X-linked intellectual disability-cerebellar hypoplasia syndrome

disease

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Also known as intellectual developmental disorder, X-linked syndromic, Billuart type, X-linked recessiveintellectual disability X-linked 60 (formerly)intellectual disability X-linked with cerebellar hypoplasia and distinctive facial appearanceintellectual disability, X-linked, with cerebellar hypoplasia and distinctive facial appearancemental retardation X-linked 60 (formerly)mental retardation X-linked with cerebellar hypoplasia and distinctive facial appearancemental retardation, X-linked 60mental retardation, X-linked 60, formerlymental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearanceMRX60 (formerly)Oligophrenin-1 syndromeOPHN1 deficiencyOPHN1 syndromeOPHN1 XLMROPHN1 XLMR, X-linked intellectual disabilityOPHN1- related XLIDX-linked intellectual Deficit with cerebellar Hypoplasia

Summary

X-linked intellectual disability-cerebellar hypoplasia syndrome (MONDO:0010337) is a disease caused by OPHN1 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: OPHN1 (GenCC Definitive)
Cohort genes: 2
ClinVar variants: 104
Phenotypes (HPO): 33
Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		14	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001321	Cerebellar hypoplasia	Very frequent (80-99%)
HP:0012760	Reduced social responsiveness	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000490	Deeply set eye	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000817	Reduced eye contact	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001290	Generalized hypotonia	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002119	Ventriculomegaly	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002384	Focal impaired awareness seizure	Frequent (30-79%)
HP:0002465	Poor speech	Frequent (30-79%)
HP:0002951	Partial absence of cerebellar vermis	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0400000	Tall chin	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000431	Wide nasal bridge	Occasional (5-29%)
HP:0000448	Prominent nose	Occasional (5-29%)
HP:0002080	Intention tremor	Occasional (5-29%)
HP:0002172	Postural instability	Occasional (5-29%)
HP:0002280	Enlarged cisterna magna	Occasional (5-29%)
HP:0002340	Caudate atrophy	Occasional (5-29%)
HP:0006817	Aplasia/Hypoplasia of the cerebellar vermis	Occasional (5-29%)
HP:0006913	Frontal cortical atrophy	Occasional (5-29%)
HP:0006951	Retrocerebellar cyst	Occasional (5-29%)
HP:0007018	Attention deficit hyperactivity disorder	Occasional (5-29%)
HP:0007112	Temporal cortical atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked intellectual disability-cerebellar hypoplasia syndrome
Mondo ID	MONDO:0010337
MeSH	C537456
OMIM	300486
Orphanet	137831
DOID	DOID:0080311
SNOMED CT	719136005
UMLS	C1845366
MedGen	336920
GARD	0009947
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, X-linked syndromic, Billuart type, X-linked recessive · intellectual disability X-linked 60 (formerly) · intellectual disability X-linked with cerebellar hypoplasia and distinctive facial appearance · intellectual disability, X-linked, with cerebellar hypoplasia and distinctive facial appearance · mental retardation X-linked 60 (formerly) · mental retardation X-linked with cerebellar hypoplasia and distinctive facial appearance · mental retardation, X-linked 60 · mental retardation, X-linked 60, formerly · mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance · MRX60 (formerly) · Oligophrenin-1 syndrome · OPHN1 deficiency · OPHN1 syndrome · OPHN1 XLMR · OPHN1 XLMR, X-linked intellectual disability · OPHN1- related XLID · X-linked intellectual Deficit with cerebellar Hypoplasia · X-linked intellectual disability-cerebellar hypoplasia syndrome

Data availability: 104 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system malformation › X-linked intellectual disability-cerebellar hypoplasia syndrome

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

104 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 27 likely pathogenic, 23 pathogenic, 8 benign/likely benign, 7 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
195200	NM_001367721.1(CASK):c.79C>T (p.Arg27Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
11577	NM_002547.3(OPHN1):c.1579del (p.Ile527fs)	OPHN1	Pathogenic	no assertion criteria provided
11578	NM_002547.3(OPHN1):c.745_752dup (p.Lys251fs)	OPHN1	Pathogenic	no assertion criteria provided
11579	NM_002547.3(OPHN1):c.184C>T (p.Gln62Ter)	OPHN1	Pathogenic	no assertion criteria provided
11580	NG_008960.1:g.337629_355297del	OPHN1	Pathogenic	no assertion criteria provided
11581	NM_002547.3(OPHN1):c.644_645del (p.Val215fs)	OPHN1	Pathogenic	no assertion criteria provided
1164011	NM_002547.3(OPHN1):c.170T>A (p.Val57Asp)	OPHN1	Pathogenic	no assertion criteria provided
1164012	NM_002547.3(OPHN1):c.2159-1G>C	OPHN1	Pathogenic	no assertion criteria provided
1180786	NM_002547.3(OPHN1):c.468_471del (p.Lys156fs)	OPHN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1251919	NC_000023.11:g.68119248_68212212dup	OPHN1	Pathogenic	no assertion criteria provided
1323384	NM_002547.3(OPHN1):c.384+1G>A	OPHN1	Pathogenic	criteria provided, single submitter
1326263	Single allele	OPHN1	Pathogenic	no assertion criteria provided
159477	NM_002547.3(OPHN1):c.496C>T (p.Gln166Ter)	OPHN1	Pathogenic	criteria provided, single submitter
1685999	NM_002547.3(OPHN1):c.597+2T>C	OPHN1	Pathogenic	criteria provided, single submitter
2920720	NM_002547.2(OPHN1):c.313_326del	OPHN1	Pathogenic	criteria provided, single submitter
29934	NG_008960.1:g.224486-?_245539+?del	OPHN1	Pathogenic	no assertion criteria provided
379804	NM_002547.3(OPHN1):c.1246C>T (p.Gln416Ter)	OPHN1	Pathogenic	criteria provided, multiple submitters, no conflicts
4056418	NM_002547.3(OPHN1):c.250+1G>T	OPHN1	Pathogenic	criteria provided, single submitter
421280	NM_002547.3(OPHN1):c.1225C>T (p.Arg409Cys)	OPHN1	Pathogenic	criteria provided, single submitter
4530612	NM_002547.3(OPHN1):c.932_933+3delinsTA	OPHN1	Pathogenic	criteria provided, single submitter
4533353	NM_002547.3(OPHN1):c.1026-2A>G	OPHN1	Pathogenic	criteria provided, single submitter
4688274	NM_002547.3(OPHN1):c.2048del (p.Lys683fs)	OPHN1	Pathogenic	criteria provided, single submitter
620153	NM_002547.3(OPHN1):c.1489C>T (p.Arg497Ter)	OPHN1	Pathogenic	criteria provided, multiple submitters, no conflicts
804020	NM_002547.3(OPHN1):c.1138+1G>A	OPHN1	Pathogenic	criteria provided, single submitter
1064589	NM_002547.3(OPHN1):c.702+4A>G	OPHN1	Likely pathogenic	criteria provided, single submitter
1064619	NM_002547.3(OPHN1):c.1202-1G>A	OPHN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1193428	NM_002547.3(OPHN1):c.977C>T (p.Thr326Met)	OPHN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1285464	NM_002547.3(OPHN1):c.1526+1G>A	OPHN1	Likely pathogenic	criteria provided, single submitter
1698727	NM_002547.3(OPHN1):c.702+4A>T	OPHN1	Likely pathogenic	criteria provided, single submitter
1700065	NM_002547.3(OPHN1):c.1586G>A (p.Gly529Glu)	OPHN1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 4 · 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
OPHN1	Definitive	X-linked	X-linked intellectual disability-cerebellar hypoplasia syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OPHN1	Orphanet:137831	X-linked intellectual disability-cerebellar hypoplasia syndrome
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

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OPHN1	HGNC:8148	ENSG00000079482	O60890	Oligophrenin-1	gencc,clinvar
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OPHN1	Oligophrenin-1	Stimulates GTP hydrolysis of members of the Rho family.
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.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Kinase	1	13.9×	0.112
Scaffold/PPI	1	8.6×	0.112

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OPHN1	Scaffold/PPI	no		RhoGAP_dom, PH_domain, BAR_dom
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
corpus callosum	1
sural nerve	1
buccal mucosa cell	1
cortical plate	1
hair follicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OPHN1	138	ubiquitous	marker	corpus callosum, calcaneal tendon, sural nerve
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CASK	4,223
OPHN1	1,229

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CASK	O14936	22

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OPHN1	O60890	74.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Dopamine Neurotransmitter Release Cycle	1	248.3×	0.019	CASK
Nephrin family interactions	1	237.9×	0.019	CASK
Syndecan interactions	1	211.5×	0.019	CASK
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.019	CASK
Sensory processing of sound by outer hair cells of the cochlea	1	102.0×	0.019	CASK
RHOJ GTPase cycle	1	100.2×	0.019	OPHN1
Neurexins and neuroligins	1	98.5×	0.019	CASK
RHOQ GTPase cycle	1	90.6×	0.019	OPHN1
Sensory processing of sound by inner hair cells of the cochlea	1	81.6×	0.019	CASK
RHOB GTPase cycle	1	77.2×	0.019	OPHN1
RHOG GTPase cycle	1	74.2×	0.019	OPHN1
RHOC GTPase cycle	1	73.2×	0.019	OPHN1
RAC2 GTPase cycle	1	63.4×	0.020	OPHN1
RAC3 GTPase cycle	1	59.5×	0.020	OPHN1
RHOA GTPase cycle	1	37.3×	0.029	OPHN1
CDC42 GTPase cycle	1	36.1×	0.029	OPHN1
RAC1 GTPase cycle	1	30.5×	0.032	OPHN1

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of cellular response to growth factor stimulus	1	4213.0×	0.006	CASK
maintenance of postsynaptic specialization structure	1	2808.7×	0.006	OPHN1
cerebellar granule cell differentiation	1	1053.2×	0.006	OPHN1
cell junction assembly	1	842.6×	0.006	OPHN1
substrate-dependent cell migration, cell extension	1	766.0×	0.006	OPHN1
cell morphogenesis involved in neuron differentiation	1	766.0×	0.006	OPHN1
negative regulation of proteasomal protein catabolic process	1	702.2×	0.006	OPHN1
negative regulation of wound healing	1	648.1×	0.006	CASK
cerebral cortex neuron differentiation	1	601.9×	0.006	OPHN1
establishment of epithelial cell apical/basal polarity	1	526.6×	0.006	OPHN1
positive regulation of calcium ion import	1	468.1×	0.006	CASK
negative regulation of cell-matrix adhesion	1	443.5×	0.006	CASK
regulation of synaptic vesicle endocytosis	1	443.5×	0.006	OPHN1
calcium ion import	1	401.2×	0.006	CASK
regulation of neurotransmitter secretion	1	383.0×	0.006	CASK
negative regulation of keratinocyte proliferation	1	351.1×	0.006	CASK
regulation of postsynaptic neurotransmitter receptor internalization	1	312.1×	0.006	OPHN1
regulation of Rho protein signal transduction	1	255.3×	0.007	OPHN1
regulation of synaptic transmission, glutamatergic	1	255.3×	0.007	OPHN1
regulation of endocytosis	1	240.7×	0.007	OPHN1
regulation of synaptic vesicle exocytosis	1	227.7×	0.007	CASK
synaptic vesicle endocytosis	1	216.1×	0.007	OPHN1
establishment of localization in cell	1	80.2×	0.017	CASK
neuron projection development	1	61.1×	0.022	OPHN1
intracellular protein localization	1	52.3×	0.024	CASK
neuron differentiation	1	50.1×	0.024	OPHN1
axon guidance	1	45.3×	0.026	OPHN1
actin cytoskeleton organization	1	39.6×	0.029	OPHN1
nervous system development	1	23.0×	0.048	OPHN1
cell adhesion	1	18.7×	0.056	CASK

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
CASK	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CASK	9	4
OPHN1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
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): 1.

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

Symbol	Assays	Type breakdown
CASK	92	Binding:92

Cohort enzymes (BRENDA EC)

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

9 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)
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)	1	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	1	OPHN1

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)
OPHN1	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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

Cohort genes: OPHN1, CASK