Legius syndrome

Summary

Legius syndrome (MONDO:0012669) is a disease caused by SPRED1 (GenCC Definitive), with 1 cohort gene and 5 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: SPRED1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 817
• Phenotypes (HPO): 42
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 100 000	2.2	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0007565	Multiple cafe-au-lait spots	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000997	Axillary freckling	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0030052	Inguinal freckling	Frequent (30-79%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0000766	Abnormal sternum morphology	Occasional (5-29%)
HP:0001012	Multiple lipomas	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0001067	Neurofibromas	Excluded (0%)
HP:0009734	Optic nerve glioma	Excluded (0%)
HP:0009737	Lisch nodules	Excluded (0%)
HP:0100006	Neoplasm of the central nervous system	Excluded (0%)
HP:0100252	Diaphyseal dysplasia	Excluded (0%)
HP:0000365	Hearing impairment	Very rare (<1-4%)
HP:0000518	Cataract	Very rare (<1-4%)
HP:0000750	Delayed speech and language development	Very rare (<1-4%)
HP:0000787	Nephrolithiasis	Very rare (<1-4%)
HP:0001114	Xanthelasma	Very rare (<1-4%)
HP:0001250	Seizure	Very rare (<1-4%)
HP:0001252	Hypotonia	Very rare (<1-4%)
HP:0001270	Motor delay	Very rare (<1-4%)
HP:0001332	Dystonia	Very rare (<1-4%)
HP:0001634	Mitral valve prolapse	Very rare (<1-4%)
HP:0001642	Pulmonic stenosis	Very rare (<1-4%)
HP:0002650	Scoliosis	Very rare (<1-4%)
HP:0002667	Nephroblastoma	Very rare (<1-4%)
HP:0004209	Clinodactyly of the 5th finger	Very rare (<1-4%)
HP:0004845	Acute monocytic leukemia	Very rare (<1-4%)
HP:0006671	Paroxysmal atrial tachycardia	Very rare (<1-4%)
HP:0007018	Attention deficit hyperactivity disorder	Very rare (<1-4%)
HP:0007099	Chiari type I malformation	Very rare (<1-4%)
HP:0009588	Vestibular schwannoma	Very rare (<1-4%)
HP:0010442	Polydactyly	Very rare (<1-4%)
HP:0030358	Non-small cell lung carcinoma	Very rare (<1-4%)
HP:0032077	Male urethral meatus stenosis	Very rare (<1-4%)
HP:0100245	Desmoid tumors	Very rare (<1-4%)
HP:0100543	Cognitive impairment	Very rare (<1-4%)
HP:0100615	Ovarian neoplasm	Very rare (<1-4%)
HP:0410263	Brain imaging abnormality	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Legius syndrome
Mondo ID	MONDO:0012669
MeSH	C548032
OMIM	611431
Orphanet	137605
DOID	DOID:0070484
ICD-11	1025118245
NCIT	C176941
SNOMED CT	703541007
UMLS	C1969623
MedGen	370709
GARD	0010714
Is cancer (heuristic)	no

Also known as: Legius syndrome · neurofibromatosis 1-like syndrome · neurofibromatosis type 1 like syndrome · NF1-like syndrome

Data availability: 817 ClinVar variants · 7 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › integumentary system disorder › skin disorder › skin pigmentation disorder › hyperpigmentation of the skin › Legius syndrome

Related subtypes (23): dyschromatosis universalis hereditaria, cafe au lait spots, multiple, dermatopathia pigmentosa reticularis, dyschromatosis symmetrica hereditaria, extrasystoles-short stature-hyperpigmentation-microcephaly syndrome, gastrocutaneous syndrome, hyperkeratosis-hyperpigmentation syndrome, familial generalized lentiginosis, Naegeli-Franceschetti-Jadassohn syndrome, schwannomatosis, Dowling-Degos disease, H syndrome, familial progressive hyperpigmentation, linear and whorled nevoid hypermelanosis, reticulate acropigmentation of Kitamura, nail and teeth abnormalities-marginal palmoplantar keratoderma-oral hyperpigmentation syndrome, severe growth deficiency-strabismus-extensive dermal melanocytosis-intellectual disability syndrome, leukonychia totalis-acanthosis-nigricans-like lesions-abnormal hair syndrome, osteopathia striata-pigmentary dermopathy-white forelock syndrome, phakomatosis pigmentovascularis, acromelanosis, hyperpigmentation, progressive cribriform and zosteriform, mosaic Legius 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:

264 uncertain significance, 159 likely benign, 79 pathogenic, 36 conflicting classifications of pathogenicity, 23 benign, 22 likely pathogenic, 9 benign/likely benign, 8 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068067	NM_152594.3(SPRED1):c.207+1G>T	SPRED1	Pathogenic	criteria provided, single submitter
1068652	NM_152594.3(SPRED1):c.1232_1241del (p.Ser411fs)	SPRED1	Pathogenic	criteria provided, single submitter
1068945	NM_152594.3(SPRED1):c.794dup (p.Asp265fs)	SPRED1	Pathogenic	criteria provided, single submitter
1072751	NM_152594.3(SPRED1):c.385G>T (p.Glu129Ter)	SPRED1	Pathogenic	criteria provided, single submitter
1073447	NC_000015.9:g.(?38545367)(38545438_?)del	SPRED1	Pathogenic	criteria provided, single submitter
1073448	NC_000015.9:g.(?38591568)(38643870_?)del	SPRED1	Pathogenic	criteria provided, single submitter
1073547	NM_152594.3(SPRED1):c.841C>T (p.Gln281Ter)	SPRED1	Pathogenic	criteria provided, single submitter
1075013	NM_152594.3(SPRED1):c.783C>A (p.Tyr261Ter)	SPRED1	Pathogenic	criteria provided, single submitter
1300146	NM_152594.3(SPRED1):c.148C>T (p.Gln50Ter)	SPRED1	Pathogenic	criteria provided, multiple submitters, no conflicts
1334204	NM_152594.3(SPRED1):c.1044_1056del (p.Gly350fs)	SPRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334310	NM_152594.3(SPRED1):c.229A>T (p.Lys77Ter)	SPRED1	Pathogenic	criteria provided, multiple submitters, no conflicts
1335175	NM_152594.3(SPRED1):c.751C>T (p.Arg251Ter)	SPRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1386579	NM_152594.3(SPRED1):c.40del (p.Tyr14fs)	SPRED1	Pathogenic	criteria provided, single submitter
1389357	NM_152594.3(SPRED1):c.1175C>A (p.Ser392Ter)	SPRED1	Pathogenic	criteria provided, single submitter
1391856	NM_152594.3(SPRED1):c.1011C>A (p.Tyr337Ter)	SPRED1	Pathogenic	criteria provided, single submitter
1401830	NM_152594.3(SPRED1):c.1132_1139del (p.His378fs)	SPRED1	Pathogenic	criteria provided, single submitter
1407466	NM_152594.3(SPRED1):c.305C>T (p.Thr102Met)	SPRED1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1415230	NM_152594.3(SPRED1):c.692del (p.Pro230_Leu231insTer)	SPRED1	Pathogenic	criteria provided, single submitter
1420112	NM_152594.3(SPRED1):c.305del (p.Thr102fs)	SPRED1	Pathogenic	criteria provided, single submitter
1451597	NM_152594.3(SPRED1):c.613C>T (p.Gln205Ter)	SPRED1	Pathogenic	criteria provided, single submitter
1452330	NM_152594.3(SPRED1):c.1237_1238del (p.Ile413fs)	SPRED1	Pathogenic	criteria provided, single submitter
1457112	NC_000015.9:g.(?38545387)(38643865_?)del	SPRED1	Pathogenic	criteria provided, single submitter
1693579	NM_152594.3(SPRED1):c.1273del (p.Met425fs)	SPRED1	Pathogenic	criteria provided, single submitter
1699114	NM_152594.3(SPRED1):c.475del (p.Gln159fs)	SPRED1	Pathogenic	criteria provided, single submitter
1804995	NM_152594.3(SPRED1):c.950C>G (p.Ser317Ter)	SPRED1	Pathogenic	criteria provided, single submitter
1809	NM_152594.3(SPRED1):c.349C>T (p.Arg117Ter)	SPRED1	Pathogenic	criteria provided, multiple submitters, no conflicts
1810	NM_152594.3(SPRED1):c.70C>T (p.Arg24Ter)	SPRED1	Pathogenic	criteria provided, multiple submitters, no conflicts
1811	NM_152594.3(SPRED1):c.423+1G>A	SPRED1	Pathogenic	no assertion criteria provided
1812	NM_152594.3(SPRED1):c.643C>T (p.Gln215Ter)	SPRED1	Pathogenic	no assertion criteria provided
1813	NM_152594.3(SPRED1):c.190C>T (p.Arg64Ter)	SPRED1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SPRED1	Definitive	Autosomal dominant	Legius syndrome	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPRED1	Orphanet:137605	Legius syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SPRED1	HGNC:20249	ENSG00000166068	Q7Z699	Sprouty-related, EVH1 domain-containing protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPRED1	Sprouty-related, EVH1 domain-containing protein 1	Tyrosine kinase substrate that inhibits growth-factor-mediated activation of MAP kinase.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPRED1	Other/Unknown	no		WH1/EVH1_dom, Sprouty, PH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
mucosa of sigmoid colon	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPRED1	248	ubiquitous	marker	ventricular zone, mucosa of sigmoid colon, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SPRED1	2,744

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SPRED1	Q7Z699	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 1 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×	0.005	SPRED1
FGFRL1 modulation of FGFR1 signaling	1	878.5×	0.005	SPRED1
Signaling by FGFR1	1	815.7×	0.005	SPRED1
Signaling by FGFR	1	346.1×	0.009	SPRED1
Oncogenic MAPK signaling	1	248.3×	0.010	SPRED1
Regulation of RAS by GAPs	1	193.6×	0.011	SPRED1
MAPK1/MAPK3 signaling	1	131.3×	0.014	SPRED1
MAPK family signaling cascades	1	102.9×	0.016	SPRED1
RAF/MAP kinase cascade	1	61.1×	0.023	SPRED1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.023	SPRED1
Signaling by Receptor Tyrosine Kinases	1	51.7×	0.023	SPRED1
Disease	1	13.1×	0.083	SPRED1
Signal Transduction	1	10.2×	0.098	SPRED1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vasculogenesis involved in coronary vascular morphogenesis	1	5617.3×	0.002	SPRED1
negative regulation of lens fiber cell differentiation	1	2808.7×	0.002	SPRED1
negative regulation of intracellular signal transduction	1	2106.5×	0.002	SPRED1
positive regulation of DNA damage response, signal transduction by p53 class mediator	1	991.3×	0.002	SPRED1
negative regulation of cell migration involved in sprouting angiogenesis	1	991.3×	0.002	SPRED1
regulation of MAPK cascade	1	455.5×	0.004	SPRED1
negative regulation of epithelial to mesenchymal transition	1	411.0×	0.004	SPRED1
negative regulation of MAPK cascade	1	300.9×	0.005	SPRED1
negative regulation of ERK1 and ERK2 cascade	1	216.1×	0.006	SPRED1
negative regulation of transforming growth factor beta receptor signaling pathway	1	173.7×	0.006	SPRED1
negative regulation of angiogenesis	1	168.5×	0.006	SPRED1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
SPRED1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
E	Difficult family or no structure, no drug	1	SPRED1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SPRED1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04395495	Not specified	RECRUITING	RASopathy Biorepository
NCT04888936	Not specified	RECRUITING	Clinical, Genetic, and Epidemiologic Study of Children and Adults With RASopathies
NCT05361811	Not specified	RECRUITING	Acceptance and Commitment Therapy for Caregivers of Children With a RASopathy: An Internal Pilot Feasibility Study and Follow-up Randomized Controlled Trial
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT00111384	Not specified	COMPLETED	Study of Disease Severity in Adults With Neurofibromatosis Type 1 (NF1)