Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.
CdLS
Cornelia de Lange Syndrome
HDAC8
NIPBL
RAD21
SMC1A
SMC3
cohesin
genome
transcription
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
revised:
02
05
2023
received:
23
03
2023
accepted:
03
05
2023
pmc-release:
01
08
2024
medline:
19
7
2023
pubmed:
28
6
2023
entrez:
28
6
2023
Statut:
ppublish
Résumé
Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.
Identifiants
pubmed: 37377026
doi: 10.1002/ajmg.a.63247
pmc: PMC10524367
mid: NIHMS1900466
doi:
Substances chimiques
Nuclear Proteins
0
Transcription Factors
0
Cell Cycle Proteins
0
AFF4 protein, human
0
Transcriptional Elongation Factors
0
HDAC8 protein, human
EC 3.5.1.98
Histone Deacetylases
EC 3.5.1.98
Repressor Proteins
0
BRD4 protein, human
0
NIPBL 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
2113-2131Subventions
Organisme : NICHD NIH HHS
ID : R03 HD099530
Pays : United States
Organisme : NICHD NIH HHS
ID : P01 HD052860
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD039323
Pays : United States
Informations de copyright
© 2023 Wiley Periodicals LLC.
Références
Curr Biol. 2004 Sep 7;14(17):1598-603
pubmed: 15341749
Am J Med Genet. 2001 Dec 15;104(4):267-76
pubmed: 11754058
Genome Res. 2007 Nov;17(11):1665-74
pubmed: 17921354
Sci Rep. 2021 Jul 29;11(1):15459
pubmed: 34326454
Biomed Res Int. 2016;2016:8742939
pubmed: 26925417
Nat Genet. 2004 Jun;36(6):631-5
pubmed: 15146186
J Clin Invest. 2015 Feb;125(2):636-51
pubmed: 25574841
Am J Med Genet A. 2007 Jun 15;143A(12):1287-96
pubmed: 17508425
Am J Hum Genet. 2012 Jun 8;90(6):1014-27
pubmed: 22633399
Gene. 2020 Jun 15;743:144612
pubmed: 32222533
Am J Med Genet. 1993 Nov 15;47(7):940-6
pubmed: 8291537
Prenat Diagn. 2006 Nov;26(11):1054-7
pubmed: 16958143
Clin Genet. 2016 Jan;89(1):74-81
pubmed: 25652421
Nat Genet. 2018 Mar;50(3):329-332
pubmed: 29379197
Eur J Hum Genet. 2007 Apr;15(4):505-8
pubmed: 17264868
Hum Mol Genet. 1995 Feb;4(2):251-5
pubmed: 7757075
Eur J Hum Genet. 2012 Jul;20(7):734-41
pubmed: 22353942
Hum Mutat. 2010 Jan;31(1):5-10
pubmed: 19842212
Mol Cell Biol. 2004 Apr;24(8):3100-11
pubmed: 15060134
Curr Opin Psychiatry. 2017 Mar;30(2):92-96
pubmed: 28125439
Am J Med Genet A. 2012 Jun;158A(6):1481-5
pubmed: 22581668
Am J Med Genet C Semin Med Genet. 2016 Jun;172(2):163-70
pubmed: 27125329
J Appl Genet. 2013 Feb;54(1):27-33
pubmed: 23254390
Cold Spring Harb Mol Case Stud. 2020 Jun 12;6(3):
pubmed: 32532882
Am J Hum Genet. 2007 Mar;80(3):485-94
pubmed: 17273969
Am J Med Genet. 1994 Sep 1;52(3):267-8
pubmed: 7810556
Nat Cell Biol. 2004 Oct;6(10):991-6
pubmed: 15448702
Genet Med. 2020 May;22(5):927-936
pubmed: 31911672
Mol Syndromol. 2016 Oct;7(5):262-273
pubmed: 27867341
J Med Genet. 2020 May;57(5):289-295
pubmed: 31704779
Clin Genet. 2015 Jul;88(1):1-12
pubmed: 25209348
Nature. 2008 Jul 17;454(7202):297-301
pubmed: 18596691
Hum Genet. 2017 Mar;136(3):307-320
pubmed: 28120103
Nat Genet. 2006 May;38(5):528-30
pubmed: 16604071
J Pediatr Ophthalmol Strabismus. 1990 Mar-Apr;27(2):94-102
pubmed: 2348318
Prenat Diagn. 2002 Feb;22(2):144-7
pubmed: 11857622
Nature. 2012 Sep 13;489(7415):313-7
pubmed: 22885700
Am J Med Genet A. 2017 Aug;173(8):2108-2125
pubmed: 28548707
Am J Med Genet A. 2020 Jul;182(7):1690-1696
pubmed: 32476269
Arch Otolaryngol Head Neck Surg. 1990 Sep;116(9):1044-6
pubmed: 2383389
Gene. 2020 Oct 20;758:144966
pubmed: 32687945
Am J Hum Genet. 2004 Oct;75(4):610-23
pubmed: 15318302
Hum Genet. 2004 Jul;115(2):139-48
pubmed: 15168106
Genet Med. 2012 Mar;14(3):313-22
pubmed: 22241092
Front Pediatr. 2019 May 15;7:203
pubmed: 31157197
Hum Mutat. 2013 Dec;34(12):1589-96
pubmed: 24038889
Mol Cell. 2000 Feb;5(2):243-54
pubmed: 10882066
Hum Mutat. 2009 Nov;30(11):1535-42
pubmed: 19701948
J Med Genet. 2014 Oct;51(10):659-68
pubmed: 25125236
Nat Rev Genet. 2018 Oct;19(10):649-666
pubmed: 29995837
Am J Med Genet C Semin Med Genet. 2016 Jun;172(2):155-62
pubmed: 27120260
Hum Mutat. 2015 Apr;36(4):454-62
pubmed: 25655089
J Med Genet. 1991 Sep;28(9):639-40
pubmed: 1956066
Genome Res. 2009 Sep;19(9):1682-90
pubmed: 19592680
Am J Med Genet B Neuropsychiatr Genet. 2014 Apr;165B(3):223-9
pubmed: 24706566