Details of Disease

General Information of Disease (ID: DISEQSXO)

• Disease Name: Cornelia de Lange syndrome
• Synonyms: CDLS; Cornelia de Lange syndrome; Brachmann-de Lange syndrome; De Lange syndrome; Brachmann de Lange syndrome
• Definition: A rare syndrome characterized by low birth weight, delayed growth, intellectual disabillity, behavioral problems, and a distinctive facial appearance (thin, arched eyebrows, low set ears, small teeth, and small nose). The majority of cases are caused by mutations in the NIPBL gene. Less severe forms of the syndrome are caused by mutations in the SMC1A and SMC3 genes.
• Disease Hierarchy:
  DIS6SVEE: Syndromic disease
  DISYKSRF: Genetic disease
  DIS3LICD: Congenital limb malformation
  DISHPNVX: Dysplasia
  DISDOXWZ: Multiple congenital anomalies/dysmorphic syndrome-intellectual disability
  DISEQSXO: Cornelia de Lange syndrome
• Disease Identifiers:
  MONDO ID: MONDO_0016033
  MESH ID: D003635
  UMLS CUI: C0270972
  MedGen ID: 78752
  Orphanet ID: 199
  SNOMED CT ID: 40354009

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 7 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
BRD4	TTRA6BO	Supportive	Autosomal dominant	[1]
BRD4	TTSRAOU	Strong	Biomarker	[2]
KMT2A	TT1GNDM	Strong	Genetic Variation	[3]
PTPN11	TT7WUAV	Strong	Biomarker	[4]
RAF1	TTAN5W2	Strong	Biomarker	[5]
TNKS	TTVUSO7	Strong	Biomarker	[6]
HDAC8	TTT6LFV	Definitive	X-linked	[7]

This Disease Is Related to 26 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
BRD4	OT2Y2TCW	Supportive	Autosomal dominant	[1]
SMC1A	OT9ZMRK9	Supportive	Autosomal dominant	[8]
CARS1	OTOUZF6O	moderate	Genetic Variation	[9]
CHRD	OTNM60Y1	moderate	Altered Expression	[10]
DYM	OTQ670WI	moderate	Biomarker	[11]
EPS15L1	OTTFPZY2	moderate	Genetic Variation	[2]
GALNT14	OT9BSDDQ	moderate	Genetic Variation	[12]
GSC	OT4DH7PR	moderate	Altered Expression	[10]
MAU2	OTALDF8Q	moderate	Genetic Variation	[13]
PHIP	OTZY806Z	moderate	Biomarker	[14]
SETD5	OTRPAVEO	moderate	GermlineCausalMutation	[3]
SHOX2	OTLCZZJW	moderate	Biomarker	[15]
STAG1	OT564IX4	moderate	Genetic Variation	[16]
STAG2	OTR6X1Q7	moderate	Genetic Variation	[16]
AFF4	OTTL5Y8R	Strong	Genetic Variation	[17]
DDX11	OT1WR3MD	Strong	Biomarker	[18]
ESCO2	OTJEMAQU	Strong	Biomarker	[19]
LZTR1	OTIDM6XO	Strong	Biomarker	[20]
PDS5A	OT34P56Z	Strong	Biomarker	[21]
PDS5B	OT3U3X8Z	Strong	Genetic Variation	[21]
RIT1	OTVNOGOH	Strong	Biomarker	[22]
SOS1	OTTCWXC3	Strong	Biomarker	[23]
HDAC8	OT5L4RYX	Definitive	X-linked	[7]
NIPBL	OTF6OOLU	Definitive	Autosomal dominant	[7]
RAD21	OTQS84ZF	Definitive	Autosomal dominant	[7]
SMC3	OTWGFRHD	Definitive	Autosomal dominant	[7]

References

• [1] BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome. Nat Genet. 2018 Mar;50(3):329-332. doi: 10.1038/s41588-018-0042-y. Epub 2018 Jan 29.
• [2] Confirmation of BRD4 haploinsufficiency role in Cornelia de Lange-like phenotype and delineation of a 19p13.12p13.11 gene contiguous syndrome.Ann Hum Genet. 2019 Mar;83(2):100-109. doi: 10.1111/ahg.12289. Epub 2018 Oct 10.
• [3] Mutations in chromatin regulators functionally link Cornelia de Lange syndrome and clinically overlapping phenotypes.Hum Genet. 2017 Mar;136(3):307-320. doi: 10.1007/s00439-017-1758-y. Epub 2017 Jan 24.
• [4] Mouse model of Noonan syndrome reveals cell type- and gene dosage-dependent effects of Ptpn11 mutation.Nat Med. 2004 Aug;10(8):849-57. doi: 10.1038/nm1084. Epub 2004 Jul 25.
• [5] Increased BRAF heterodimerization is the common pathogenic mechanism for noonan syndrome-associated RAF1 mutants.Mol Cell Biol. 2012 Oct;32(19):3872-90. doi: 10.1128/MCB.00751-12. Epub 2012 Jul 23.
• [6] Genotype-phenotype correlations in a new case of 8p23.1 deletion and review of the literature.Eur J Med Genet. 2011 Jan-Feb;54(1):55-9. doi: 10.1016/j.ejmg.2010.10.003. Epub 2010 Oct 20.
• [7] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [8] Cornelia de Lange Syndrome. 2005 Sep 16 [updated 2020 Oct 15]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [9] Autism traits in children and adolescents with Cornelia de Lange syndrome.Am J Med Genet A. 2014 Jun;164A(6):1400-10. doi: 10.1002/ajmg.a.36573. Epub 2014 Apr 9.
• [10] Genomic organisation of the human chordin gene and mutation screening of candidate Cornelia de Lange syndrome genes.Hum Genet. 1999 Jul-Aug;105(1-2):104-11. doi: 10.1007/s004399900068.
• [11] Cornelia de Lange syndrome mutations in SMC1A or SMC3 affect binding to DNA.Hum Mol Genet. 2009 Feb 1;18(3):418-27. doi: 10.1093/hmg/ddn369. Epub 2008 Nov 7.
• [12] Rare copy number variants contribute pathogenic alleles in patients with intestinal malrotation.Mol Genet Genomic Med. 2019 Mar;7(3):e549. doi: 10.1002/mgg3.549. Epub 2019 Jan 10.
• [13] Isolated NIBPL missense mutations that cause Cornelia de Lange syndrome alter MAU2 interaction.Eur J Hum Genet. 2012 Mar;20(3):271-6. doi: 10.1038/ejhg.2011.175. Epub 2011 Sep 21.
• [14] Comprehensive genetic analysis of 57 families with clinically suspected Cornelia de Lange syndrome.J Hum Genet. 2019 Oct;64(10):967-978. doi: 10.1038/s10038-019-0643-z. Epub 2019 Jul 23.
• [15] SHOT, a SHOX-related homeobox gene, is implicated in craniofacial, brain, heart, and limb development.Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2406-11. doi: 10.1073/pnas.95.5.2406.
• [16] Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.Genet Med. 2019 Mar;21(3):663-675. doi: 10.1038/s41436-018-0085-6. Epub 2018 Aug 30.
• [17] Germline gain-of-function mutations in AFF4 cause a developmental syndrome functionally linking the super elongation complex and cohesin. Nat Genet. 2015 Apr;47(4):338-44. doi: 10.1038/ng.3229. Epub 2015 Mar 2.
• [18] Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1.Am J Hum Genet. 2010 Feb 12;86(2):262-6. doi: 10.1016/j.ajhg.2010.01.008. Epub 2010 Feb 4.
• [19] CyclinD1 Down-Regulation and Increased Apoptosis Are Common Features of Cohesinopathies.J Cell Physiol. 2016 Mar;231(3):613-22. doi: 10.1002/jcp.25106.
• [20] Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination.Science. 2018 Dec 7;362(6419):1177-1182. doi: 10.1126/science.aap7607. Epub 2018 Nov 15.
• [21] Dosage effects of cohesin regulatory factor PDS5 on mammalian development: implications for cohesinopathies.PLoS One. 2009;4(5):e5232. doi: 10.1371/journal.pone.0005232. Epub 2009 May 1.
• [22] New Noonan syndrome model mice with RIT1 mutation exhibit cardiac hypertrophy and susceptibility to -adrenergic stimulation-induced cardiac fibrosis.EBioMedicine. 2019 Apr;42:43-53. doi: 10.1016/j.ebiom.2019.03.014. Epub 2019 Mar 18.
• [23] Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndromeassociated Sos1 mutation.J Clin Invest. 2010 Dec;120(12):4353-65. doi: 10.1172/JCI43910.