intellectual disability, X-linked syndromic, Turner type

Summary

intellectual disability, X-linked syndromic, Turner type (MONDO:0010407) is a disease caused by HUWE1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: HUWE1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 234

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked syndromic, Turner type
Mondo ID	MONDO:0010407
MeSH	C563154, C567476
OMIM	300612, 300706, 309590
Orphanet	3056, 85328
DOID	DOID:0060811, DOID:0060829
SNOMED CT	725912001
UMLS	C2678046
MedGen	394425
GARD	0000081
Is cancer (heuristic)	no

Also known as: Brooks Wisniewski Brown syndrome · Brooks-Wisniewski-Brown Syndrome · Brooks-Wisniewski-Brown syndrome · intellectual disability, X-linked syndromic, Turner type · mental retardation and macrocephaly syndrome · mental retardation, X-linked, syndromic, Brooks-Wisniewski-Brown Type · mental retardation, X-linked, syndromic, Brooks-Wisniewski-Brown type · mental retardation, X-linked, syndromic, Turner type · mental retardation, X-Linked, with growth retardation, deafness, and microgenitalism · MRXST · X-linked intellectual disability, Turner type · X-linked mental retardation Brooks type

Data availability: 234 ClinVar variants · 5 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 disability, X-linked syndromic, Turner type

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, 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, with pigmentary mosaicism and coarse facies, 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

234 retrieved; paginated sample, class counts are floors:

151 uncertain significance, 34 likely pathogenic, 22 conflicting classifications of pathogenicity, 9 benign/likely benign, 7 pathogenic, 5 pathogenic/likely pathogenic, 3 benign, 2 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
10676	NM_031407.7(HUWE1):c.12037C>T (p.Arg4013Trp)	HUWE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10677	NM_031407.7(HUWE1):c.8942G>A (p.Arg2981His)	HUWE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320047	NM_031407.7(HUWE1):c.12404A>C (p.His4135Pro)	HUWE1	Pathogenic	criteria provided, single submitter
1334036	NM_031407.7(HUWE1):c.646-1G>A	HUWE1	Pathogenic	criteria provided, single submitter
1703066	NM_031407.7(HUWE1):c.2960del (p.Gly987fs)	HUWE1	Pathogenic	criteria provided, single submitter
280723	NM_031407.7(HUWE1):c.9208C>T (p.Arg3070Cys)	HUWE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3393024	NM_031407.7(HUWE1):c.12091T>C (p.Tyr4031His)	HUWE1	Pathogenic	criteria provided, single submitter
375709	NM_031407.7(HUWE1):c.329G>A (p.Arg110Gln)	HUWE1	Pathogenic	criteria provided, multiple submitters, no conflicts
375711	NM_031407.7(HUWE1):c.567+1G>C	HUWE1	Pathogenic	criteria provided, multiple submitters, no conflicts
375725	NM_031407.7(HUWE1):c.12928G>C (p.Gly4310Arg)	HUWE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419084	NM_031407.7(HUWE1):c.12691T>C (p.Tyr4231His)	HUWE1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
841299	NM_031407.7(HUWE1):c.9209G>A (p.Arg3070His)	HUWE1	Pathogenic	criteria provided, multiple submitters, no conflicts
3897882	NM_031407.7:c.[10052T>C];[10049_10050delinsGG]		Likely pathogenic	criteria provided, single submitter
1344905	NM_031407.7(HUWE1):c.12559C>A (p.Arg4187Ser)	HUWE1	Likely pathogenic	criteria provided, single submitter
1679378	NM_031407.7(HUWE1):c.9883G>A (p.Gly3295Ser)	HUWE1	Likely pathogenic	criteria provided, single submitter
1805743	NM_031407.7(HUWE1):c.6311A>G (p.Glu2104Gly)	HUWE1	Likely pathogenic	criteria provided, single submitter
216942	NM_031407.7(HUWE1):c.4013C>T (p.Ala1338Val)	HUWE1	Likely pathogenic	criteria provided, single submitter
2505506	NM_031407.7(HUWE1):c.2320-19A>G	HUWE1	Likely pathogenic	criteria provided, single submitter
2572050	NM_031407.7(HUWE1):c.12227C>G (p.Pro4076Arg)	HUWE1	Likely pathogenic	criteria provided, single submitter
2577165	NM_031407.7(HUWE1):c.12619G>A (p.Val4207Ile)	HUWE1	Likely pathogenic	criteria provided, single submitter
2580158	NM_031407.7(HUWE1):c.12719C>T (p.Ser4240Phe)	HUWE1	Likely pathogenic	criteria provided, single submitter
3254790	NM_031407.7(HUWE1):c.12577G>A (p.Gly4193Arg)	HUWE1	Likely pathogenic	criteria provided, single submitter
374333	NM_031407.7(HUWE1):c.3239G>A (p.Arg1080His)	HUWE1	Likely pathogenic	no assertion criteria provided
375710	NM_031407.7(HUWE1):c.344C>T (p.Ser115Phe)	HUWE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
375712	NM_031407.7(HUWE1):c.1978G>A (p.Gly660Arg)	HUWE1	Likely pathogenic	criteria provided, single submitter
375713	NM_031407.7(HUWE1):c.2007T>G (p.His669Gln)	HUWE1	Likely pathogenic	criteria provided, single submitter
375714	NM_031407.7(HUWE1):c.3982A>G (p.Met1328Val)	HUWE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
375716	NM_031407.7(HUWE1):c.6267T>G (p.Ile2089Met)	HUWE1	Likely pathogenic	criteria provided, single submitter
375717	NM_031407.7(HUWE1):c.9581T>C (p.Phe3194Ser)	HUWE1	Likely pathogenic	criteria provided, single submitter
375719	NM_031407.7(HUWE1):c.12205A>T (p.Ile4069Phe)	HUWE1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
HUWE1	Definitive	X-linked	intellectual disability, X-linked syndromic, Turner type	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HUWE1	Orphanet:528084	Non-specific syndromic intellectual disability

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
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_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
right lobe of thyroid gland	1
skin of abdomen	1
skin of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HUWE1	300	ubiquitous	marker	skin of leg, skin of abdomen, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HUWE1	5,793

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HUWE1	Q7Z6Z7	19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Antigen processing: Ubiquitination & Proteasome degradation	1	37.2×	0.043	HUWE1
Neutrophil degranulation	1	23.1×	0.043	HUWE1

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
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	2808.7×	0.004	HUWE1
negative regulation of mitochondrial fusion	1	2106.5×	0.004	HUWE1
positive regulation of type 2 mitophagy	1	1532.0×	0.004	HUWE1
protein branched polyubiquitination	1	842.6×	0.005	HUWE1
membrane fusion	1	624.1×	0.005	HUWE1
obsolete positive regulation of protein targeting to mitochondrion	1	495.6×	0.005	HUWE1
base-excision repair	1	468.1×	0.005	HUWE1
protein monoubiquitination	1	343.9×	0.006	HUWE1
circadian regulation of gene expression	1	234.1×	0.008	HUWE1
positive regulation of protein ubiquitination	1	213.3×	0.008	HUWE1
protein K48-linked ubiquitination	1	168.5×	0.009	HUWE1
Golgi organization	1	133.8×	0.011	HUWE1
protein polyubiquitination	1	115.4×	0.011	HUWE1
ubiquitin-dependent protein catabolic process	1	74.2×	0.016	HUWE1
positive regulation of canonical NF-kappaB signal transduction	1	72.6×	0.016	HUWE1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.020	HUWE1
cell differentiation	1	29.1×	0.034	HUWE1

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
HUWE1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HUWE1	4	Binding:3, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase

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	1	HUWE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
HUWE1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.