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

Andrea Accogli 1, 2 Sara Calabretta 3 Judith St-Onge 1 Nassima Boudrahem-Addour 1 Alexandre Dionne-Laporte 4 Pascal Joset 5 Silvia Azzarello-Burri 6 Anita Rauch 5 Juan Pallais 7 Marie Mcdonald 8 Sharon Freedman 9 Jean-Baptiste Rivière 10, 1 Joël Lafond-Lapalme 1 Brittany Simpson 11 Robert Hopkin 12 Aurelien Trimouille 13 Julien Van-Gils 14 Amber Begtrup 15 Kirsty Mcwalter 15 Heron Delphine 16 Boris Keren 16 David Geneviève 17 Emanuela Argilli 18 Elliott Sherr 18 Mariasavina Severino 19 Guy Rouleau 1 Patricia Yam 3 Frédéric Charron 1 Myriam Srour 1 Maria Acosta David Adams 20 Pankaj Agrawal 21 Mercedes Alejandro Patrick Allard 22 Justin Alvey Ashley Andrews Euan Ashley Mahshid Azamian Carlos Bacino Guney Bademci Eva Baker Ashok Balasubramanyam Dustin Baldridge Jim Bale Deborah Barbouth Gabriel Batzli Pinar Bayrak-Toydemir Alan Beggs 23 Gill Bejerano 24 Hugo Bellen Jonathan Bernstein 25 Anna Bican David Bick Camille Birch Stephanie Bivona John Bohnsack Carsten Bonnenmann Devon Bonner Braden Boone 26 Bret Bostwick Lorenzo Botto 27 Lauren Briere Elly Brokamp Donna Brown Matthew Brush Elizabeth Burke Lindsay Burrage Manish Butte John Carey 28 Olveen Carrasquillo Ta Chen Peter Chang Hsiao-Tuan Chao Gary Clark Terra Coakley Laurel Cobban Joy Cogan F. Sessions Cole Heather Colley Cynthia Cooper Heidi Cope William Craigen 29 Precilla D’souza Surendra Dasari 30 Mariska Davids Jyoti Dayal Esteban Dell’angelica Shweta Dhar Naghmeh Dorrani Daniel Dorset Emilie Douine David Draper Laura Duncan David Eckstein Lisa Emrick Christine Eng Cecilia Esteves Tyra Estwick Liliana Fernandez Carlos Ferreira 31 Elizabeth Fieg Paul Fisher Brent Fogel Irman Forghani Laure Fresard 32 William Gahl Rena Godfrey Alica Goldman David Goldstein Jean-Philippe Gourdine Alana Grajewski Catherine Groden Andrea Gropman 33 Melissa Haendel 34 Rizwan Hamid Neil Hanchard 35 Nichole Hayes Frances High Ingrid Holm Jason Hom Alden Huang Yong Huang Rosario Isasi Fariha Jamal Yong-Hui Jiang Jean Johnston Angela Jones Lefkothea Karaviti Emily Kelley Dana Kiley David Koeller Isaac Kohane 36 Jennefer Kohler 37 Deborah Krakow 38 Donna Krasnewich Susan Korrick Mary Koziura Joël Krier 7 Jennifer Kyle Seema Lalani Byron Lam Brendan Lanpher Ian Lanza C. Christopher Lau Jozef Lazar Kimberly Leblanc Brendan Lee 39 Hane Lee Roy Levitt Shawn Levy 26 Richard Lewis 40 Sharyn Lincoln 41 Pengfei Liu 42 Xue Zhong Liu Nicola Longo Sandra Loo 43 Joseph Loscalzo Richard Maas Ellen Macnamara Calum Macrae Valerie Maduro Marta Majcherska May Christine V. Malicdan Laura Mamounas Teri Manolio Rong Mao Thomas Markello Ronit Marom Gabor Marth Beth Martin Martin Martin Julian Martinez-Agosto 44 Shruti Marwaha Thomas May Jacob Mccauley Allyn Mcconkie-Rosell Colleen Mccormack Alexa Mccray Thomas Metz 45 Matthew Might Eva Morava-Kozicz Paolo Moretti 46 Marie Morimoto John Mulvihill David Murdock Avi Nath Stan Nelson 47 J. Scott Newberry John Newman Sarah Nicholas Donna Novacic Devin Oglesbee James Orengo Laura Pace Stephen Pak J. Carl Pallais Christina G.S. Palmer Jeanette Papp Neil Parker John Phillips 48 Jennifer Posey John Postlethwait 49 Lorraine Potocki 39 Barbara Pusey Aaron Quinlan Archana Raja Genecee Renteria Chloe Reuter Lynette Rives Amy Robertson Lance Rodan 50 Jill Rosenfeld 51 Robb Rowley Maura Ruzhnikov Ralph Sacco 52 Jacinda Sampson Susan Samson Mario Saporta Judy Schaechter Timothy Schedl Kelly Schoch 8 Daryl Scott Lisa Shakachite Prashant Sharma Vandana Shashi 8 Kathleen Shields Jimann Shin Rebecca Signer Catherine Sillari Edwin Silverman Janet Sinsheimer Kathy Sisco Kevin Smith Lilianna Solnica-Krezel 53 Rebecca Spillmann Joan Stoler Nicholas Stong 54 Jennifer Sullivan 55 Shirley Sutton 56 David Sweetser Holly Tabor Cecelia Tamburro Queenie K.-G. Tan Mustafa Tekin 57 Fred Telischi Willa Thorson Cynthia Tifft Camilo Toro Alyssa Tran Tiina Urv Matt Velinder Dave Viskochil Tiphanie Vogel Colleen Wahl Nicole Walley Chris Walsh Melissa Walker Jennifer Wambach Jijun Wan Lee-Kai Wang Michael Wangler Patricia Ward Katrina Waters Bobbie-Jo Webb-Robertson 45 Daniel Wegner Monte Westerfield 58 Matthew Wheeler Anastasia Wise Lynne Wolfe Jeremy Woods Elizabeth Worthey Shinya Yamamoto 59 John Yang Amanda Yoon Guoyun Yu Diane Zastrow Chunli Zhao Stephan Züchner 60 Geneviève David 17 Gerard T. Berry
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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).
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https://hal.umontpellier.fr/hal-02556784
Contributeur : Nathalie Salvy-Cordoba <>
Soumis le : mardi 28 avril 2020 - 11:45:32
Dernière modification le : mercredi 14 octobre 2020 - 03:48:59

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Andrea Accogli, Sara Calabretta, Judith St-Onge, Nassima Boudrahem-Addour, Alexandre Dionne-Laporte, et al.. De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Callosum, Axon, Cardiac, Ocular, and Genital Defects. American Journal of Human Genetics, Elsevier (Cell Press), 2019, 105 (4), pp.854-868. ⟨10.1016/j.ajhg.2019.09.005⟩. ⟨hal-02556784⟩

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