Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.
Abnormalities, Multiple
/ genetics
Adolescent
Child
Child, Preschool
DNA-Binding Proteins
Developmental Disabilities
/ complications
Face
/ abnormalities
Female
Hand Deformities, Congenital
/ genetics
Humans
Intellectual Disability
/ complications
Male
Micrognathism
/ genetics
Mutation
Neck
/ abnormalities
Reelin Protein
Syndrome
Transcription Factors
/ genetics
Bafopathy
developmental delay
dysmorphisms
genotype-phenotype correlation
intellectual disability
neurodevelopmental disorder
speech delay
transcriptome
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 01 2019
03 01 2019
Historique:
received:
15
06
2018
accepted:
14
11
2018
pubmed:
26
12
2018
medline:
5
11
2019
entrez:
25
12
2018
Statut:
ppublish
Résumé
SMARCC2 (BAF170) is one of the invariable core subunits of the ATP-dependent chromatin remodeling BAF (BRG1-associated factor) complex and plays a crucial role in embryogenesis and corticogenesis. Pathogenic variants in genes encoding other components of the BAF complex have been associated with intellectual disability syndromes. Despite its significant biological role, variants in SMARCC2 have not been directly associated with human disease previously. Using whole-exome sequencing and a web-based gene-matching program, we identified 15 individuals with variable degrees of neurodevelopmental delay and growth retardation harboring one of 13 heterozygous variants in SMARCC2, most of them novel and proven de novo. The clinical presentation overlaps with intellectual disability syndromes associated with other BAF subunits, such as Coffin-Siris and Nicolaides-Baraitser syndromes and includes prominent speech impairment, hypotonia, feeding difficulties, behavioral abnormalities, and dysmorphic features such as hypertrichosis, thick eyebrows, thin upper lip vermilion, and upturned nose. Nine out of the fifteen individuals harbor variants in the highly conserved SMARCC2 DNA-interacting domains (SANT and SWIRM) and present with a more severe phenotype. Two of these individuals present cardiac abnormalities. Transcriptomic analysis of fibroblasts from affected individuals highlights a group of differentially expressed genes with possible roles in regulation of neuronal development and function, namely H19, SCRG1, RELN, and CACNB4. Our findings suggest a novel SMARCC2-related syndrome that overlaps with neurodevelopmental disorders associated with variants in BAF-complex subunits.
Identifiants
pubmed: 30580808
pii: S0002-9297(18)30410-5
doi: 10.1016/j.ajhg.2018.11.007
pmc: PMC6323608
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
Reelin Protein
0
SMARCC2 protein, human
0
Transcription Factors
0
RELN protein, human
EC 3.4.21.-
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
164-178Subventions
Organisme : NHGRI NIH HHS
ID : U01 HG007672
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG007942
Pays : United States
Organisme : CIHR
Pays : Canada
Investigateurs
David R Adams
(DR)
Mercedes E Alejandro
(ME)
Patrick Allard
(P)
Mahshid S Azamian
(MS)
Carlos A Bacino
(CA)
Ashok Balasubramanyam
(A)
Hayk Barseghyan
(H)
Gabriel F Batzli
(GF)
Alan H Beggs
(AH)
Babak Behnam
(B)
Anna Bican
(A)
David P Bick
(DP)
Camille L Birch
(CL)
Devon Bonner
(D)
Braden E Boone
(BE)
Bret L Bostwick
(BL)
Lauren C Briere
(LC)
Donna M Brown
(DM)
Matthew Brush
(M)
Elizabeth A Burke
(EA)
Lindsay C Burrage
(LC)
Shan Chen
(S)
Gary D Clark
(GD)
Terra R Coakley
(TR)
Joy D Cogan
(JD)
Cynthia M Cooper
(CM)
Heidi Cope
(H)
William J Craigen
(WJ)
Precilla D'Souza
(P)
Mariska Davids
(M)
Jyoti G Dayal
(JG)
Esteban C Dell'Angelica
(EC)
Shweta U Dhar
(SU)
Ani Dillon
(A)
Katrina M Dipple
(KM)
Laurel A Donnell-Fink
(LA)
Naghmeh Dorrani
(N)
Daniel C Dorset
(DC)
Emilie D Douine
(ED)
David D Draper
(DD)
David J Eckstein
(DJ)
Lisa T Emrick
(LT)
Christine M Eng
(CM)
Ascia Eskin
(A)
Cecilia Esteves
(C)
Tyra Estwick
(T)
Carlos Ferreira
(C)
Brent L Fogel
(BL)
Noah D Friedman
(ND)
William A Gahl
(WA)
Emily Glanton
(E)
Rena A Godfrey
(RA)
David B Goldstein
(DB)
Sarah E Gould
(SE)
Jean-Philippe F Gourdine
(JF)
Catherine A Groden
(CA)
Andrea L Gropman
(AL)
Melissa Haendel
(M)
Rizwan Hamid
(R)
Neil A Hanchard
(NA)
Lori H Handley
(LH)
Matthew R Herzog
(MR)
Ingrid A Holm
(IA)
Jason Hom
(J)
Ellen M Howerton
(EM)
Yong Huang
(Y)
Howard J Jacob
(HJ)
Mahim Jain
(M)
Yong-Hui Jiang
(YH)
Jean M Johnston
(JM)
Angela L Jones
(AL)
Isaac S Kohane
(IS)
Donna M Krasnewich
(DM)
Elizabeth L Krieg
(EL)
Joel B Krier
(JB)
Seema R Lalani
(SR)
C Christopher Lau
(CC)
Jozef Lazar
(J)
Brendan H Lee
(BH)
Hane Lee
(H)
Shawn E Levy
(SE)
Richard A Lewis
(RA)
Sharyn A Lincoln
(SA)
Allen Lipson
(A)
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)
Thomas C Markello
(TC)
Ronit Marom
(R)
Julian A Martínez-Agosto
(JA)
Shruti Marwaha
(S)
Thomas May
(T)
Allyn McConkie-Rosell
(A)
Colleen E McCormack
(CE)
Alexa T McCray
(AT)
Matthew Might
(M)
Paolo M Moretti
(PM)
Marie Morimoto
(M)
John J Mulvihill
(JJ)
Jennifer L Murphy
(JL)
Donna M Muzny
(DM)
Michele E Nehrebecky
(ME)
Stan F Nelson
(SF)
J Scott Newberry
(JS)
John H Newman
(JH)
Sarah K Nicholas
(SK)
Donna Novacic
(D)
Jordan S Orange
(JS)
J Carl Pallais
(JC)
Christina G S Palmer
(CGS)
Jeanette C Papp
(JC)
Neil H Parker
(NH)
Loren D M Pena
(LDM)
John A Phillips
(JA)
Jennifer E Posey
(JE)
John H Postlethwait
(JH)
Lorraine Potocki
(L)
Barbara N Pusey
(BN)
Chloe M Reuter
(CM)
Amy K Robertson
(AK)
Lance H Rodan
(LH)
Jill A Rosenfeld
(JA)
Jacinda B Sampson
(JB)
Susan L Samson
(SL)
Kelly Schoch
(K)
Molly C Schroeder
(MC)
Daryl A Scott
(DA)
Prashant Sharma
(P)
Vandana Shashi
(V)
Rebecca Signer
(R)
Edwin K Silverman
(EK)
Janet S Sinsheimer
(JS)
Kevin S Smith
(KS)
Rebecca C Spillmann
(RC)
Kimberly Splinter
(K)
Joan M Stoler
(JM)
Nicholas Stong
(N)
Jennifer A Sullivan
(JA)
David A Sweetser
(DA)
Cynthia J Tifft
(CJ)
Camilo Toro
(C)
Alyssa A Tran
(AA)
Tiina K Urv
(TK)
Zaheer M Valivullah
(ZM)
Eric Vilain
(E)
Tiphanie P Vogel
(TP)
Colleen E Wahl
(CE)
Nicole M Walley
(NM)
Chris A Walsh
(CA)
Patricia A Ward
(PA)
Katrina M Waters
(KM)
Monte Westerfield
(M)
Anastasia L Wise
(AL)
Lynne A Wolfe
(LA)
Elizabeth A Worthey
(EA)
Shinya Yamamoto
(S)
Yaping Yang
(Y)
Guoyun Yu
(G)
Diane B Zastrow
(DB)
Allison Zheng
(A)
Informations de copyright
Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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