NS4
MCID: NNN011
MIFTS: 40

Noonan Syndrome 4 (NS4)

Categories: Cardiovascular diseases, Ear diseases, Endocrine diseases, Eye diseases, Fetal diseases, Genetic diseases, Nephrological diseases, Neuronal diseases, Rare diseases, Reproductive diseases, Skin diseases

Aliases & Classifications for Noonan Syndrome 4

Summaries for Noonan Syndrome 4

UniProtKB/Swiss-Prot : 75 Noonan syndrome 4: A form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells. Some patients with NS4 have polyarticular villonodular synovitis.

MalaCards based summary : Noonan Syndrome 4, also known as ns4, is related to noonan syndrome 3 and hepatitis. An important gene associated with Noonan Syndrome 4 is SOS1 (SOS Ras/Rac Guanine Nucleotide Exchange Factor 1), and among its related pathways/superpathways is Class I PI3K signaling events. The drugs Interferon-alpha and Immunologic Factors have been mentioned in the context of this disorder. Affiliated tissues include skin, heart and eye, and related phenotypes are macrocephaly and hypertelorism

Disease Ontology : 12 A Noonan syndrome that has material basis in heterozygous mutation in the SOS1 gene on chromosome 2p22.

Description from OMIM: 610733

Related Diseases for Noonan Syndrome 4

Diseases in the Noonan Syndrome 1 family:

Noonan Syndrome 2 Noonan Syndrome 3
Noonan Syndrome 4 Noonan Syndrome 5
Noonan Syndrome 6 Noonan Syndrome 7
Noonan Syndrome 8 Noonan Syndrome 9
Noonan Syndrome 10

Diseases related to Noonan Syndrome 4 via text searches within MalaCards or GeneCards Suite gene sharing:

(show all 15)
# Related Disease Score Top Affiliating Genes
1 noonan syndrome 3 29.3 BMPER ITPA SOS1 STAT2
2 hepatitis 10.6
3 hepatitis c virus 10.6
4 hepatitis c 10.6
5 hepatocellular carcinoma 9.9
6 noonan syndrome 2 9.9
7 noonan syndrome 5 9.9
8 dengue virus 9.9
9 hepatitis b 9.9
10 liver cirrhosis 9.9
11 vaccinia 9.9
12 rubella 9.9
13 viral infectious disease 9.9
14 noonan syndrome 6 9.8 CTTNBP2 ITPA
15 noonan syndrome 1 9.5 BMPER CTTNBP2 RD3 SOS1 STAT2

Graphical network of the top 20 diseases related to Noonan Syndrome 4:



Diseases related to Noonan Syndrome 4

Symptoms & Phenotypes for Noonan Syndrome 4

Symptoms via clinical synopsis from OMIM:

57
Head And Neck Head:
macrocephaly

Head And Neck Neck:
short neck
webbed neck

Head And Neck Teeth:
dental malocclusion

Cardiovascular Heart:
hypertrophic cardiomyopathy
pulmonic stenosis
congenital heart defect
ventricular septal defects

Skeletal Limbs:
cubitus valgus
blunt fingertips
polyarticular villonodular synovitis in knees, ankles, wrists, and/or elbows (in some patients)

Head And Neck Mouth:
thick lips

Head And Neck Nose:
flat nasal bridge

Head And Neck Ears:
low-set posteriorly rotated ears

Neoplasia:
multiple giant cell granulomas (bones, joints, soft tissues)

Hematology:
prolonged bleeding time (less common)

Head And Neck Eyes:
hypertelorism
ptosis
downslanting palpebral fissures
epicanthal folds
blue eyes
more
Skeletal Spine:
scoliosis

Growth Height:
short stature

Genitourinary Internal Genitalia Male:
cryptorchidism

Skin Nails Hair Hair:
curly hair
high anterior hairline
sparse eyebrows

Chest Breasts:
widely spaced nipples

Skin Nails Hair Skin:
keratosis pilaris
ectodermal symptoms

Chest Ribs Sternum Clavicles And Scapulae:
pectus excavatum inferiorly

Neurologic Central Nervous System:
mild cognitive impairment (less common)

Laboratory Abnormalities:
partial deficiency of factor xi (less common)
partial deficiency of factor xiii (less common)


Clinical features from OMIM:

610733

Human phenotypes related to Noonan Syndrome 4:

32 (show all 25)
# Description HPO Frequency HPO Source Accession
1 macrocephaly 32 HP:0000256
2 hypertelorism 32 HP:0000316
3 short neck 32 HP:0000470
4 ptosis 32 HP:0000508
5 scoliosis 32 HP:0002650
6 dental malocclusion 32 HP:0000689
7 depressed nasal bridge 32 HP:0005280
8 short stature 32 HP:0004322
9 hypertrophic cardiomyopathy 32 HP:0001639
10 thick lower lip vermilion 32 HP:0000179
11 epicanthus 32 HP:0000286
12 cryptorchidism 32 HP:0000028
13 cubitus valgus 32 HP:0002967
14 wide intermamillary distance 32 HP:0006610
15 webbed neck 32 HP:0000465
16 blue irides 32 HP:0000635
17 low-set, posteriorly rotated ears 32 HP:0000368
18 downslanted palpebral fissures 32 HP:0000494
19 ventricular septal defect 32 HP:0001629
20 prolonged bleeding time 32 occasional (7.5%) HP:0003010
21 pulmonic stenosis 32 HP:0001642
22 curly hair 32 HP:0002212
23 high anterior hairline 32 HP:0009890
24 sparse and thin eyebrow 32 HP:0000535
25 pectus excavatum of inferior sternum 32 HP:0000915

Drugs & Therapeutics for Noonan Syndrome 4

Drugs for Noonan Syndrome 4 (from DrugBank, HMDB, Dgidb, PharmGKB, IUPHAR, NovoSeek, BitterDB):

(show all 10)
# Name Status Phase Clinical Trials Cas Number PubChem Id
1 Interferon-alpha Phase 1, Phase 2
2 Immunologic Factors Phase 1, Phase 2
3 Vaccines Phase 1, Phase 2
4 Pharmaceutical Solutions Phase 1
5
Histamine Approved, Investigational 51-45-6, 75614-87-8 774
6 Neurotransmitter Agents
7
Histamine Phosphate 51-74-1 65513
8 Histamine Antagonists
9 Histamine H2 Antagonists
10 Histamine H1 Antagonists

Interventional clinical trials:


# Name Status NCT ID Phase Drugs
1 Autologous Dendritic Cell Vaccine for Treatment of Patients With Chronic HCV-Infection Recruiting NCT03119025 Phase 1, Phase 2
2 Evaluation of Safety, Tolerability, and Immunogenicity Study of GLS-6150 in Healthy Volunteers and in Persons Previously Treated for Hepatitis C Virus Infection Recruiting NCT03674125 Phase 1
3 TG4040 in Patients With Chronic HCV Withdrawn NCT00449124 Phase 1 Placebo
4 Physical Condition in Lipedema and Obesity Completed NCT01759004 Not Applicable
5 Efficacy of Antihistamine Dosing-up and add-on Treatment With H2-receptor Antagonist Recruiting NCT03293225

Search NIH Clinical Center for Noonan Syndrome 4

Genetic Tests for Noonan Syndrome 4

Genetic tests related to Noonan Syndrome 4:

# Genetic test Affiliating Genes
1 Noonan Syndrome 4 29 SOS1

Anatomical Context for Noonan Syndrome 4

MalaCards organs/tissues related to Noonan Syndrome 4:

41
Skin, Heart, Eye, Bone, Liver, T Cells, B Cells

Publications for Noonan Syndrome 4

Articles related to Noonan Syndrome 4:

(show all 32)
# Title Authors Year
1
Dengue virus NS2 and NS4: Minor proteins, mammoth roles. ( 29674002 )
2018
2
Discrepancy between Hepatitis C Virus Genotypes and NS4-Based Serotypes: Association with Their Subgenomic Sequences. ( 28106726 )
2017
3
Bluetongue Virus NS4 Protein Is an Interferon Antagonist and a Determinant of Virus Virulence. ( 27009961 )
2016
4
Impact of Hepatitis C Virus/Schistosoma mansoni Coinfection on the Circulating Levels of HCV-NS4 Protein and Extracellular-Matrix Deposition in Patients with Different Hepatic Fibrosis Stages. ( 27527625 )
2016
5
Characterising Non-Structural Protein NS4 of African Horse Sickness Virus. ( 25915516 )
2015
6
Biotransformation and mass balance of faldaprevir, a hepatitis C NS3/NS4 protease inhibitor in rats. ( 24831541 )
2014
7
Nonstructural protein NS4 of Rice Stripe Virus plays a critical role in viral spread in the body of vector insects. ( 24523924 )
2014
8
Diagnostic performances of hepatitis C virus-NS4 antigen in patients with different liver pathologies. ( 23085447 )
2012
9
Rational approach to endo/exocoordinated heteronuclear macrocyclic network: supramolecular Hg(ll), Cu(ll), and Hg(ll)/Cu(ll) complexes of a NS4 macrocycle. ( 21604706 )
2011
10
Generation and characterization of chimeric antibodies against NS3, NS4, NS5, and core antigens of hepatitis C virus. ( 20427624 )
2010
11
The Journey to the Discovery of Boceprevir: an NS3-NS4 HCV protease inhibitor for the treatment of chronic hepatitis C. ( 20855037 )
2010
12
Effect of disease state on ionization during bioanalysis of MK-7009, a selective HCV NS3/NS4 protease inhibitor, in human plasma and human Tween-treated urine by high-performance liquid chromatography with tandem mass spectrometric detection. ( 19328051 )
2009
13
Priming and stimulation of hepatitis C virus-specific CD4+ and CD8+ T cells against HCV antigens NS4, NS5a or NS5b from HCV-naive individuals: implications for prophylactic vaccine. ( 18006878 )
2008
14
Minimal T-cell-stimulatory sequences and spectrum of HLA restriction of immunodominant CD4+ T-cell epitopes within hepatitis C virus NS3 and NS4 proteins. ( 16160170 )
2005
15
Low-level hepatitis C viremia and humoral immune response to NS4 in chronic hepatitis B virus-hepatitis C virus coinfection. ( 15513365 )
2004
16
Bovine coronaviruses associated with enteric and respiratory diseases in Canadian dairy cattle display different reactivities to anti-HE monoclonal antibodies and distinct amino acid changes in their HE, S and ns4.9 protein. ( 11376845 )
2001
17
Antigenic heterogeneity of the hepatitis C virus NS4 protein as modeled with synthetic peptides. ( 10208931 )
1999
18
Artificial NS4 mosaic antigen of hepatitis C virus. ( 10534724 )
1999
19
Serological Genotyping Using Synthetic Peptides Derived from the NS4 Region. ( 21374361 )
1999
20
Immune response to an epitope of the NS4 protein of hepatitis C virus in HCV-related disorders. ( 9614926 )
1998
21
Hepatitis C virus serotype-specific core and NS4 antibodies in injecting drug users participating in the Amsterdam cohort studies. ( 9738057 )
1998
22
Recognition of a novel naturally processed, A2 restricted, HCV-NS4 epitope triggers IFN-gamma release in absence of detectable cytopathicity. ( 9831133 )
1998
23
Concordance of hepatitis C virus typing methods based on restriction fragment length polymorphism analysis in 5' noncoding region and NS4 serotyping, but not in core PCR or a line probe assay. ( 8968938 )
1997
24
Identification of strain-specific nucleotide sequences in E1 and NS4 genes of rubella virus vaccine strains in Japan. ( 9330471 )
1997
25
Linear B-cell epitopes of the NS3-NS4-NS5 proteins of the hepatitis C virus as modeled with synthetic peptides. ( 7530398 )
1995
26
Cloning and phylogenetic analysis of the core, E2, and NS3/NS4 regions of the hepatitis C virus type 5a. ( 7520237 )
1994
27
Properties of a human monoclonal antibody specific for the NS4 region of hepatitis C virus. ( 7691925 )
1993
28
Compartmentalization of T lymphocytes to the site of disease: intrahepatic CD4+ T cells specific for the protein NS4 of hepatitis C virus in patients with chronic hepatitis C. ( 8100267 )
1993
29
Immunohistochemical detection of the NS4 antigen of hepatitis C virus and its relation to histopathology. ( 8256849 )
1993
30
Nonstructural protein 3 of the hepatitis C virus encodes a serine-type proteinase required for cleavage at the NS3/4 and NS4/5 junctions. ( 8389908 )
1993
31
Production and characterization of a human monoclonal antibody to the hepatitis C virus NS4 region. ( 8396822 )
1993
32
Mouse hepatitis virus S RNA sequence reveals that nonstructural proteins ns4 and ns5a are not essential for murine coronavirus replication. ( 1654456 )
1991

Variations for Noonan Syndrome 4

UniProtKB/Swiss-Prot genetic disease variations for Noonan Syndrome 4:

75 (show all 37)
# Symbol AA change Variation ID SNP ID
1 SOS1 p.Glu108Lys VAR_030423 rs397517164
2 SOS1 p.Thr266Lys VAR_030424 rs137852812
3 SOS1 p.Met269Arg VAR_030425 rs137852813
4 SOS1 p.Asp309Tyr VAR_030426 rs397517180
5 SOS1 p.Tyr337Cys VAR_030427 rs724160007
6 SOS1 p.Trp432Arg VAR_030428 rs267607080
7 SOS1 p.Glu433Lys VAR_030429 rs397517147
8 SOS1 p.Gly434Arg VAR_030430 rs397517148
9 SOS1 p.Cys441Tyr VAR_030431 rs727504295
10 SOS1 p.Ser548Arg VAR_030432 rs397517149
11 SOS1 p.Leu550Pro VAR_030433 rs397517153
12 SOS1 p.Arg552Gly VAR_030434 rs137852814
13 SOS1 p.Arg552Lys VAR_030435 rs397517154
14 SOS1 p.Arg552Ser VAR_030436 rs267607079
15 SOS1 p.Tyr702His VAR_030438 rs727505381
16 SOS1 p.Trp729Leu VAR_030439
17 SOS1 p.Ile733Phe VAR_030440 rs574088829
18 SOS1 p.Glu846Lys VAR_030441 rs397517159
19 SOS1 p.Met269Thr VAR_064504 rs137852813
20 SOS1 p.Gln477Arg VAR_064505 rs730881044
21 SOS1 p.Arg497Gln VAR_064506 rs371314838
22 SOS1 p.Pro102Arg VAR_066032
23 SOS1 p.Pro112Arg VAR_066033 rs397517166
24 SOS1 p.Lys170Glu VAR_066034 rs397517172
25 SOS1 p.Ile252Thr VAR_066035 rs142094234
26 SOS1 p.Met422Val VAR_066037
27 SOS1 p.Glu424Lys VAR_066038 rs730881041
28 SOS1 p.Gly434Lys VAR_066041 rs730881048
29 SOS1 p.Ile437Thr VAR_066042 rs397517150
30 SOS1 p.Pro478Arg VAR_066044
31 SOS1 p.Gly482Arg VAR_066045 rs143157438
32 SOS1 p.Leu490Arg VAR_066046
33 SOS1 p.Thr549Lys VAR_066047 rs730881046
34 SOS1 p.Arg552Met VAR_066048
35 SOS1 p.Arg552Thr VAR_066049 rs397517154
36 SOS1 p.Phe623Ile VAR_066052
37 SOS1 p.Pro894Arg VAR_066055 rs136771475

ClinVar genetic disease variations for Noonan Syndrome 4:

6 (show all 30)
# Gene Variation Type Significance SNP ID Assembly Location
1 SOS1 NM_005633.3(SOS1): c.797C> A (p.Thr266Lys) single nucleotide variant Pathogenic rs137852812 GRCh37 Chromosome 2, 39278352: 39278352
2 SOS1 NM_005633.3(SOS1): c.797C> A (p.Thr266Lys) single nucleotide variant Pathogenic rs137852812 GRCh38 Chromosome 2, 39051211: 39051211
3 SOS1 NM_005633.3(SOS1): c.806T> G (p.Met269Arg) single nucleotide variant Pathogenic rs137852813 GRCh37 Chromosome 2, 39278343: 39278343
4 SOS1 NM_005633.3(SOS1): c.806T> G (p.Met269Arg) single nucleotide variant Pathogenic rs137852813 GRCh38 Chromosome 2, 39051202: 39051202
5 SOS1 NM_005633.3(SOS1): c.1654A> G (p.Arg552Gly) single nucleotide variant Pathogenic rs137852814 GRCh37 Chromosome 2, 39249915: 39249915
6 SOS1 NM_005633.3(SOS1): c.1654A> G (p.Arg552Gly) single nucleotide variant Pathogenic rs137852814 GRCh38 Chromosome 2, 39022774: 39022774
7 SOS1 NM_005633.3(SOS1): c.1656G> C (p.Arg552Ser) single nucleotide variant Pathogenic rs267607079 GRCh37 Chromosome 2, 39249913: 39249913
8 SOS1 NM_005633.3(SOS1): c.1656G> C (p.Arg552Ser) single nucleotide variant Pathogenic rs267607079 GRCh38 Chromosome 2, 39022772: 39022772
9 SOS1 NM_005633.3(SOS1): c.1294T> C (p.Trp432Arg) single nucleotide variant Pathogenic rs267607080 GRCh37 Chromosome 2, 39250275: 39250275
10 SOS1 NM_005633.3(SOS1): c.1294T> C (p.Trp432Arg) single nucleotide variant Pathogenic rs267607080 GRCh38 Chromosome 2, 39023134: 39023134
11 SOS1 NM_005633.3(SOS1): c.806T> C (p.Met269Thr) single nucleotide variant Pathogenic rs137852813 GRCh37 Chromosome 2, 39278343: 39278343
12 SOS1 NM_005633.3(SOS1): c.806T> C (p.Met269Thr) single nucleotide variant Pathogenic rs137852813 GRCh38 Chromosome 2, 39051202: 39051202
13 SOS1 NM_005633.3(SOS1): c.1655G> A (p.Arg552Lys) single nucleotide variant Pathogenic rs397517154 GRCh37 Chromosome 2, 39249914: 39249914
14 SOS1 NM_005633.3(SOS1): c.1655G> A (p.Arg552Lys) single nucleotide variant Pathogenic rs397517154 GRCh38 Chromosome 2, 39022773: 39022773
15 SOS1 NM_005633.3(SOS1): c.1656G> T (p.Arg552Ser) single nucleotide variant Pathogenic rs267607079 GRCh37 Chromosome 2, 39249913: 39249913
16 SOS1 NM_005633.3(SOS1): c.1656G> T (p.Arg552Ser) single nucleotide variant Pathogenic rs267607079 GRCh38 Chromosome 2, 39022772: 39022772
17 SOS1 NM_005633.3(SOS1): c.2183A> T (p.Lys728Ile) single nucleotide variant Pathogenic/Likely pathogenic rs397517156 GRCh37 Chromosome 2, 39239474: 39239474
18 SOS1 NM_005633.3(SOS1): c.2183A> T (p.Lys728Ile) single nucleotide variant Pathogenic/Likely pathogenic rs397517156 GRCh38 Chromosome 2, 39012333: 39012333
19 SOS1 NM_005633.3(SOS1): c.3347-1G> A single nucleotide variant Uncertain significance rs141565234 GRCh37 Chromosome 2, 39216456: 39216456
20 SOS1 NM_005633.3(SOS1): c.3347-1G> A single nucleotide variant Uncertain significance rs141565234 GRCh38 Chromosome 2, 38989315: 38989315
21 SOS1 NM_005633.3(SOS1): c.3418T> A (p.Leu1140Ile) single nucleotide variant Uncertain significance rs375550588 GRCh37 Chromosome 2, 39214706: 39214706
22 SOS1 NM_005633.3(SOS1): c.3418T> A (p.Leu1140Ile) single nucleotide variant Uncertain significance rs375550588 GRCh38 Chromosome 2, 38987565: 38987565
23 SOS1 NM_005633.3(SOS1): c.1310T> C (p.Ile437Thr) single nucleotide variant Pathogenic rs397517150 GRCh37 Chromosome 2, 39250259: 39250259
24 SOS1 NM_005633.3(SOS1): c.1310T> C (p.Ile437Thr) single nucleotide variant Pathogenic rs397517150 GRCh38 Chromosome 2, 39023118: 39023118
25 SOS1 NM_005633.3(SOS1): c.2138G> A (p.Arg713Gln) single nucleotide variant Uncertain significance rs483352826 GRCh38 Chromosome 2, 39013489: 39013489
26 SOS1 NM_005633.3(SOS1): c.2138G> A (p.Arg713Gln) single nucleotide variant Uncertain significance rs483352826 GRCh37 Chromosome 2, 39240630: 39240630
27 SOS1 NM_005633.3(SOS1): c.1574T> C (p.Ile525Thr) single nucleotide variant Uncertain significance rs146722878 GRCh37 Chromosome 2, 39249995: 39249995
28 SOS1 NM_005633.3(SOS1): c.1574T> C (p.Ile525Thr) single nucleotide variant Uncertain significance rs146722878 GRCh38 Chromosome 2, 39022854: 39022854
29 SOS1 NM_005633.3(SOS1): c.979A> G (p.Ile327Val) single nucleotide variant Uncertain significance rs758546951 GRCh37 Chromosome 2, 39262448: 39262448
30 SOS1 NM_005633.3(SOS1): c.979A> G (p.Ile327Val) single nucleotide variant Uncertain significance rs758546951 GRCh38 Chromosome 2, 39035307: 39035307

Expression for Noonan Syndrome 4

Search GEO for disease gene expression data for Noonan Syndrome 4.

Pathways for Noonan Syndrome 4

Pathways related to Noonan Syndrome 4 according to GeneCards Suite gene sharing:

# Super pathways Score Top Affiliating Genes
1 10.24 ITK SOS1

GO Terms for Noonan Syndrome 4

Biological processes related to Noonan Syndrome 4 according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 retina development in camera-type eye GO:0060041 8.62 PDE6B RD3

Sources for Noonan Syndrome 4

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 ExPASy
19 FMA
28 GO
29 GTR
30 HGMD
31 HMDB
32 HPO
33 ICD10
34 ICD10 via Orphanet
35 ICD9CM
36 IUPHAR
37 KEGG
38 LifeMap
40 LOVD
42 MedGen
44 MeSH
45 MESH via Orphanet
46 MGI
49 NCI
50 NCIt
51 NDF-RT
54 NINDS
55 Novoseek
57 OMIM
58 OMIM via Orphanet
62 PubMed
64 QIAGEN
69 SNOMED-CT via HPO
70 SNOMED-CT via Orphanet
71 TGDB
72 Tocris
73 UMLS
74 UMLS via Orphanet
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