intellectual disability, X-linked 49

Summary

intellectual disability, X-linked 49 (MONDO:0010250) is a disease caused by CLCN4 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CLCN4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 102
• Phenotypes (HPO): 45

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)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0002120	Cerebral cortical atrophy	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0000252	Microcephaly	Occasional (5-29%)
HP:0000256	Macrocephaly	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000722	Compulsive behaviors	Occasional (5-29%)
HP:0000729	Autistic behavior	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0000752	Hyperactivity	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0002020	Gastroesophageal reflux	Occasional (5-29%)
HP:0002061	Lower limb spasticity	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002073	Progressive cerebellar ataxia	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002121	Generalized non-motor (absence) seizure	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0006970	Periventricular leukomalacia	Occasional (5-29%)
HP:0007302	Bipolar affective disorder	Occasional (5-29%)
HP:0008947	Floppy infant	Occasional (5-29%)
HP:0011167	Focal tonic seizure	Occasional (5-29%)
HP:0011193	EEG with focal spikes	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)
HP:0012448	Delayed myelination	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)
HP:0100716	Self-injurious behavior	Occasional (5-29%)
HP:0000023	Inguinal hernia	Very rare (<1-4%)
HP:0000028	Cryptorchidism	Very rare (<1-4%)
HP:0000276	Long face	Very rare (<1-4%)
HP:0000307	Pointed chin	Very rare (<1-4%)
HP:0001763	Pes planus	Very rare (<1-4%)
HP:0002072	Chorea	Very rare (<1-4%)
HP:0002317	Unsteady gait	Very rare (<1-4%)
HP:0006986	Upper limb spasticity	Very rare (<1-4%)
HP:0011800	Midface retrusion	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability, X-linked 49
Mondo ID	MONDO:0010250
OMIM	300114
Orphanet	485350
DOID	DOID:0112060
UMLS	C0796221
MedGen	923000
GARD	0017880
Is cancer (heuristic)	no

Also known as: CLCN4-related X-linked intellectual disability syndrome · intellectual disability, X-linked 15 · intellectual disability, X-linked 49 · mental retardation, X-linked 15 · mental retardation, X-linked 49 · MRX49 · Raynaud-Claes syndrome, X-linked dominant

Data availability: 102 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 disability, X-linked 49

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, 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, 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

102 retrieved; paginated sample, class counts are floors:

53 uncertain significance, 17 likely pathogenic, 14 pathogenic, 11 conflicting classifications of pathogenicity, 4 benign/likely benign, 2 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
100781	NM_001830.4(CLCN4):c.1630G>A (p.Gly544Arg)	CLCN4	Pathogenic	criteria provided, multiple submitters, no conflicts
1164025	NM_001830.4(CLCN4):c.875G>A (p.Trp292Ter)	CLCN4	Pathogenic	no assertion criteria provided
1679299	NM_001830.4(CLCN4):c.112G>T (p.Glu38Ter)	CLCN4	Pathogenic	criteria provided, single submitter
1691411	NM_001830.4(CLCN4):c.925_928del (p.Asn309fs)	CLCN4	Pathogenic	criteria provided, single submitter
209115	NM_001830.4(CLCN4):c.1664C>T (p.Ala555Val)	CLCN4	Pathogenic	criteria provided, multiple submitters, no conflicts
209116	NM_001830.4(CLCN4):c.2152C>T (p.Arg718Trp)	CLCN4	Pathogenic	criteria provided, multiple submitters, no conflicts
253112	NM_001830.4(CLCN4):c.43_55del (p.Asp15fs)	CLCN4	Pathogenic	no assertion criteria provided
253113	NM_001830.4(CLCN4):c.2191G>C (p.Gly731Arg)	CLCN4	Pathogenic	no assertion criteria provided
253115	NM_001830.4(CLCN4):c.661C>G (p.Leu221Val)	CLCN4	Pathogenic	no assertion criteria provided
253116	NM_001830.4(CLCN4):c.1606G>A (p.Val536Met)	CLCN4	Pathogenic	no assertion criteria provided
3024251	NM_001830.4(CLCN4):c.1631G>A (p.Gly544Glu)	CLCN4	Pathogenic	criteria provided, single submitter
3235813	NM_001830.4(CLCN4):c.980G>A (p.Trp327Ter)	CLCN4	Pathogenic	criteria provided, single submitter
422822	NM_001830.4(CLCN4):c.949G>A (p.Val317Ile)	CLCN4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4278017	NM_001830.4(CLCN4):c.369del (p.Phe123fs)	CLCN4	Pathogenic	criteria provided, single submitter
4532136	NM_001830.4(CLCN4):c.1319_1320insCGACC (p.Ala441fs)	CLCN4	Pathogenic	criteria provided, single submitter
1320175	NM_001830.4(CLCN4):c.740dup (p.Asn248fs)	CLCN4	Likely pathogenic	criteria provided, single submitter
1691402	NM_001830.4(CLCN4):c.608C>T (p.Thr203Ile)	CLCN4	Likely pathogenic	criteria provided, single submitter
1691412	NM_001830.4(CLCN4):c.1987_1990del (p.Gln663fs)	CLCN4	Likely pathogenic	criteria provided, single submitter
1691415	NM_001830.4(CLCN4):c.835C>G (p.Leu279Val)	CLCN4	Likely pathogenic	criteria provided, single submitter
1691416	NM_001830.4(CLCN4):c.840A>T (p.Glu280Asp)	CLCN4	Likely pathogenic	criteria provided, single submitter
3024323	NM_001830.4(CLCN4):c.1622A>T (p.Glu541Val)	CLCN4	Likely pathogenic	criteria provided, single submitter
3358993	NM_001830.4(CLCN4):c.1684G>C (p.Val562Leu)	CLCN4	Likely pathogenic	criteria provided, single submitter
3374725	NM_001830.4(CLCN4):c.2043del (p.Glu682fs)	CLCN4	Likely pathogenic	criteria provided, single submitter
3901834	NM_001830.4(CLCN4):c.812C>G (p.Pro271Arg)	CLCN4	Likely pathogenic	criteria provided, single submitter
4072393	NM_001830.4(CLCN4):c.1795G>A (p.Val599Ile)	CLCN4	Likely pathogenic	no assertion criteria provided
4538459	NM_001830.4(CLCN4):c.592T>C (p.Tyr198His)	CLCN4	Likely pathogenic	criteria provided, single submitter
4819914	NM_001830.4(CLCN4):c.281G>A (p.Trp94Ter)	CLCN4	Likely pathogenic	criteria provided, single submitter
807385	NM_001830.4(CLCN4):c.1399G>A (p.Gly467Ser)	CLCN4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
976142	NM_001830.4(CLCN4):c.373del (p.Asp125fs)	CLCN4	Likely pathogenic	criteria provided, single submitter
976472	NM_001830.4(CLCN4):c.1646T>C (p.Ile549Thr)	CLCN4	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
CLCN4	Strong	X-linked	intellectual disability, X-linked 49	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN4	Orphanet:485350	CLCN4-related X-linked intellectual disability syndrome
CLCN4	Orphanet:777	X-linked non-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
CLCN4	HGNC:2022	ENSG00000073464	P51793	H(+)/Cl(-) exchange transporter 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN4	H(+)/Cl(-) exchange transporter 4	Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CLCN4	Other/Unknown	no		CBS_dom, ClC, Cl_channel-4

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
Brodmann (1909) area 23	1
middle temporal gyrus	1
postcentral gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN4	247	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, postcentral gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN4	962

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CLCN4	P51793	84.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Stimuli-sensing channels	1	135.9×	0.007	CLCN4

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
chloride transport	1	455.5×	0.005	CLCN4
non-motile cilium assembly	1	290.6×	0.005	CLCN4
monoatomic ion transmembrane transport	1	208.1×	0.005	CLCN4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLCN4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	CLCN4

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)
CLCN4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.