Watson syndrome

Summary

Watson syndrome (MONDO:0008672) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 685

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Watson syndrome
Mondo ID	MONDO:0008672
OMIM	193520
Orphanet	3444
DOID	DOID:0070483
ICD-11	1674178232
SNOMED CT	403820003
UMLS	C0553586
MedGen	107817
GARD	0005540
Is cancer (heuristic)	no

Also known as: Watson syndrome · WTSN

Data availability: 685 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › neurofibromatosis-Noonan syndrome › Watson syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

247 conflicting classifications of pathogenicity, 116 uncertain significance, 64 pathogenic, 61 likely benign, 42 pathogenic/likely pathogenic, 37 benign/likely benign, 20 likely pathogenic, 13 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
3237178	GRCh37/hg19 17q11.2(chr17:29000019-30416429)	CRLF3	Pathogenic	criteria provided, single submitter
1069238	NM_001042492.3(NF1):c.60+2T>C	LOC111811965	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
186896	NM_001042492.3(NF1):c.55G>T (p.Glu19Ter)	LOC111811965	Pathogenic	criteria provided, multiple submitters, no conflicts
230597	NM_001042492.3(NF1):c.31C>T (p.Gln11Ter)	LOC111811965	Pathogenic	criteria provided, multiple submitters, no conflicts
2736490	NM_001042492.3(NF1):c.3G>T (p.Met1Ile)	LOC111811965	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1036158	NM_001042492.3(NF1):c.3586C>T (p.Leu1196Phe)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1048696	NM_001042492.3(NF1):c.3104del (p.Met1035fs)	NF1	Pathogenic	criteria provided, single submitter
1069722	NM_001042492.3(NF1):c.3628G>T (p.Glu1210Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1070937	NM_001042492.3(NF1):c.5585T>G (p.Leu1862Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072070	NM_001042492.3(NF1):c.5158del (p.Glu1720fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1213688	NM_001042492.3(NF1):c.1882del (p.Tyr628fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1360877	NM_001042492.3(NF1):c.4980dup (p.Lys1661Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387584	NM_001042492.3(NF1):c.4760del (p.Ala1586_Leu1587insTer)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1421521	NM_001042492.3(NF1):c.4515del (p.Ala1506fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1527847	NM_001042492.3(NF1):c.6897del (p.Lys2300fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
184261	NM_001042492.3(NF1):c.7909C>T (p.Arg2637Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
185021	NM_001042492.3(NF1):c.499_502del (p.Cys167fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
185082	NM_001042492.3(NF1):c.6855C>A (p.Tyr2285Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
185354	NM_001042492.3(NF1):c.5609G>A (p.Arg1870Gln)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
186215	NM_001042492.3(NF1):c.1756_1759del (p.Thr586fs)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
187652	NM_001042492.3(NF1):c.5782G>T (p.Glu1928Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
187722	NM_001042492.3(NF1):c.910C>T (p.Arg304Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2024252	NM_001042492.3(NF1):c.1062+2T>A	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2025724	NM_001042492.3(NF1):c.1131dup (p.Asp378Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2039653	NM_001042492.3(NF1):c.7063-2A>T	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
208853	NM_001042492.3(NF1):c.5488C>T (p.Arg1830Cys)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts
208854	NM_001042492.3(NF1):c.5489G>T (p.Arg1830Leu)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
220152	NM_001042492.3(NF1):c.4600C>T (p.Arg1534Ter)	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
220715	NM_001042492.3(NF1):c.7153AACTTT[1] (p.2385NF[1])	NF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228381	NM_001042492.3(NF1):c.5305C>T (p.Arg1769Ter)	NF1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NF1	Orphanet:139474	17q11.2 microduplication syndrome
NF1	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
NF1	Orphanet:293199	Pleomorphic rhabdomyosarcoma
NF1	Orphanet:363700	Neurofibromatosis type 1 due to NF1 mutation or intragenic deletion
NF1	Orphanet:638	Neurofibromatosis-Noonan syndrome
NF1	Orphanet:86834	Juvenile myelomonocytic leukemia
NF1	Orphanet:97685	17q11 microdeletion syndrome
NF1	Orphanet:99756	Alveolar rhabdomyosarcoma
NF1	Orphanet:99757	Embryonal rhabdomyosarcoma

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CRLF3	HGNC:17177	ENSG00000176390	Q8IUI8	Cytokine receptor-like factor 3	clinvar
MIR4733HG	HGNC:55332	ENSG00000264107		MIR4733 host gene	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRLF3	Cytokine receptor-like factor 3	May play a role in the negative regulation of cell cycle progression.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Antibody/Immunoglobulin	1	9.7×	0.199
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRLF3	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, FN3_sf
MIR4733HG	Other/Unknown	no
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	1
mononuclear cell	1
trabecular bone tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
sural nerve	1
adrenal tissue	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRLF3	287	ubiquitous	marker	trabecular bone tissue, mononuclear cell, leukocyte
MIR4733HG	130		yes	sural nerve, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NF1	5,540
CRLF3	776
MIR4733HG	0

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NF1	P21359	26

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CRLF3	Q8IUI8	90.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RAS signaling downstream of NF1 loss-of-function variants	1	1631.4×	0.006	NF1
Oncogenic MAPK signaling	1	248.3×	0.015	NF1
Regulation of RAS by GAPs	1	193.6×	0.015	NF1
MAPK1/MAPK3 signaling	1	131.3×	0.017	NF1
MAPK family signaling cascades	1	102.9×	0.017	NF1
RAF/MAP kinase cascade	1	61.1×	0.023	NF1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	NF1
Disease	1	13.1×	0.086	NF1
Signal Transduction	1	10.2×	0.098	NF1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of mast cell apoptotic process	1	8426.0×	0.003	NF1
regulation of glial cell differentiation	1	8426.0×	0.003	NF1
observational learning	1	8426.0×	0.003	NF1
gamma-aminobutyric acid secretion, neurotransmission	1	4213.0×	0.003	NF1
Schwann cell proliferation	1	2808.7×	0.003	NF1
forebrain astrocyte development	1	2808.7×	0.003	NF1
Schwann cell migration	1	2808.7×	0.003	NF1
glutamate secretion, neurotransmission	1	2808.7×	0.003	NF1
negative regulation of mast cell proliferation	1	2808.7×	0.003	NF1
negative regulation of Schwann cell migration	1	2808.7×	0.003	NF1
vascular associated smooth muscle cell migration	1	2808.7×	0.003	NF1
mast cell apoptotic process	1	2106.5×	0.003	NF1
negative regulation of Rac protein signal transduction	1	2106.5×	0.003	NF1
myeloid leukocyte migration	1	2106.5×	0.003	NF1
mast cell proliferation	1	1685.2×	0.004	NF1
amygdala development	1	1404.3×	0.004	NF1
regulation of blood vessel endothelial cell migration	1	1404.3×	0.004	NF1
vascular associated smooth muscle cell proliferation	1	1404.3×	0.004	NF1
negative regulation of Schwann cell proliferation	1	1203.7×	0.004	NF1
negative regulation of neurotransmitter secretion	1	1203.7×	0.004	NF1
hair follicle maturation	1	1053.2×	0.005	NF1
negative regulation of leukocyte migration	1	842.6×	0.005	NF1
negative regulation of vascular associated smooth muscle cell migration	1	842.6×	0.005	NF1
regulation of bone resorption	1	766.0×	0.005	NF1
negative regulation of astrocyte differentiation	1	766.0×	0.005	NF1
regulation of long-term synaptic potentiation	1	766.0×	0.005	NF1
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	766.0×	0.005	NF1
forebrain morphogenesis	1	702.2×	0.005	NF1
regulation of cell-matrix adhesion	1	648.1×	0.005	NF1
negative regulation of neuroblast proliferation	1	601.9×	0.006	NF1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CRLF3	0	0
MIR4733HG	0	0
NF1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	CRLF3
E	Difficult family or no structure, no drug	2	MIR4733HG, NF1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CRLF3	0	—
MIR4733HG	0	—
NF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.