X-linked intellectual disability-hypotonia-movement disorder syndrome

Summary

X-linked intellectual disability-hypotonia-movement disorder syndrome (MONDO:0018709) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 23

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		38	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Obligate (100%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000504	Abnormality of vision	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000752	Hyperactivity	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0002136	Broad-based gait	Frequent (30-79%)
HP:0100660	Dyskinesia	Frequent (30-79%)
HP:0000202	Orofacial cleft	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000826	Precocious puberty	Occasional (5-29%)
HP:0001000	Abnormality of skin pigmentation	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001999	Abnormal facial shape	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002539	Cortical dysplasia	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked intellectual disability-hypotonia-movement disorder syndrome
Mondo ID	MONDO:0018709
Orphanet	457260
UMLS	C5681121
MedGen	1814468
GARD	0012715
Is cancer (heuristic)	no

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record · 3 cell lines.

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 › X-linked intellectual disability-hypotonia-movement disorder syndrome

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 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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
207812	NM_001356.5(DDX3X):c.1535_1536del (p.His512fs)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
452283	NM_001356.5(DDX3X):c.1423C>T (p.Arg475Cys)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
DDX3X	Definitive	X-linked	intellectual disability, X-linked 102	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DDX3X	Orphanet:3338	Toriello-Carey syndrome
DDX3X	Orphanet:457260	X-linked intellectual disability-hypotonia-movement disorder syndrome
DDX3X	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia

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
DDX3X	HGNC:2745	ENSG00000215301	O00571	ATP-dependent RNA helicase DDX3X	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DDX3X	ATP-dependent RNA helicase DDX3X	Multifunctional ATP-dependent RNA helicase.

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)
DDX3X	Enzyme (other)	yes	3.6.4.13	RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom

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
choroid plexus epithelium	1
oocyte	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDX3X	294	ubiquitous	marker	choroid plexus epithelium, oocyte, sperm

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDX3X	6,454

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DDX3X	O00571	17

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
Dengue virus activates/modulates innate and adaptive immune responses	1	335.9×	0.006	DDX3X
Neutrophil degranulation	1	23.1×	0.043	DDX3X

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
positive regulation of toll-like receptor 8 signaling pathway	1	5617.3×	0.003	DDX3X
positive regulation of translation in response to endoplasmic reticulum stress	1	4213.0×	0.003	DDX3X
positive regulation of toll-like receptor 7 signaling pathway	1	3370.4×	0.003	DDX3X
positive regulation of chemokine (C-C motif) ligand 5 production	1	2808.7×	0.003	DDX3X
cytosolic ribosome assembly	1	2407.4×	0.003	DDX3X
cellular response to arsenic-containing substance	1	2106.5×	0.003	DDX3X
positive regulation of protein K63-linked ubiquitination	1	2106.5×	0.003	DDX3X
protein localization to cytoplasmic stress granule	1	2106.5×	0.003	DDX3X
cellular response to osmotic stress	1	1203.7×	0.004	DDX3X
positive regulation of mitochondrial translation	1	1123.5×	0.004	DDX3X
cytoplasmic pattern recognition receptor signaling pathway	1	887.0×	0.004	DDX3X
gamete generation	1	887.0×	0.004	DDX3X
positive regulation of translational initiation	1	842.6×	0.004	DDX3X
negative regulation of intrinsic apoptotic signaling pathway	1	766.0×	0.004	DDX3X
positive regulation of interferon-alpha production	1	648.1×	0.004	DDX3X
stress granule assembly	1	601.9×	0.004	DDX3X
positive regulation of viral genome replication	1	581.1×	0.004	DDX3X
positive regulation of NLRP3 inflammasome complex assembly	1	581.1×	0.004	DDX3X
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	1	581.1×	0.004	DDX3X
negative regulation of non-canonical NF-kappaB signal transduction	1	510.7×	0.005	DDX3X
negative regulation of protein-containing complex assembly	1	455.5×	0.005	DDX3X
positive regulation of type I interferon production	1	421.3×	0.005	DDX3X
extrinsic apoptotic signaling pathway via death domain receptors	1	401.2×	0.005	DDX3X
positive regulation of G1/S transition of mitotic cell cycle	1	401.2×	0.005	DDX3X
positive regulation of interferon-beta production	1	391.9×	0.005	DDX3X
translational initiation	1	358.6×	0.005	DDX3X
intrinsic apoptotic signaling pathway	1	358.6×	0.005	DDX3X
lipid homeostasis	1	337.0×	0.005	DDX3X
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.006	DDX3X
positive regulation of translation	1	227.7×	0.007	DDX3X

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
DDX3X	IMATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DDX3X	1	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMATINIB	4	DDX3X

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
DDX3X	32	Binding:31, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DDX3X	3.6.4.13	RNA helicase

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

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)
IMATINIB	4	DDX3X

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	DDX3X
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.