X-linked intellectual disability

Summary

X-linked intellectual disability (MONDO:0100284) is a disease caused by HCFC1 (GenCC Definitive), with 8 cohort genes and 1 clinical trial.

At a glance

• Causal gene: HCFC1 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 7
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked intellectual disability
Mondo ID	MONDO:0100284
UMLS	C1136249
MedGen	211749
Is cancer (heuristic)	no

Also known as: X-linked intellectual disability

Data availability: 7 ClinVar variants · 6 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked intellectual disability

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked sideroblastic anemia 1, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, leukemia, acute, X-linked

Subtypes (2): non-syndromic X-linked intellectual disability, X-linked syndromic 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

7 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic; risk factor, 1 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
11051	NM_181332.3(NLGN4X):c.1254_1255del (p.Glu418fs)	NLGN4X	Pathogenic; risk factor	no assertion criteria provided
11052	NC_000023.11:g.5250357_6007153del	NLGN4X	Pathogenic; risk factor	no assertion criteria provided
375710	NM_031407.7(HUWE1):c.344C>T (p.Ser115Phe)	HUWE1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
167032	NM_025184.4(EFHC2):c.404G>A (p.Arg135Gln)	EFHC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1699032	NM_005334.3(HCFC1):c.1583C>T (p.Pro528Leu)	HCFC1	Uncertain significance	criteria provided, single submitter
2672106	NM_005334.3(HCFC1):c.1456G>C (p.Val486Leu)	HCFC1	Uncertain significance	criteria provided, single submitter
2441856	NM_001282874.2(SMARCA1):c.3068T>C (p.Ile1023Thr)	SMARCA1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 22 · Orphanet: 5 · 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
HCFC1	Definitive	X-linked	X-linked intellectual disability	8
ARHGEF6	Supportive	X-linked	non-syndromic X-linked intellectual disability	8
ZNF81	Supportive	X-linked	non-syndromic X-linked intellectual disability	4
ZNF674	Disputed Evidence	X-linked	intellectual disability	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HCFC1	Orphanet:369962	Methylmalonic acidemia with homocystinuria, type cblX
HCFC1	Orphanet:777	X-linked non-syndromic intellectual disability
ZNF81	Orphanet:777	X-linked non-syndromic intellectual disability
ARHGEF6	Orphanet:777	X-linked non-syndromic intellectual disability
HUWE1	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HCFC1	HGNC:4839	ENSG00000172534	P51610	Host cell factor 1	gencc,clinvar
ZNF81	HGNC:13156	ENSG00000197779	P51508	Zinc finger protein 81	gencc
ZNF674	HGNC:17625	ENSG00000251192	Q2M3X9	Zinc finger protein 674	gencc
ARHGEF6	HGNC:685	ENSG00000129675	Q15052	Rho guanine nucleotide exchange factor 6	gencc
SMARCA1	HGNC:11097	ENSG00000102038	P28370	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 1	clinvar
NLGN4X	HGNC:14287	ENSG00000146938	Q8N0W4	Neuroligin-4, X-linked	clinvar
EFHC2	HGNC:26233	ENSG00000183690	Q5JST6	EF-hand domain-containing family member C2	clinvar
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HCFC1	Host cell factor 1	Transcriptional coregulator.
ZNF81	Zinc finger protein 81	May be involved in transcriptional regulation.
ZNF674	Zinc finger protein 674	May be involved in transcriptional regulation.
ARHGEF6	Rho guanine nucleotide exchange factor 6	Acts as a RAC1 guanine nucleotide exchange factor (GEF).
SMARCA1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 1	ATPase that possesses intrinsic ATP-dependent chromatin-remodeling activity.
NLGN4X	Neuroligin-4, X-linked	Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
EFHC2	EF-hand domain-containing family member C2	Microtubule inner protein (MIP) part of the dynein-decorated doublet microtubules (DMTs) in cilia axoneme, which is required for motile cilia beating.
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.

Protein-family classification

Druggable: 2 · Difficult: 4 · Unknown: 2 · Druggable fraction: 0.25

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	3	3.1×	0.311
Antibody/Immunoglobulin	1	3.6×	0.608
Scaffold/PPI	1	2.2×	0.627
Enzyme (other)	1	1.5×	0.627
Other/Unknown	2	0.5×	0.984

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HCFC1	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Kelch-typ_b-propeller
ZNF81	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
ZNF674	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf
ARHGEF6	Scaffold/PPI	no		DH_dom, SH3_domain, CH_dom
SMARCA1	Transcription factor	no		SNF2_N, SANT/Myb, Helicase_C-like
NLGN4X	Other/Unknown	no		Nlgn, CarbesteraseB, Carboxylesterase_B_CS
EFHC2	Other/Unknown	no		EF_hand_dom, DM10_dom, EF-hand-dom_pair
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_sf

Expression context

Cohort genes with no expression data: 0.

6 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
primordial germ cell in gonad	2
parotid gland	1
skeletal muscle tissue of rectus abdominis	1
tendon of biceps brachii	1
colonic epithelium	1
germinal epithelium of ovary	1
cortical plate	1
male germ line stem cell (sensu Vertebrata) in testis	1
biceps brachii	1
medial globus pallidus	1
skeletal muscle tissue of biceps brachii	1
adrenal tissue	1
choroid plexus epithelium	1
tibia	1
Brodmann (1909) area 23	1
dorsal root ganglion	1
middle temporal gyrus	1
bronchial epithelial cell	1
bronchus	1
epithelium of bronchus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HCFC1	274	ubiquitous	marker	tendon of biceps brachii, parotid gland, skeletal muscle tissue of rectus abdominis
ZNF81	249	ubiquitous	yes	colonic epithelium, primordial germ cell in gonad, germinal epithelium of ovary
ZNF674	167	ubiquitous	yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, cortical plate
ARHGEF6	289	ubiquitous	marker	biceps brachii, skeletal muscle tissue of biceps brachii, medial globus pallidus
SMARCA1	286	ubiquitous	marker	adrenal tissue, choroid plexus epithelium, tibia
NLGN4X	223	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, dorsal root ganglion
EFHC2	207	broad	marker	bronchial epithelial cell, epithelium of bronchus, bronchus
HUWE1	300	ubiquitous	marker	skin of leg, skin of abdomen, right lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HUWE1	5,793
SMARCA1	4,447
HCFC1	2,637
EFHC2	2,428
NLGN4X	1,823
ARHGEF6	1,668
ZNF81	918
ZNF674	587

Intra-cohort edges

A	B	Sources
ARHGEF6	ZNF81	string_interaction
NLGN4X	ZNF674	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HUWE1	Q7Z6Z7	19
HCFC1	P51610	11
EFHC2	Q5JST6	4
NLGN4X	Q8N0W4	3
ARHGEF6	Q15052	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMARCA1	P28370	75.48
ZNF674	Q2M3X9	65.55
ZNF81	P51508	63.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 27. Enrichment computed across 8 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
G-protein beta:gamma signalling	1	475.8×	0.038	ARHGEF6
Regulation of cytoskeletal remodeling and cell spreading by IPP complex components	1	356.9×	0.038	ARHGEF6
Cell-extracellular matrix interactions	1	167.9×	0.047	ARHGEF6
G beta:gamma signalling through CDC42	1	142.8×	0.047	ARHGEF6
RHOU GTPase cycle	1	69.6×	0.048	ARHGEF6
Formation of WDR5-containing histone-modifying complexes	1	66.4×	0.048	HCFC1
Cell death signalling via NRAGE, NRIF and NADE	1	54.9×	0.048	ARHGEF6
Transcriptional activation of mitochondrial biogenesis	1	51.0×	0.048	HCFC1
Neurexins and neuroligins	1	49.2×	0.048	NLGN4X
p75 NTR receptor-mediated signalling	1	46.8×	0.048	ARHGEF6
Cell junction organization	1	46.8×	0.048	ARHGEF6
NRAGE signals death through JNK	1	46.0×	0.048	ARHGEF6
Death Receptor Signaling	1	34.8×	0.052	ARHGEF6
Cell-Cell communication	1	34.4×	0.052	ARHGEF6
G alpha (12/13) signalling events	1	34.4×	0.052	ARHGEF6
UCH proteinases	1	31.0×	0.054	HCFC1
HATs acetylate histones	1	19.8×	0.079	HCFC1
CDC42 GTPase cycle	1	18.1×	0.081	ARHGEF6
RAC1 GTPase cycle	1	15.3×	0.088	ARHGEF6
RHO GTPase cycle	1	15.0×	0.088	ARHGEF6
GPCR downstream signalling	1	10.9×	0.114	ARHGEF6
Signaling by GPCR	1	10.0×	0.118	ARHGEF6
Antigen processing: Ubiquitination & Proteasome degradation	1	9.3×	0.121	HUWE1
Signaling by Rho GTPases	1	8.6×	0.123	ARHGEF6
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	8.4×	0.123	ARHGEF6
Neutrophil degranulation	1	5.8×	0.169	HUWE1
Signal Transduction	1	2.5×	0.339	ARHGEF6

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
release from viral latency	1	702.2×	0.036	HCFC1
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	351.1×	0.036	HUWE1
brainstem development	1	263.3×	0.036	NLGN4X
negative regulation of mitochondrial fusion	1	263.3×	0.036	HUWE1
presynaptic membrane assembly	1	210.7×	0.036	NLGN4X
positive regulation of type 2 mitophagy	1	191.5×	0.036	HUWE1
neuron differentiation	2	25.1×	0.036	SMARCA1, NLGN4X
chromatin remodeling	2	18.2×	0.036	HCFC1, SMARCA1
negative regulation of excitatory postsynaptic potential	1	162.0×	0.037	NLGN4X
presynapse assembly	1	150.5×	0.037	NLGN4X
neuron cell-cell adhesion	1	123.9×	0.038	NLGN4X
vocalization behavior	1	110.9×	0.038	NLGN4X
protein branched polyubiquitination	1	105.3×	0.038	HUWE1
organ growth	1	91.6×	0.038	NLGN4X
regulation of protein-containing complex assembly	1	91.6×	0.038	HCFC1
regulation of synapse assembly	1	87.8×	0.038	NLGN4X
developmental process	1	84.3×	0.038	ZNF674
cell-cell junction organization	1	78.0×	0.038	NLGN4X
membrane fusion	1	78.0×	0.038	HUWE1
blastocyst hatching	1	68.0×	0.040	HCFC1
obsolete positive regulation of protein targeting to mitochondrion	1	62.0×	0.040	HUWE1
base-excision repair	1	58.5×	0.040	HUWE1
adult behavior	1	58.5×	0.040	NLGN4X
lamellipodium assembly	1	55.4×	0.040	ARHGEF6
positive regulation of cell cycle	1	55.4×	0.040	HCFC1
regulation of neuron projection development	1	54.0×	0.040	EFHC2
cerebellum development	1	44.8×	0.046	NLGN4X
protein monoubiquitination	1	43.0×	0.046	HUWE1
regulation of DNA-templated transcription	2	7.9×	0.048	HCFC1, SMARCA1
learning	1	35.1×	0.049	NLGN4X

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 4 of 8 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HCFC1	1	2
ZNF81	0	0
ZNF674	0	0
ARHGEF6	0	0
SMARCA1	0	0
NLGN4X	0	0
EFHC2	0	0
HUWE1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	HCFC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
HCFC1	8	Binding:8
ARHGEF6	6	Binding:6
HUWE1	4	Binding:3, Functional:1
SMARCA1	1	Binding: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: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	HCFC1

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	1	HCFC1
C	Druggable family + PDB, no drug	1	HUWE1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	ZNF81, ZNF674, ARHGEF6, SMARCA1, NLGN4X, EFHC2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZNF81	0	—
ZNF674	0	—
ARHGEF6	6	—
SMARCA1	1	—
NLGN4X	0	—
EFHC2	0	—
HUWE1	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06500260	Not specified	RECRUITING	CNKSR2 Natural History Study