De Novo Pathogenic Variants in N-cadherin Cause a Syndromic Neurodevelopmental Disorder with Corpus Collosum, Axon, Cardiac, Ocular, and Genital Defects.
ACOG
CDH2
N-cadherin
cardiac defects
cell-cell adhesion
corpus callosum
eye defects
genital defects
intellectual disability
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 10 2019
03 10 2019
Historique:
received:
28
05
2019
accepted:
05
09
2019
entrez:
5
10
2019
pubmed:
5
10
2019
medline:
3
4
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 31585109
pii: S0002-9297(19)30344-1
doi: 10.1016/j.ajhg.2019.09.005
pmc: PMC6817525
pii:
doi:
Substances chimiques
Cadherins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
854-868Subventions
Organisme : NINDS NIH HHS
ID : R01 NS058721
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007690
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : CIHR
ID : FDN334023
Pays : Canada
Investigateurs
Maria T Acosta
(MT)
David R Adams
(DR)
Pankaj Agrawal
(P)
Mercedes E Alejandro
(ME)
Patrick Allard
(P)
Justin Alvey
(J)
Ashley Andrews
(A)
Euan A Ashley
(EA)
Mahshid S Azamian
(MS)
Carlos A Bacino
(CA)
Guney Bademci
(G)
Eva Baker
(E)
Ashok Balasubramanyam
(A)
Dustin Baldridge
(D)
Jim Bale
(J)
Deborah Barbouth
(D)
Gabriel F Batzli
(GF)
Pinar Bayrak-Toydemir
(P)
Alan H Beggs
(AH)
Gill Bejerano
(G)
Hugo J Bellen
(HJ)
Jonathan A Bernstein
(JA)
Gerard T Berry
(GT)
Anna Bican
(A)
David P Bick
(DP)
Camille L Birch
(CL)
Stephanie Bivona
(S)
John Bohnsack
(J)
Carsten Bonnenmann
(C)
Devon Bonner
(D)
Braden E Boone
(BE)
Bret L Bostwick
(BL)
Lorenzo Botto
(L)
Lauren C Briere
(LC)
Elly Brokamp
(E)
Donna M Brown
(DM)
Matthew Brush
(M)
Elizabeth A Burke
(EA)
Lindsay C Burrage
(LC)
Manish J Butte
(MJ)
John Carey
(J)
Olveen Carrasquillo
(O)
Ta Chen Peter Chang
(TCP)
Hsiao-Tuan Chao
(HT)
Gary D Clark
(GD)
Terra R Coakley
(TR)
Laurel A Cobban
(LA)
Joy D Cogan
(JD)
F Sessions Cole
(FS)
Heather A Colley
(HA)
Cynthia M Cooper
(CM)
Heidi Cope
(H)
William J Craigen
(WJ)
Precilla D'Souza
(P)
Surendra Dasari
(S)
Mariska Davids
(M)
Jyoti G Dayal
(JG)
Esteban C Dell'Angelica
(EC)
Shweta U Dhar
(SU)
Naghmeh Dorrani
(N)
Daniel C Dorset
(DC)
Emilie D Douine
(ED)
David D Draper
(DD)
Laura Duncan
(L)
David J Eckstein
(DJ)
Lisa T Emrick
(LT)
Christine M Eng
(CM)
Cecilia Esteves
(C)
Tyra Estwick
(T)
Liliana Fernandez
(L)
Carlos Ferreira
(C)
Elizabeth L Fieg
(EL)
Paul G Fisher
(PG)
Brent L Fogel
(BL)
Irman Forghani
(I)
Laure Fresard
(L)
William A Gahl
(WA)
Rena A Godfrey
(RA)
Alica M Goldman
(AM)
David B Goldstein
(DB)
Jean-Philippe F Gourdine
(JF)
Alana Grajewski
(A)
Catherine A Groden
(CA)
Andrea L Gropman
(AL)
Melissa Haendel
(M)
Rizwan Hamid
(R)
Neil A Hanchard
(NA)
Nichole Hayes
(N)
Frances High
(F)
Ingrid A Holm
(IA)
Jason Hom
(J)
Alden Huang
(A)
Yong Huang
(Y)
Rosario Isasi
(R)
Fariha Jamal
(F)
Yong-Hui Jiang
(YH)
Jean M Johnston
(JM)
Angela L Jones
(AL)
Lefkothea Karaviti
(L)
Emily G Kelley
(EG)
Dana Kiley
(D)
David M Koeller
(DM)
Isaac S Kohane
(IS)
Jennefer N Kohler
(JN)
Deborah Krakow
(D)
Donna M Krasnewich
(DM)
Susan Korrick
(S)
Mary Koziura
(M)
Joel B Krier
(JB)
Jennifer E Kyle
(JE)
Seema R Lalani
(SR)
Byron Lam
(B)
Brendan C Lanpher
(BC)
Ian R Lanza
(IR)
C Christopher Lau
(CC)
Jozef Lazar
(J)
Kimberly LeBlanc
(K)
Brendan H Lee
(BH)
Hane Lee
(H)
Roy Levitt
(R)
Shawn E Levy
(SE)
Richard A Lewis
(RA)
Sharyn A Lincoln
(SA)
Pengfei Liu
(P)
Xue Zhong Liu
(XZ)
Nicola Longo
(N)
Sandra K Loo
(SK)
Joseph Loscalzo
(J)
Richard L Maas
(RL)
Ellen F Macnamara
(EF)
Calum A MacRae
(CA)
Valerie V Maduro
(VV)
Marta M Majcherska
(MM)
May Christine V Malicdan
(MCV)
Laura A Mamounas
(LA)
Teri A Manolio
(TA)
Rong Mao
(R)
Thomas C Markello
(TC)
Ronit Marom
(R)
Gabor Marth
(G)
Beth A Martin
(BA)
Martin G Martin
(MG)
Julian A Martínez-Agosto
(JA)
Shruti Marwaha
(S)
Thomas May
(T)
Jacob McCauley
(J)
Allyn McConkie-Rosell
(A)
Colleen E McCormack
(CE)
Alexa T McCray
(AT)
Thomas O Metz
(TO)
Matthew Might
(M)
Eva Morava-Kozicz
(E)
Paolo M Moretti
(PM)
Marie Morimoto
(M)
John J Mulvihill
(JJ)
David R Murdock
(DR)
Avi Nath
(A)
Stan F Nelson
(SF)
J Scott Newberry
(JS)
John H Newman
(JH)
Sarah K Nicholas
(SK)
Donna Novacic
(D)
Devin Oglesbee
(D)
James P Orengo
(JP)
Laura Pace
(L)
Stephen Pak
(S)
J Carl Pallais
(JC)
Christina G S Palmer
(CGS)
Jeanette C Papp
(JC)
Neil H Parker
(NH)
John A Phillips
(JA)
Jennifer E Posey
(JE)
John H Postlethwait
(JH)
Lorraine Potocki
(L)
Barbara N Pusey
(BN)
Aaron Quinlan
(A)
Archana N Raja
(AN)
Genecee Renteria
(G)
Chloe M Reuter
(CM)
Lynette Rives
(L)
Amy K Robertson
(AK)
Lance H Rodan
(LH)
Jill A Rosenfeld
(JA)
Robb K Rowley
(RK)
Maura Ruzhnikov
(M)
Ralph Sacco
(R)
Jacinda B Sampson
(JB)
Susan L Samson
(SL)
Mario Saporta
(M)
Judy Schaechter
(J)
Timothy Schedl
(T)
Kelly Schoch
(K)
Daryl A Scott
(DA)
Lisa Shakachite
(L)
Prashant Sharma
(P)
Vandana Shashi
(V)
Kathleen Shields
(K)
Jimann Shin
(J)
Rebecca Signer
(R)
Catherine H Sillari
(CH)
Edwin K Silverman
(EK)
Janet S Sinsheimer
(JS)
Kathy Sisco
(K)
Kevin S Smith
(KS)
Lilianna Solnica-Krezel
(L)
Rebecca C Spillmann
(RC)
Joan M Stoler
(JM)
Nicholas Stong
(N)
Jennifer A Sullivan
(JA)
Shirley Sutton
(S)
David A Sweetser
(DA)
Holly K Tabor
(HK)
Cecelia P Tamburro
(CP)
Queenie K-G Tan
(QK)
Mustafa Tekin
(M)
Fred Telischi
(F)
Willa Thorson
(W)
Cynthia J Tifft
(CJ)
Camilo Toro
(C)
Alyssa A Tran
(AA)
Tiina K Urv
(TK)
Matt Velinder
(M)
Dave Viskochil
(D)
Tiphanie P Vogel
(TP)
Colleen E Wahl
(CE)
Nicole M Walley
(NM)
Chris A Walsh
(CA)
Melissa Walker
(M)
Jennifer Wambach
(J)
Jijun Wan
(J)
Lee-Kai Wang
(LK)
Michael F Wangler
(MF)
Patricia A Ward
(PA)
Katrina M Waters
(KM)
Bobbie-Jo M Webb-Robertson
(BM)
Daniel Wegner
(D)
Monte Westerfield
(M)
Matthew T Wheeler
(MT)
Anastasia L Wise
(AL)
Lynne A Wolfe
(LA)
Jeremy D Woods
(JD)
Elizabeth A Worthey
(EA)
Shinya Yamamoto
(S)
John Yang
(J)
Amanda J Yoon
(AJ)
Guoyun Yu
(G)
Diane B Zastrow
(DB)
Chunli Zhao
(C)
Stephan Zuchner
(S)
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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