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

Andrea Accogli; Sara Calabretta; Judith St-Onge; Nassima Boudrahem-Addour; Alexandre Dionne-Laporte; Pascal Joset; Silvia Azzarello-Burri; Anita Rauch; Juan Pallais; Marie Mcdonald; Sharon Freedman; Jean-Baptiste Rivière; Joël Lafond-Lapalme; Brittany Simpson; Robert Hopkin; Aurelien Trimouille; Julien Van-Gils; Amber Begtrup; Kirsty Mcwalter; Heron Delphine; Boris Keren; David Geneviève; Emanuela Argilli; Elliott Sherr; Mariasavina Severino; Guy Rouleau; Patricia Yam; Frédéric Charron; Myriam Srour; Maria Acosta; David Adams; Pankaj Agrawal; Mercedes Alejandro; Patrick Allard; 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 H. Beggs; Gill Bejerano; Hugo Bellen; Jonathan Bernstein; Anna Bican; David Bick; Camille Birch; Stephanie Bivona; John Bohnsack; Carsten Bonnenmann; Devon Bonner; Braden E. Boone; Bret Bostwick; Lorenzo Botto; Lauren Briere; Elly Brokamp; Donna Brown; Matthew Brush; Elizabeth Burke; Lindsay Burrage; Manish Butte; John Carey; 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; Precilla D’souza; Surendra Dasari; 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 G. Ferreira; Elizabeth Fieg; Paul Fisher; Brent Fogel; Irman Forghani; Laure Fresard; William Gahl; Rena Godfrey; Alica Goldman; David Goldstein; Jean-Philippe Gourdine; Alana Grajewski; Catherine Groden; Andrea Gropman; Melissa Haendel; Rizwan Hamid; Neil A Hanchard; 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; Jennefer Kohler; Deborah Krakow; Donna Krasnewich; Susan Korrick; Mary Koziura; Joël Krier; Jennifer Kyle; Seema Lalani; Byron Lam; Brendan Lanpher; Ian Lanza; C. Christopher Lau; Jozef Lazar; Kimberly Leblanc; Brendan Lee; Hane Lee; Roy Levitt; Shawn E. Levy; Richard Lewis; Sharyn Lincoln; Pengfei Liu; Xue Zhong Liu; Nicola Longo; Sandra K. Loo; 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; Shruti Marwaha; Thomas May; Jacob Mccauley; Allyn Mcconkie-Rosell; Colleen Mccormack; Alexa Mccray; Thomas Metz; Matthew Might; Eva Morava-Kozicz; Paolo Moretti; Marie Morimoto; John Mulvihill; David Murdock; Avi Nath; Stan Nelson; 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 W P Phillips; Jennifer Posey; John Postlethwait; Lorraine Potocki; Barbara Pusey; Aaron Quinlan; Archana Raja; Genecee Renteria; Chloe Reuter; Lynette Rives; Amy Robertson; Lance H Rodan; Jill A. Rosenfeld; Robb Rowley; Maura Ruzhnikov; Ralph Sacco; Jacinda Sampson; Susan Samson; Mario Saporta; Judy Schaechter; Timothy Schedl; Kelly Schoch; Daryl Scott; Lisa Shakachite; Prashant Sharma; Vandana Shashi; Kathleen Shields; Jimann Shin; Rebecca Signer; Catherine Sillari; Edwin Silverman; Janet Sinsheimer; Kathy Sisco; Kevin Smith; Lilianna Solnica-Krezel; Rebecca Spillmann; Joan Stoler; Nicholas Stong; Jennifer Sullivan; Shirley Sutton; David Sweetser; Holly Tabor; Cecelia Tamburro; Queenie K.-G. Tan; Mustafa Tekin; 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; Daniel Wegner; Monte Westerfield; Matthew Wheeler; Anastasia Wise; Lynne Wolfe; Jeremy Woods; Elizabeth Worthey; Shinya Yamamoto; John Yang; Amanda Yoon; Guoyun Yu; Diane Zastrow; Chunli Zhao; Stephan Züchner; Geneviève David; Gerard T. Berry

doi:10.1016/j.ajhg.2019.09.005

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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

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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, Sara Calabretta, Judith St-Onge, Nassima Boudrahem-Addour, Alexandre Dionne-Laporte, Pascal Joset, Silvia Azzarello-Burri, Anita Rauch, Juan Pallais, Marie Mcdonald, …

American Journal of Human Genetics, Vol.105(4), pp.854-868

10/2019

DOI: https://doi.org/10.1016/j.ajhg.2019.09.005

PMCID: PMC6817525

Abstract

cell-cell adhesion

CDH2

N-cadherin

cardiac defects

eye defects

genital defects

intellectual disability

corpus callosum

ACOG

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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Title: De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Callosum, Axon, Cardiac, Ocular, and Genital Defects
Creators - without role: Andrea Accogli - McGill University Health Centre
Sara Calabretta - Montreal Clinical Research Institute
Judith St-Onge - McGill University Health Centre
Nassima Boudrahem-Addour - McGill University Health Centre
Alexandre Dionne-Laporte - Montreal Neurological Institute and Hospital
Pascal Joset - University Hospital of Zurich
Silvia Azzarello-Burri - University of Zurich
Anita Rauch - University Hospital of Zurich
Juan Pallais - Brigham and Women's Hospital
Marie Mcdonald - Duke University
Sharon Freedman - Duke University Hospital
Jean-Baptiste Rivière - McGill University
Joël Lafond-Lapalme - McGill University Health Centre
Brittany Simpson - University of Cincinnati
Robert Hopkin - Cincinnati Children's Hospital Medical Center
Aurelien Trimouille - Inserm
Julien Van-Gils - Université de Bordeaux
Amber Begtrup - Genex Systems
Kirsty Mcwalter - Genex Systems
Heron Delphine - Sorbonne Université
Boris Keren - Sorbonne Université
David Geneviève - Université de Montpellier, Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB
Emanuela Argilli - University of California, San Francisco
Elliott Sherr - University of California, San Francisco
Mariasavina Severino - Istituto di Ricovero e Cura a Carattere Scientifico
Guy Rouleau - McGill University Health Centre
Patricia Yam - Montreal Clinical Research Institute
Frédéric Charron - McGill University Health Centre
Myriam Srour - McGill University Health Centre
Maria Acosta
David Adams - Bicêtre Hospital
Pankaj Agrawal - Institute of Physics, Bhubaneshwar
Mercedes Alejandro
Patrick Allard
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 H. Beggs - Genomics
Gill Bejerano - Représentations musicales
Hugo Bellen
Jonathan Bernstein - NetApp
Anna Bican
David Bick
Camille Birch
Stephanie Bivona
John Bohnsack
Carsten Bonnenmann
Devon Bonner
Braden E. Boone - HudsonAlpha Institute for Biotechnology
Bret Bostwick
Lorenzo Botto - Queen Mary University of London
Lauren Briere
Elly Brokamp
Donna Brown
Matthew Brush
Elizabeth Burke - Brigham and Women's Hospital
Lindsay Burrage
Manish Butte
John Carey - Institute of Child Health
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 - Baylor College of Medicine
Precilla D’souza
Surendra Dasari - Division of Biomedical Statistics and Informatics
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 G. Ferreira - Universitat de València
Elizabeth Fieg - Brigham and Women's Hospital
Paul Fisher
Brent Fogel
Irman Forghani
Laure Fresard - Department of Pathology
William Gahl
Rena Godfrey
Alica Goldman
David Goldstein
Jean-Philippe Gourdine
Alana Grajewski
Catherine Groden
Andrea Gropman - Comanche National Museum and Cultural Center
Melissa Haendel - Oregon Health & Science University
Rizwan Hamid
Neil A Hanchard - Baylor College of Medicine
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 - Harvard University
Jennefer Kohler - Stanford University
Deborah Krakow - University of California, Los Angeles
Donna Krasnewich
Susan Korrick
Mary Koziura
Joël Krier - Brigham and Women's Hospital
Jennifer Kyle
Seema Lalani
Byron Lam
Brendan Lanpher
Ian Lanza
C. Christopher Lau
Jozef Lazar
Kimberly Leblanc
Brendan Lee - Human Genetics
Hane Lee
Roy Levitt
Shawn E. Levy - HudsonAlpha Institute for Biotechnology
Richard Lewis - University of Sussex
Sharyn Lincoln - Boston University
Pengfei Liu - Laboratoire Bordelais de Recherche en Informatique
Xue Zhong Liu
Nicola Longo
Sandra K. Loo - Bioinformatics Research Center
Joseph Loscalzo
Richard Maas
Ellen Macnamara
Calum Macrae
Valerie Maduro
Marta Majcherska
May Christine V. Malicdan
Laura Mamounas
Teri Manolio - McGill University Health Centre
Rong Mao
Thomas Markello
Ronit Marom
Gabor Marth
Beth Martin - Brigham and Women's Hospital
Martin Martin - University of California, Los Angeles
Julian Martinez-Agosto - University of California, Los Angeles
Shruti Marwaha
Thomas May
Jacob Mccauley
Allyn Mcconkie-Rosell - Duke University
Colleen Mccormack
Alexa Mccray
Thomas Metz - Richland College
Matthew Might
Eva Morava-Kozicz
Paolo Moretti - Departament de Fisica i Enginyeria Nuclear
Marie Morimoto - Duke University
John Mulvihill
David Murdock
Avi Nath - Istituto Giannina Gaslini
Stan Nelson - Institute of Human Genetics
J. Scott Newberry
John Newman
Sarah Nicholas
Donna Novacic
Devin Oglesbee
James Orengo
Laura Pace
Stephen Pak
J. Carl Pallais - Brigham and Women's Hospital
Christina G.S. Palmer
Jeanette Papp
Neil Parker
John W P Phillips - National University of Singapore
Jennifer Posey
John Postlethwait - Institute of Neuroscience [Eugene, OR, États-Unis]
Lorraine Potocki - Institute of Human Genetics
Barbara Pusey
Aaron Quinlan
Archana Raja
Genecee Renteria
Chloe Reuter
Lynette Rives
Amy Robertson
Lance H Rodan - Boston Children's Hospital
Jill A. Rosenfeld - Baylor Genetics
Robb Rowley
Maura Ruzhnikov
Ralph Sacco - Metacohorts Consortium
Jacinda Sampson
Susan Samson
Mario Saporta
Judy Schaechter
Timothy Schedl
Kelly Schoch - Duke University
Daryl Scott
Lisa Shakachite
Prashant Sharma
Vandana Shashi - Duke University
Kathleen Shields
Jimann Shin
Rebecca Signer
Catherine Sillari
Edwin Silverman
Janet Sinsheimer
Kathy Sisco
Kevin Smith
Lilianna Solnica-Krezel - Department of Biological Sciences [Nashville]
Rebecca Spillmann
Joan Stoler
Nicholas Stong - Columbia University Irving Medical Center
Jennifer Sullivan - University College Dublin
Shirley Sutton - Stanford Medicine
David Sweetser - Université de Montpellier
Holly Tabor
Cecelia Tamburro
Queenie K.-G. Tan
Mustafa Tekin - Genomics
Fred Telischi - Montreal Clinical Research Institute
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 - Montreal Clinical Research Institute
Katrina Waters
Bobbie-Jo Webb-Robertson - Biological Sciences Division
Daniel Wegner
Monte Westerfield - University of Oregon
Matthew Wheeler
Anastasia Wise
Lynne Wolfe
Jeremy Woods
Elizabeth Worthey - Brigham and Women's Hospital
Shinya Yamamoto - Graduate School of Information Systems
John Yang
Amanda Yoon
Guoyun Yu
Diane Zastrow
Chunli Zhao
Stephan Züchner - Dr. John T. Macdonald Foundation
Geneviève David - Université de Montpellier, Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB
Gerard T. Berry
Publication Details: American Journal of Human Genetics, Vol.105(4), pp.854-868
Identifiers: 9940227409311
Academic Unit: Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB
Language: English
Resource Type: Journal article
Local Fields: hal-02556784