intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies

Summary

intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies (MONDO:0859080) is a disease caused by TFE3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: TFE3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies
Mondo ID	MONDO:0859080
OMIM	301066
UMLS	C5561930
MedGen	1794140
Is cancer (heuristic)	no

Data availability: 22 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, ATR-X-related syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

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

22 retrieved; paginated sample, class counts are floors:

8 pathogenic, 6 likely pathogenic, 6 uncertain significance, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1064791	NM_006521.6(TFE3):c.350G>A (p.Arg117Gln)	TFE3	Pathogenic	criteria provided, multiple submitters, no conflicts
1301857	NM_006521.6(TFE3):c.356A>C (p.Gln119Pro)	TFE3	Pathogenic	no assertion criteria provided
1301858	NM_006521.6(TFE3):c.602A>C (p.Gln201Pro)	TFE3	Pathogenic	no assertion criteria provided
1301861	NM_006521.6(TFE3):c.560C>G (p.Thr187Arg)	TFE3	Pathogenic	no assertion criteria provided
1301863	NM_006521.6(TFE3):c.780+1G>A	TFE3	Pathogenic	no assertion criteria provided
1320026	NM_006521.6(TFE3):c.559A>G (p.Thr187Ala)	TFE3	Pathogenic	criteria provided, single submitter
2444265	NM_006521.6(TFE3):c.560C>A (p.Thr187Lys)	TFE3	Pathogenic	criteria provided, single submitter
3338578	NM_006521.6(TFE3):c.572T>C (p.Leu191Pro)	TFE3	Pathogenic	criteria provided, single submitter
985315	NM_006521.6(TFE3):c.560C>T (p.Thr187Met)	TFE3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320027	NM_006521.6(TFE3):c.569A>G (p.His190Arg)	TFE3	Likely pathogenic	criteria provided, single submitter
1710361	NM_006521.6(TFE3):c.556C>T (p.Pro186Ser)	TFE3	Likely pathogenic	criteria provided, single submitter
1804071	NM_006521.6(TFE3):c.374_379del (p.123AQ[1])	TFE3	Likely pathogenic	criteria provided, single submitter
2505508	NM_006521.6(TFE3):c.556C>A (p.Pro186Thr)	TFE3	Likely pathogenic	criteria provided, single submitter
4056438	NM_006521.6(TFE3):c.608T>C (p.Leu203Pro)	TFE3	Likely pathogenic	criteria provided, single submitter
992855	NM_006521.6(TFE3):c.557C>T (p.Pro186Leu)	TFE3	Likely pathogenic	criteria provided, single submitter
2660498	NM_006521.6(TFE3):c.1592G>A (p.Gly531Glu)	TFE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1333242	NM_006521.6(TFE3):c.583_597dup (p.Arg195_Val199dup)	TFE3	Uncertain significance	criteria provided, single submitter
1333284	NM_006521.6(TFE3):c.569_583del (p.His190_Ala194del)	TFE3	Uncertain significance	criteria provided, single submitter
2578549	NM_006521.6(TFE3):c.593A>C (p.Gln198Pro)	TFE3	Uncertain significance	criteria provided, single submitter
2671717	NM_006521.6(TFE3):c.780+1_780+2dup	TFE3	Uncertain significance	criteria provided, single submitter
3362341	NM_006521.6(TFE3):c.659C>T (p.Pro220Leu)	TFE3	Uncertain significance	criteria provided, single submitter
3894567	NM_006521.6(TFE3):c.534+8G>A	TFE3	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 3 · 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
TFE3	Definitive	X-linked	intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TFE3	Orphanet:157791	Epithelioid hemangioendothelioma
TFE3	Orphanet:163699	Alveolar soft tissue sarcoma
TFE3	Orphanet:319308	MiT family translocation renal cell carcinoma

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
TFE3	HGNC:11752	ENSG00000068323	P19532	Transcription factor E3	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TFE3	Transcription factor E3	Transcription factor that acts as a master regulator of lysosomal biogenesis and immune response.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TFE3	Transcription factor	no		bHLH_dom, MiT/TFE_C, bHLHzip_TFE3

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
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
olfactory bulb	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TFE3	292	ubiquitous	marker	inferior olivary complex, dorsal motor nucleus of vagus nerve, olfactory bulb

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TFE3	2,278

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TFE3	P19532	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.013	TFE3
MITF-M-regulated melanocyte development	1	114.2×	0.013	TFE3
Developmental Biology	1	14.5×	0.069	TFE3

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
regulation of osteoclast differentiation	1	1532.0×	0.005	TFE3
positive regulation of brown fat cell differentiation	1	991.3×	0.005	TFE3
negative regulation of cold-induced thermogenesis	1	343.9×	0.006	TFE3
lysosome organization	1	306.4×	0.006	TFE3
humoral immune response	1	280.9×	0.006	TFE3
positive regulation of cell adhesion	1	271.8×	0.006	TFE3
adaptive immune response	1	84.3×	0.017	TFE3
positive regulation of DNA-templated transcription	1	27.9×	0.045	TFE3
positive regulation of transcription by RNA polymerase II	1	14.9×	0.075	TFE3
regulation of transcription by RNA polymerase II	1	11.7×	0.086	TFE3

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TFE3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
TFE3	3	Binding:3

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	TFE3

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)
TFE3	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.