Details of Disease

General Information of Disease (ID: DIS7Q7DN)

• Disease Name: Noonan syndrome
• Synonyms: Noonan-Ehmke syndrome; Ullrich-Noonan syndrome; pseudo-Ullrich-Turner syndrome; Turner's phenotype, karyotype normal; Noonan's syndrome; Noonan syndrome
• Definition: Noonan Syndrome (NS) is characterized by short stature, typical facial dysmorphism and congenital heart defects.
• Disease Hierarchy:
  DIS7667R: Multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome
  DIS6SVEE: Syndromic disease
  DIS4D8VL: Lymphatic malformation
  DISTATYK: Noonan syndrome and Noonan-related syndrome
  DIS7Q7DN: Noonan syndrome
• Disease Identifiers:
  MONDO ID: MONDO_0018997
  MESH ID: D009634
  UMLS CUI: C0028326
  MedGen ID: 18073
  Orphanet ID: 648
  SNOMED CT ID: 205684007

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Fluoxymesterone	DMUHCF1	Approved	Small molecular drug	[1]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 22 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
HRAS	TT28ZON	Limited	CausalMutation	[2]
MAP2K1	TTIDAPM	Limited	Autosomal dominant	[3]
MAP2K1	TTIDAPM	Limited	Biomarker	[4]
MAP2K2	TT8H9GB	Limited	Autosomal dominant	[3]
MAP2K2	TT8H9GB	Limited	Genetic Variation	[5]
MVD	TTE5J6X	Disputed	Genetic Variation	[6]
RASA1	TTPNZ1F	Disputed	Autosomal dominant	[3]
RASA1	TTPNZ1F	Disputed	Biomarker	[7]
CBL	TT7QT13	Supportive	Autosomal dominant	[8]
BRAF	TT0EOB8	Moderate	Autosomal dominant	[3]
BRAF	TT0EOB8	moderate	Genetic Variation	[5]
ARAF	TT5TURO	Strong	Genetic Variation	[9]
CBL	TT7QT13	Strong	Biomarker	[10]
EPHA2	TTRJB2G	Strong	Genetic Variation	[11]
EPHB2	TTKPV6O	Strong	Genetic Variation	[12]
KAT6B	TTH4VJL	Strong	GermlineCausalMutation	[13]
KRAS	TTRHMTC	Definitive	Autosomal dominant	[3]
NRAS	TTW2R9X	Definitive	Autosomal dominant	[3]
NRAS	TTW2R9X	Definitive	Genetic Variation	[14]
PTPN11	TT7WUAV	Definitive	Autosomal dominant	[3]
RAF1	TTB18GJ	Definitive	Autosomal dominant	[3]
RAF1	TTAN5W2	Definitive	Genetic Variation	[15]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC25A3	DTCRIWV	Strong	Biomarker	[16]

This Disease Is Related to 35 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
MAP2K1	OT4Y9NQI	Limited	Autosomal dominant	[3]
MAP2K2	OTUE7Z91	Limited	Autosomal dominant	[3]
PPP1CB	OTYFTYFR	Limited	Genetic Variation	[17]
RASA1	OTZJ3LP4	Disputed	Autosomal dominant	[3]
SHOC2	OTUNQ2CT	Disputed	Autosomal dominant	[3]
A2ML1	OTWNUXIS	Supportive	Autosomal dominant	[18]
CBL	OTTKELCU	Supportive	Autosomal dominant	[8]
RASA2	OTL06RG2	Supportive	Autosomal dominant	[19]
BRAF	OT7S81XQ	Moderate	Autosomal dominant	[3]
MRAS	OTNCVCQW	Moderate	Autosomal dominant	[3]
RRAS	OTBBF28C	Moderate	Autosomal dominant	[20]
CDAN1	OTCVZRG6	Strong	Genetic Variation	[21]
DSG4	OTWIQDC4	Strong	Biomarker	[22]
DTX1	OTYX91DX	Strong	Biomarker	[23]
MED18	OT6M6CQ8	Strong	Biomarker	[24]
MPZL1	OTJSUUHR	Strong	Biomarker	[25]
MTG1	OTC9U1LI	Strong	Genetic Variation	[26]
NCK2	OTUYPF55	Strong	Biomarker	[27]
NF1	OTC29NHH	Strong	Genetic Variation	[28]
PTPRT	OTV5TXNN	Strong	Biomarker	[16]
PTPRU	OTHDO0QG	Strong	Biomarker	[16]
REG1A	OTMHUH1D	Strong	Biomarker	[16]
RPL6	OTRU71O4	Strong	Biomarker	[29]
SHOX	OTE0YZJO	Strong	Genetic Variation	[30]
SPRED1	OTKX7P8G	Strong	Genetic Variation	[31]
ACP1	OTJ9CKLU	Definitive	Genetic Variation	[32]
KRAS	OT78QCN8	Definitive	Autosomal dominant	[3]
LZTR1	OTIDM6XO	Definitive	Autosomal dominant	[3]
NRAS	OTVQ1DG3	Definitive	Autosomal dominant	[3]
PTPN11	OTFH9M73	Definitive	Autosomal dominant	[3]
RAF1	OT51LSFO	Definitive	Autosomal dominant	[3]
RIT1	OTVNOGOH	Definitive	Autosomal dominant	[3]
RRAS2	OT83NCEB	Definitive	Autosomal dominant	[3]
SOS1	OTTCWXC3	Definitive	Autosomal dominant	[3]
SOS2	OTV3XRE5	Definitive	Autosomal dominant	[3]

References

• [1] Fluoxymesterone FDA Label
• [2] ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.Genet Med. 2018 Nov;20(11):1334-1345. doi: 10.1038/gim.2018.3. Epub 2018 Mar 1.
• [3] 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.
• [4] Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome.Circulation. 2019 Jul 16;140(3):207-224. doi: 10.1161/CIRCULATIONAHA.118.037227. Epub 2019 Jun 5.
• [5] Chondroblastoma-like mass of the temporal bone, secondary aneurysmal bone cyst, and intracerebral hemorrhage in a patient with cardiofaciocutaneous syndrome: case report.J Neurosurg Pediatr. 2019 May 24;24(2):153-158. doi: 10.3171/2019.3.PEDS18607.
• [6] Functional evaluation of circulating hematopoietic progenitors in Noonan syndrome.Oncol Rep. 2013 Aug;30(2):553-9. doi: 10.3892/or.2013.2535. Epub 2013 Jun 11.
• [7] RASA1 somatic mutation and variable expressivity in capillary malformation/arteriovenous malformation (CM/AVM) syndrome.Am J Med Genet A. 2016 Jun;170(6):1450-4. doi: 10.1002/ajmg.a.37613. Epub 2016 Mar 11.
• [8] Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations. Hum Mutat. 2015 Aug;36(8):787-96. doi: 10.1002/humu.22809. Epub 2015 Jun 1.
• [9] SHOC2 complex-driven RAF dimerization selectively contributes to ERK pathway dynamics.Proc Natl Acad Sci U S A. 2019 Jul 2;116(27):13330-13339. doi: 10.1073/pnas.1902658116. Epub 2019 Jun 18.
• [10] Adults with germline CBL mutation complicated with juvenile myelomonocytic leukemia at infancy.J Hum Genet. 2016 Jun;61(6):523-6. doi: 10.1038/jhg.2016.8. Epub 2016 Feb 25.
• [11] Involvement of EphA2-mediated tyrosine phosphorylation of Shp2 in Shp2-regulated activation of extracellular signal-regulated kinase.Oncogene. 2013 Nov 7;32(45):5292-301. doi: 10.1038/onc.2012.571. Epub 2013 Jan 14.
• [12] Cellular interplay via cytokine hierarchy causes pathological cardiac hypertrophy in RAF1-mutant Noonan syndrome.Nat Commun. 2017 May 26;8:15518. doi: 10.1038/ncomms15518.
• [13] Disruption of the histone acetyltransferase MYST4 leads to a Noonan syndrome-like phenotype and hyperactivated MAPK signaling in humans and mice.J Clin Invest. 2011 Sep;121(9):3479-91. doi: 10.1172/JCI43428. Epub 2011 Aug 1.
• [14] Molecular and phenotypic spectrum of Noonan syndrome in Chinese patients.Clin Genet. 2019 Oct;96(4):290-299. doi: 10.1111/cge.13588. Epub 2019 Jul 10.
• [15] Dermatological manifestations in Noonan syndrome: aprospective multicentric study of 129 patients positive for mutation.Br J Dermatol. 2019 Jun;180(6):1438-1448. doi: 10.1111/bjd.17404. Epub 2019 Jan 18.
• [16] Identification of demethylincisterol A(3) as a selective inhibitor of protein tyrosine phosphatase Shp2.Eur J Pharmacol. 2017 Jan 15;795:124-133. doi: 10.1016/j.ejphar.2016.12.012. Epub 2016 Dec 8.
• [17] Delineation of LZTR1 mutation-positive patients with Noonan syndrome and identification of LZTR1 binding to RAF1-PPP1CB complexes.Hum Genet. 2019 Jan;138(1):21-35. doi: 10.1007/s00439-018-1951-7. Epub 2018 Oct 27.
• [18] Heterozygous germline mutations in A2ML1 are associated with a disorder clinically related to Noonan syndrome. Eur J Hum Genet. 2015 Mar;23(3):317-24. doi: 10.1038/ejhg.2014.115. Epub 2014 Jun 18.
• [19] Next-generation sequencing identifies rare variants associated with Noonan syndrome. Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11473-8. doi: 10.1073/pnas.1324128111. Epub 2014 Jul 21.
• [20] Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis. Hum Mol Genet. 2014 Aug 15;23(16):4315-27. doi: 10.1093/hmg/ddu148. Epub 2014 Apr 4.
• [21] Unusual dysmorphic features in five patients with Noonan's syndrome: a brief review.J Paediatr Child Health. 2002 Oct;38(5):521-5. doi: 10.1046/j.1440-1754.2002.00027.x.
• [22] Phenotypic variability associated with the invariant SHOC2 c.4A>G (p.Ser2Gly) missense mutation.Am J Med Genet A. 2014 Dec;164A(12):3120-5. doi: 10.1002/ajmg.a.36697. Epub 2014 Oct 20.
• [23] Chromosomal localization, genomic characterization, and mapping to the Noonan syndrome critical region of the human Deltex (DTX1) gene.Hum Genet. 2000 Dec;107(6):577-81. doi: 10.1007/s004390000431.
• [24] Genotype and phenotype in patients with Noonan syndrome and a RIT1 mutation.Genet Med. 2016 Dec;18(12):1226-1234. doi: 10.1038/gim.2016.32. Epub 2016 Apr 21.
• [25] Noonan syndrome-associated SHP-2/Ptpn11 mutants enhance SIRPalpha and PZR tyrosyl phosphorylation and promote adhesion-mediated ERK activation.J Biol Chem. 2008 May 30;283(22):15328-38. doi: 10.1074/jbc.M801382200. Epub 2008 Mar 31.
• [26] Activating Mutations of RRAS2 Are a Rare Cause of Noonan Syndrome. Am J Hum Genet. 2019 Jun 6;104(6):1223-1232. doi: 10.1016/j.ajhg.2019.04.013. Epub 2019 May 23.
• [27] Noonan Syndrome-Associated SHP2 Dephosphorylates GluN2B to Regulate NMDA Receptor Function.Cell Rep. 2018 Aug 7;24(6):1523-1535. doi: 10.1016/j.celrep.2018.07.006.
• [28] Increased rate of missense/in-frame mutations in individuals with NF1-related pulmonary stenosis: a novel genotype-phenotype correlation.Eur J Hum Genet. 2013 May;21(5):535-9. doi: 10.1038/ejhg.2012.221. Epub 2012 Oct 10.
• [29] The human ribosomal protein L6 gene in a critical region for Noonan syndrome.J Hum Genet. 2000;45(5):290-3. doi: 10.1007/s100380070018.
• [30] An Association of PTPN11 and SHOX Mutations in a Male Presenting With Syndromic Growth Failure.Front Endocrinol (Lausanne). 2018 Sep 20;9:557. doi: 10.3389/fendo.2018.00557. eCollection 2018.
• [31] A review of craniofacial and dental findings of the RASopathies.Orthod Craniofac Res. 2017 Jun;20 Suppl 1(Suppl 1):32-38. doi: 10.1111/ocr.12144.
• [32] Mutational analysis of PTPN11 gene in Taiwanese children with Noonan syndrome.J Formos Med Assoc. 2007 Feb;106(2):169-72. doi: 10.1016/S0929-6646(09)60235-7.