SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females.
Adolescent
Autism Spectrum Disorder
/ genetics
Child
Child, Preschool
Chromosome Deletion
Chromosome Disorders
/ genetics
Chromosomes, Human, Pair 1
/ genetics
Chromosomes, Human, X
/ genetics
DNA Methylation
/ genetics
DNA-Binding Proteins
/ genetics
Epigenesis, Genetic
/ genetics
Female
Haploinsufficiency
/ genetics
Humans
Intellectual Disability
/ genetics
Male
Neurodevelopmental Disorders
/ genetics
Phenotype
RNA-Binding Proteins
/ genetics
Young Adult
1p36
DNA methylome analysis
SPEN
X chromosome
distal 1p36 deletion syndrome
episignature
genotype-phenotype correlations
neurodevelopmental disorder
obesity
proximal 1p36 deletion syndrome
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:
04 03 2021
04 03 2021
Historique:
received:
07
12
2020
accepted:
26
01
2021
pubmed:
18
2
2021
medline:
25
3
2021
entrez:
17
2
2021
Statut:
ppublish
Résumé
Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.
Identifiants
pubmed: 33596411
pii: S0002-9297(21)00015-X
doi: 10.1016/j.ajhg.2021.01.015
pmc: PMC8008487
pii:
doi:
Substances chimiques
DNA-Binding Proteins
0
RNA-Binding Proteins
0
SPEN protein, human
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
502-516Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD098458
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG009141
Pays : United States
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : R01 MH101221
Pays : United States
Informations de copyright
Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Références
Am J Hum Genet. 2009 Apr;84(4):524-33
pubmed: 19344873
Am J Hum Genet. 2016 May 5;98(5):963-970
pubmed: 27087320
Am J Hum Genet. 2020 Mar 5;106(3):356-370
pubmed: 32109418
Annu Rev Genet. 2000;34:297-329
pubmed: 11092830
Genetics. 2020 Jul;215(3):887
pubmed: 32632026
Nat Rev Genet. 2016 Jan;17(1):9-18
pubmed: 26503795
EMBO J. 2002 Oct 15;21(20):5417-26
pubmed: 12374742
Blood Adv. 2020 Mar 24;4(6):1038-1050
pubmed: 32191807
Am J Hum Genet. 2013 Jul 11;93(1):67-77
pubmed: 23768516
Genome Res. 2020 Jun;30(6):835-848
pubmed: 32554779
Clin Genet. 2003 Oct;64(4):310-6
pubmed: 12974736
Elife. 2020 May 07;9:
pubmed: 32379046
J Biol Chem. 2004 Jul 30;279(31):32913-23
pubmed: 15131132
Onco Targets Ther. 2020 Jan 15;13:351-359
pubmed: 32021280
Genet Med. 2015 Jul;17(7):578-86
pubmed: 25356970
Cancer Res. 2015 Oct 15;75(20):4351-63
pubmed: 26297734
Nat Genet. 2010 Dec;42(12):1109-12
pubmed: 21076407
Nature. 2011 Oct 26;478(7370):483-9
pubmed: 22031440
Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12729-34
pubmed: 11070086
Am J Hum Genet. 1997 Sep;61(3):642-50
pubmed: 9326330
Am J Med Genet A. 2010 Aug;152A(8):1951-9
pubmed: 20635359
Hum Mol Genet. 1999 Feb;8(2):313-21
pubmed: 9931339
Clin Genet. 2007 Oct;72(4):329-38
pubmed: 17850629
Cell. 2013 Nov 21;155(5):1008-21
pubmed: 24267887
Mech Dev. 2007 Sep-Oct;124(9-10):792-806
pubmed: 17588724
Hum Mutat. 2018 Nov;39(11):1505-1516
pubmed: 30311385
Am J Hum Genet. 2003 May;72(5):1200-12
pubmed: 12687501
Nature. 2015 May 14;521(7551):232-6
pubmed: 25915022
Genetics. 2000 Feb;154(2):695-712
pubmed: 10655223
Immunity. 2003 Feb;18(2):301-12
pubmed: 12594956
Genesis. 2007 May;45(5):300-6
pubmed: 17457934
Gene. 2002 Jun 12;292(1-2):25-31
pubmed: 12119096
PLoS Genet. 2017 Jun 22;13(6):e1006859
pubmed: 28640815
Am J Med Genet C Semin Med Genet. 2007 Nov 15;145C(4):346-56
pubmed: 17918734
Cell. 2013 Nov 21;155(5):997-1007
pubmed: 24267886
Nature. 2018 Mar 22;555(7697):524-528
pubmed: 29539641
Genet Med. 2016 Jul;18(7):696-704
pubmed: 26633542
Clin Genet. 2016 Jun;89(6):700-7
pubmed: 26757139
Am J Hum Genet. 2020 Sep 3;107(3):499-513
pubmed: 32721402
Res Dev Disabil. 2011 Mar-Apr;32(2):419-36
pubmed: 21236634
Cell Rep. 2015 Jul 28;12(4):554-61
pubmed: 26190100
Nature. 2017 Feb 23;542(7642):433-438
pubmed: 28135719
PLoS One. 2015 Apr 29;10(4):e0124120
pubmed: 25923140
Brain. 2019 Nov 1;142(11):3367-3374
pubmed: 31608932
Epileptic Disord. 2020 Oct 1;22(5):659-663
pubmed: 33063670
PLoS One. 2014 Jan 15;9(1):e85600
pubmed: 24454898
Genet Med. 2019 Sep;21(9):2043-2058
pubmed: 30842647
Mol Cell Biol. 2005 Dec;25(23):10379-90
pubmed: 16287852
Nature. 2020 Oct;586(7831):757-762
pubmed: 33057194
Hum Mutat. 2018 May;39(5):666-675
pubmed: 29330883
Am J Med Genet A. 2008 Aug 1;146A(15):2018-22
pubmed: 18627049
Am J Med Genet A. 2010 Jan;152A(1):102-10
pubmed: 20034100
Appl Clin Genet. 2015 Aug 27;8:189-200
pubmed: 26345236
N Engl J Med. 2012 Nov 15;367(20):1921-9
pubmed: 23033978
NPJ Genom Med. 2016 Aug 3;1:160271-1602710
pubmed: 27525107
Nature. 2020 Feb;578(7795):455-460
pubmed: 32025035
Genome Res. 2015 Jan;25(1):142-54
pubmed: 25378250
Lancet. 2015 Apr 4;385(9975):1305-14
pubmed: 25529582
Genetics. 2000 May;155(1):233-44
pubmed: 10790398
Nature. 2014 Nov 13;515(7526):216-21
pubmed: 25363768
Mol Endocrinol. 2016 Sep;30(9):965-76
pubmed: 27581354
Hum Mutat. 2015 Oct;36(10):928-30
pubmed: 26220891
Nat Genet. 2015 Jun;47(6):582-8
pubmed: 25961944
Genes Dev. 2001 May 1;15(9):1140-51
pubmed: 11331609
Genes Dev. 2003 Aug 1;17(15):1909-20
pubmed: 12897056
Nat Commun. 2020 Oct 1;11(1):4932
pubmed: 33004838
Genet Med. 2020 Jun;22(6):1061-1068
pubmed: 32099069
Development. 2004 Jan;131(1):3-14
pubmed: 14645126
Pediatrics. 2008 Feb;121(2):404-10
pubmed: 18245432
Am J Hum Genet. 2019 Apr 4;104(4):685-700
pubmed: 30929737
Hum Mol Genet. 2004 Jul 1;13(13):1315-9
pubmed: 15115768
Brain Dev. 2015 May;37(5):515-26
pubmed: 25172301
Cancer Res. 2007 Jan 15;67(2):482-91
pubmed: 17234755
Curr Biol. 2000 Jul 27-Aug 10;10(15):943-6
pubmed: 10959845
J Biol Chem. 2002 Apr 12;277(15):13219-28
pubmed: 11825900
Development. 2000 Apr;127(7):1517-29
pubmed: 10704397