intellectual disability, X-linked 102

Summary

intellectual disability, X-linked 102 (MONDO:0010497) is a disease caused by DDX3X (GenCC Definitive), with 6 cohort genes and 1 clinical trial.

At a glance

• Causal gene: DDX3X (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 235
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 102
Mondo ID	MONDO:0010497
OMIM	300958
NCIT	C129931
UMLS	C5393299
MedGen	1715418
GARD	0024730
Is cancer (heuristic)	no

Also known as: DDX3X non-syndromic X-linked intellectual disability · DDX3X-related intellectual disability · intellectual developmental disorder, X-linked, syndrome, Snijders Blok type, X-linked recessive, X-linked dominant · intellectual disability, X-linked 102 · intellectual disability, X-linked type 102 · mental retardation, X-linked 102 · mental retardation, X-linked type 102 · MRX102 · non-syndromic X-linked intellectual disability caused by mutation in DDX3X

Data availability: 235 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › non-syndromic X-linked intellectual disability › intellectual disability, X-linked 102

Related subtypes (51): intellectual disability, X-linked 23, intellectual disability, X-linked 20, intellectual disability, X-linked 14, intellectual disability, X-linked 50, intellectual disability, X-linked 21, intellectual disability, X-linked 58, intellectual disability, X-linked 72, intellectual disability, X-linked 53, intellectual disability, X-linked 73, intellectual disability, X-linked 42, intellectual disability, X-linked 63, intellectual disability, X-linked, with or without seizures, ARX-related, intellectual disability, X-linked 2, intellectual disability, X-linked 81, intellectual disability, X-linked 46, intellectual disability, X-linked 77, intellectual disability, X-linked 45, intellectual disability, X-linked 84, intellectual disability, X-linked 82, intellectual disability, X-linked 30, intellectual disability, X-linked 91, intellectual disability, X-linked 93, chromosome Xp11.22 duplication syndrome, intellectual disability, X-linked 95, intellectual disability, X-linked 96, intellectual disability, X-linked 97, intellectual disability, X-linked 19, intellectual disability, X-linked 89, intellectual disability, X-linked 41, intellectual disability, X-linked 90, intellectual disability, X-linked 92, intellectual disability, X-linked 88, intellectual disability, X-linked 99, intellectual disability, X-linked 100, intellectual disability, X-linked 101, intellectual disability, X-linked 61, intellectual disability, X-linked 103, intellectual disability, X-linked 104, intellectual disability, X-linked 105, intellectual disability, X-linked 1, methylmalonic acidemia with homocystinuria, type cblX, FRAXE intellectual disability, intellectual disability, X-linked 9, intellectual developmental disorder, X-linked 108, intellectual disability, X-linked 106, intellectual disability, X-linked 107, intellectual developmental disorder, X-linked 110, intellectual developmental disorder, X-linked 111, intellectual developmental disorder, X-linked 112, intellectual developmental disorder, X-linked 113, intellectual developmental disorder, X-linked 114

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

235 retrieved; paginated sample, class counts are floors:

82 pathogenic, 71 likely pathogenic, 35 uncertain significance, 25 pathogenic/likely pathogenic, 11 conflicting classifications of pathogenicity, 6 not provided, 4 benign/likely benign, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2579274	GRCh38/hg38 Xp11.4(chrX:41333187-42099271)x1	CASK	Pathogenic	criteria provided, single submitter
1196594	NM_001356.5(DDX3X):c.453_454del (p.Ser152fs)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
1215809	NM_001356.5(DDX3X):c.119CTC[1] (p.Pro41del)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285558	NM_001356.5(DDX3X):c.1443dup (p.Glu482fs)	DDX3X	Pathogenic	criteria provided, single submitter
1302008	NM_001356.5(DDX3X):c.71C>A (p.Ser24Ter)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
1320227	NM_001356.5(DDX3X):c.1025+1G>A	DDX3X	Pathogenic	criteria provided, single submitter
1322193	NM_001356.5(DDX3X):c.1251_1252del (p.Lys418fs)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
1322194	NM_001356.5(DDX3X):c.1274C>G (p.Ser425Ter)	DDX3X	Pathogenic	criteria provided, single submitter
1322195	NM_001356.5(DDX3X):c.930dup (p.Arg311fs)	DDX3X	Pathogenic	criteria provided, single submitter
1325823	NM_001356.5(DDX3X):c.1693C>T (p.Gln565Ter)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
1325856	NM_001356.5(DDX3X):c.207T>G (p.Tyr69Ter)	DDX3X	Pathogenic	criteria provided, single submitter
1330240	NM_001356.5(DDX3X):c.1463G>C (p.Arg488Pro)	DDX3X	Pathogenic	criteria provided, single submitter
1452148	NM_001356.5(DDX3X):c.841C>T (p.Gln281Ter)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
1679537	NM_001356.5(DDX3X):c.1171-2A>G	DDX3X	Pathogenic	criteria provided, single submitter
1685691	NM_001356.5(DDX3X):c.1264_1267del (p.Val422fs)	DDX3X	Pathogenic	criteria provided, single submitter
1695343	NM_001356.5(DDX3X):c.233C>A (p.Ser78Ter)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
1703241	NM_001356.5(DDX3X):c.894C>A (p.Cys298Ter)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1802581	NM_001356.5(DDX3X):c.1439_1440insTCTC (p.Arg480fs)	DDX3X	Pathogenic	criteria provided, single submitter
1805569	NM_001356.5(DDX3X):c.229_230dup (p.Asp77fs)	DDX3X	Pathogenic	criteria provided, single submitter
207808	NM_001356.5(DDX3X):c.1541T>C (p.Ile514Thr)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207812	NM_001356.5(DDX3X):c.1535_1536del (p.His512fs)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
207813	NM_001356.5(DDX3X):c.1126C>T (p.Arg376Cys)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207816	NM_001356.5(DDX3X):c.1462C>T (p.Arg488Cys)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207817	NM_001356.5(DDX3X):c.1463G>A (p.Arg488His)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207818	NM_001356.5(DDX3X):c.1490C>T (p.Ala497Val)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208546	NM_001356.5(DDX3X):c.1520T>C (p.Ile507Thr)	DDX3X	Pathogenic	no assertion criteria provided
208547	NM_001356.5(DDX3X):c.977G>A (p.Arg326His)	DDX3X	Pathogenic	criteria provided, multiple submitters, no conflicts
208548	NM_001356.5(DDX3X):c.873C>A (p.Tyr291Ter)	DDX3X	Pathogenic	no assertion criteria provided
2105524	NM_001356.5(DDX3X):c.1769G>A (p.Ser590Asn)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224100	NM_001356.5(DDX3X):c.745G>T (p.Glu249Ter)	DDX3X	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 13 · 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
CASK	Orphanet:163937	X-linked intellectual disability, Najm type
CASK	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CASK	Orphanet:777	X-linked non-syndromic intellectual disability
PHIP	Orphanet:589905	PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome
EBF3	Orphanet:658843	Developmental delay-ataxia-hypotonia-facial dysmorphism syndrome
EBF3	Orphanet:96148	Distal deletion 10q syndrome
NPHP1	Orphanet:110	Bardet-Biedl syndrome
NPHP1	Orphanet:220497	Joubert syndrome with renal defect
NPHP1	Orphanet:3156	Senior-Loken syndrome
NPHP1	Orphanet:93592	Juvenile nephronophthisis

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DDX3X	HGNC:2745	ENSG00000215301	O00571	ATP-dependent RNA helicase DDX3X	gencc,clinvar
NLGN1	HGNC:14291	ENSG00000169760	Q8N2Q7	Neuroligin-1	clinvar
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	clinvar
PHIP	HGNC:15673	ENSG00000146247	Q8WWQ0	PH-interacting protein	clinvar
EBF3	HGNC:19087	ENSG00000108001	Q9H4W6	Transcription factor COE3	clinvar
NPHP1	HGNC:7905	ENSG00000144061	O15259	Nephrocystin-1	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.
NLGN1	Neuroligin-1	Cell surface protein involved in cell-cell-interactions via its interactions with neurexin family members.
CASK	Peripheral plasma membrane protein CASK	Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.
PHIP	PH-interacting protein	Probable regulator of the insulin and insulin-like growth factor signaling pathways.
EBF3	Transcription factor COE3	Transcriptional activator.
NPHP1	Nephrocystin-1	Together with BCAR1 it may play a role in the control of epithelial cell polarity.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 1 · Druggable fraction: 0.33

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
Scaffold/PPI	2	5.8×	0.215
Kinase	1	4.6×	0.495
Enzyme (other)	1	2.0×	0.674
Transcription factor	1	1.4×	0.674
Other/Unknown	1	0.3×	0.993

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
NLGN1	Other/Unknown	no		Nlgn, CarbesteraseB, Carboxylesterase_B_CS
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ
PHIP	Scaffold/PPI	no		Bromodomain, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
EBF3	Transcription factor	no		IPT_dom, Transcription_factor_COE, Ig-like_fold
NPHP1	Scaffold/PPI	no		SH3_domain, NPHP1_SH3, SH3-like_dom_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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	2
ventricular zone	2
bronchial epithelial cell	2
choroid plexus epithelium	1
oocyte	1
sperm	1
endothelial cell	1
buccal mucosa cell	1
hair follicle	1
epithelium of bronchus	1
subcutaneous adipose tissue	1
tendon of biceps brachii	1
tibialis anterior	1
olfactory segment of nasal mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DDX3X	294	ubiquitous	marker	choroid plexus epithelium, oocyte, sperm
NLGN1	216	broad	marker	cortical plate, ventricular zone, endothelial cell
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate
PHIP	302	ubiquitous	marker	bronchial epithelial cell, epithelium of bronchus, ventricular zone
EBF3	193	broad	marker	tibialis anterior, subcutaneous adipose tissue, tendon of biceps brachii
NPHP1	193	ubiquitous	marker	right uterine tube, bronchial epithelial cell, olfactory segment of nasal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDX3X	6,454
CASK	4,223
PHIP	3,057
NPHP1	2,302
NLGN1	1,968
EBF3	655

Structural data

PDB: 6 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PHIP	Q8WWQ0	146
CASK	O14936	22
DDX3X	O00571	17
NLGN1	Q8N2Q7	2
EBF3	Q9H4W6	2
NPHP1	O15259	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Neurexins and neuroligins	2	78.8×	0.003	NLGN1, CASK
Dopamine Neurotransmitter Release Cycle	1	99.3×	0.026	CASK
Nephrin family interactions	1	95.2×	0.026	CASK
RHOBTB2 GTPase cycle	1	95.2×	0.026	PHIP
Syndecan interactions	1	84.6×	0.026	CASK
Dengue virus activates/modulates innate and adaptive immune responses	1	67.2×	0.027	DDX3X
Assembly and cell surface presentation of NMDA receptors	1	50.8×	0.031	CASK
Sensory processing of sound by outer hair cells of the cochlea	1	40.8×	0.033	CASK
Sensory processing of sound by inner hair cells of the cochlea	1	32.6×	0.037	CASK
Anchoring of the basal body to the plasma membrane	1	22.6×	0.048	NPHP1
Neutrophil degranulation	1	4.6×	0.199	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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cytoskeletal matrix organization at active zone	1	2808.7×	0.012	NLGN1
neurexin clustering involved in presynaptic membrane assembly	1	2808.7×	0.012	NLGN1
negative regulation of cellular response to growth factor stimulus	1	1404.3×	0.012	CASK
positive regulation of synaptic vesicle exocytosis	1	1404.3×	0.012	NLGN1
positive regulation of circadian sleep/wake cycle, wakefulness	1	936.2×	0.012	NLGN1
positive regulation of toll-like receptor 8 signaling pathway	1	936.2×	0.012	DDX3X
protein localization involved in establishment of planar polarity	1	936.2×	0.012	NPHP1
positive regulation of neuromuscular synaptic transmission	1	936.2×	0.012	NLGN1
obsolete synaptic vesicle targeting	1	702.2×	0.012	NLGN1
positive regulation of translation in response to endoplasmic reticulum stress	1	702.2×	0.012	DDX3X
positive regulation of toll-like receptor 7 signaling pathway	1	561.7×	0.012	DDX3X
negative regulation of dendritic spine morphogenesis	1	561.7×	0.012	NLGN1
terminal button organization	1	561.7×	0.012	NLGN1
AMPA glutamate receptor clustering	1	561.7×	0.012	NLGN1
NMDA glutamate receptor clustering	1	561.7×	0.012	NLGN1
AMPA selective glutamate receptor signaling pathway	1	561.7×	0.012	NLGN1
visual behavior	1	468.1×	0.012	NPHP1
positive regulation of chemokine (C-C motif) ligand 5 production	1	468.1×	0.012	DDX3X
postsynaptic density protein 95 clustering	1	468.1×	0.012	NLGN1
positive regulation of synaptic vesicle endocytosis	1	468.1×	0.012	NLGN1
neuronal signal transduction	1	401.2×	0.012	NLGN1
cytosolic ribosome assembly	1	401.2×	0.012	DDX3X
postsynaptic membrane assembly	1	401.2×	0.012	NLGN1
NMDA selective glutamate receptor signaling pathway	1	401.2×	0.012	NLGN1
cellular response to arsenic-containing substance	1	351.1×	0.012	DDX3X
receptor localization to synapse	1	351.1×	0.012	NLGN1
positive regulation of protein K63-linked ubiquitination	1	351.1×	0.012	DDX3X
protein localization to cytoplasmic stress granule	1	351.1×	0.012	DDX3X
neuron projection arborization	1	312.1×	0.013	NLGN1
spermatid differentiation	1	280.9×	0.013	NPHP1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 4

Druggability breadth: 3 of 6 evidence-associated genes (50%) 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
CASK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASK	9	4
DDX3X	1	4
NLGN1	0	0
PHIP	0	0
EBF3	0	0
NPHP1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IMATINIB	4	DDX3X
FEDRATINIB	4	CASK
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
LESTAURTINIB	3	CASK
CYC-065	2	CASK
RG-547	2	CASK
AT-7519	2	CASK
BMS-387032	1	CASK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
CASK	92	Binding:92
DDX3X	32	Binding:31, ADMET:1
PHIP	17	Binding:17

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DDX3X	3.6.4.13	RNA helicase
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

10 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
FEDRATINIB	4	CASK
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
LESTAURTINIB	3	CASK
CYC-065	2	CASK
RG-547	2	CASK
AT-7519	2	CASK
BMS-387032	1	CASK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	DDX3X, CASK
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	4	NLGN1, PHIP, EBF3, NPHP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NLGN1	0	—
PHIP	17	—
EBF3	0	—
NPHP1	0	—

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
NCT03718910	Not specified	COMPLETED	DDX3X Syndrome -The Seaver Autism Center for Research and Treatment is Characterizing DDX3X-related Neurodevelopmental Disorders Using Genetic, Medical, and Neuropsychological Measures.