, Ashley EA, Azamian MS, Bacino CA, Bademci G, Baker E, Balasubramanyam A, Baldridge D, Bale J, Barbouth D, Batzli GF, Bayrak-Toydemir P, Beggs AH, Bejerano G, Bellen HJ, Bernstein JA, Berry GT, Bican A, Bick DP, Birch CL, Bivona S, Bohnsack J, Bonnenmann C, Bonner D, Boone BE, Bostwick BL, Botto L, Briere LC, Brokamp E, Brown DM, Brush M, Burke EA, Burrage LC, Butte MJ, Carey J, Carrasquillo O, Chang TCP, Chao HT, Clark GD, Coakley TR, Cobban LA, Cogan JD, Cole FS, Colley HA, Cooper CM, Cope H, Craigen WJ, D'Souza P, Dasari S, Davids M, Dayal JG, Dell'Angelica EC, Dhar SU, Dorrani N, Dorset DC, Douine ED, Draper DD, Duncan L, Eckstein DJ, Emrick LT, Eng CM, Esteves C, Estwick T, Fernandez L, Ferreira C, Fieg EL, Fisher PG, Fogel BL, Forghani I, Fresard L, Gahl WA, Godfrey RA, Goldman AM, Goldstein DB, Gourdine JF, Grajewski A, Groden CA, Gropman AL, Haendel M, Hamid R, Hanchard NA, Hayes N, High F, Holm IA, Hom J, Huang A, Huang Y, Isasi R, Jamal F, Jiang YH, Johnston JM, Jones AL, Karaviti L, Kelley EG, Kiley D, Koeller DM, Kohane IS, Kohler JN, Krakow D, Krasnewich DM, Korrick S, Koziura M, Krier JB, Kyle JE, Lalani SR, Lam B, Lanpher BC, Lanza IR, Lau CC, Lazar J, LeBlanc K, Lee BH, Lee H, Levitt R, Levy SE, Lewis RA, Lincoln SA, Liu P, Liu XZ, Longo N, Loo SK, Loscalzo J, Maas RL, Macnamara EF, MacRae CA, Maduro VV, Majcherska MM, Malicdan MCV, Mamounas LA, Manolio TA, Mao R, Markello TC, Marom R, Marth G, Martin BA, Martin MG, Martínez-Agosto JA, Marwaha S, May T, McCauley J, McConkie-Rosell A, McCormack CE, McCray AT, Metz TO, Might M, Morava-Kozicz E, Moretti PM, Morimoto M, Mulvihill JJ, Murdock DR, Nath A, Nelson SF, Newberry JS, Newman JH, Nicholas SK, Novacic D, Oglesbee D, Orengo JP, Pace L, Pak S, Pallais JC, Palmer CGS, Papp JC, Parker NH, Phillips JA 3rd, Posey JE, Postlethwait JH, Potocki L, Pusey BN, Quinlan A, Raja AN, Renteria G, Reuter CM, Rives L, Robertson AK, Rodan LH, Rosenfeld JA, Rowley RK, Ruzhnikov M, Sacco R, Sampson JB, Samson SL, Saporta M, Schaechter J, Schedl T, Schoch K, Scott DA, Shakachite L, Sharma P, Shashi V, Shields K, Shin J, Signer R, Sillari CH, Silverman EK, Sinsheimer JS, Sisco K, Smith KS, Solnica-Krezel L, Spillmann RC, Stoler JM, Stong N, Sullivan JA, Sutton S, Sweetser DA, Tabor HK, Tamburro CP, Tan QK, Tekin M, Telischi F, Thorson W, Tifft CJ, Toro C, Tran AA, Urv TK, Velinder M, Viskochil D, Vogel TP, Wahl CE, Walley NM, Walsh CA, Walker M, Wambach J, Wan J, Wang LK, Wangler MF, Ward PA, Waters KM, Webb-Robertson BM, Wegner D, Westerfield M, Wheeler MT, Wise AL, Wolfe LA, Woods JD, Worthey EA, Yamamoto S, Yang J, Yoon AJ, Yu G, Zastrow DB, Zhao C, Zuchner S.

Author information

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.

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.Leu855Valfs4]; c.2564_2567dupTGTT [p.Leu856Phefs5]) 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

PMID:
31585109
PMCID:
PMC6817525
[Available on 2020-04-03]
DOI:
10.1016/j.ajhg.2019.09.005

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