severe X-linked intellectual disability, Gustavson type

Summary

severe X-linked intellectual disability, Gustavson type (MONDO:0010661) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 34

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0008850	Severe postnatal growth retardation	Very frequent (80-99%)
HP:0012715	Profound hearing impairment	Very frequent (80-99%)
HP:0000618	Blindness	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001518	Small for gestational age	Frequent (30-79%)
HP:0002198	Dilated fourth ventricle	Frequent (30-79%)
HP:0002788	Recurrent upper respiratory tract infections	Frequent (30-79%)
HP:0005486	Small fontanelle	Frequent (30-79%)
HP:0005949	Apneic episodes in infancy	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0012444	Brain atrophy	Frequent (30-79%)
HP:0040288	Nasogastric tube feeding	Frequent (30-79%)
HP:0000076	Vesicoureteral reflux	Occasional (5-29%)
HP:0000239	Large fontanelles	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000377	Abnormal pinna morphology	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0001199	Triphalangeal thumb	Occasional (5-29%)
HP:0001305	Dandy-Walker malformation	Occasional (5-29%)
HP:0001321	Cerebellar hypoplasia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001374	Congenital hip dislocation	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001838	Rocker bottom foot	Occasional (5-29%)
HP:0001848	Calcaneovalgus deformity	Occasional (5-29%)
HP:0003196	Short nose	Occasional (5-29%)
HP:0005781	Contractures of the large joints	Occasional (5-29%)
HP:0006829	Severe muscular hypotonia	Occasional (5-29%)
HP:0006956	Dilation of lateral ventricles	Occasional (5-29%)
HP:0008110	Equinovarus deformity	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe X-linked intellectual disability, Gustavson type
Mondo ID	MONDO:0010661
MeSH	C536759
OMIM	309555
Orphanet	3078
DOID	DOID:0081123
SNOMED CT	722213009
UMLS	C0795965
MedGen	167088
GARD	0005611
Is cancer (heuristic)	no

Also known as: gust · intellectual disability X-linked severe Gustavson type · mental retardation with optic atrophy, deafness, and seizures · mental retardation X-linked severe Gustavson type · X-linked intellectual disability Gustavson type · X-linked mental retardation Gustavson type

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

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 › severe X-linked intellectual disability, Gustavson type

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, 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

3 retrieved; paginated sample, class counts are floors:

2 likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
2691753	NM_002139.4(RBMX):c.478CCT[2] (p.Pro162del)	RBMX	Likely pathogenic	criteria provided, single submitter
3064397	NM_002139.4(RBMX):c.388G>T (p.Asp130Tyr)	RBMX	Likely pathogenic	criteria provided, single submitter
3064679	NM_001164803.2(RBMX):c.560dup (p.Tyr187Ter)	RBMX	Uncertain significance	criteria provided, single submitter

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
RBMX	Moderate	X-linked	syndromic X-linked intellectual disability Shashi type	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RBMX	Orphanet:3078	Severe X-linked intellectual disability, Gustavson type
RBMX	Orphanet:85286	X-linked intellectual disability, Shashi type

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
RBMX	HGNC:9910	ENSG00000147274	P38159	RNA-binding motif protein, X chromosome	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RBMX	RNA-binding motif protein, X chromosome	RNA-binding protein that plays several role in the regulation of pre- and post-transcriptional processes.

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)
RBMX	Other/Unknown	no		RRM_dom, RRM_euk-type, RBM1CTR

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
cortical plate	1
ganglionic eminence	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RBMX	255	ubiquitous	marker	ventricular zone, ganglionic eminence, cortical plate

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RBMX	4,460

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RBMX	P38159	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
RHOBTB2 GTPase cycle	1	475.8×	0.007	RBMX
RHOBTB1 GTPase cycle	1	475.8×	0.007	RBMX
RND1 GTPase cycle	1	265.6×	0.007	RBMX
RND3 GTPase cycle	1	259.6×	0.007	RBMX
RND2 GTPase cycle	1	259.6×	0.007	RBMX
mRNA Polyadenylation	1	87.8×	0.016	RBMX
Processing of Capped Intron-Containing Pre-mRNA	1	82.2×	0.016	RBMX
mRNA Splicing - Major Pathway	1	54.6×	0.021	RBMX
Dengue Virus-Host Interactions	1	45.7×	0.022	RBMX

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
negative regulation of mRNA splicing, via spliceosome	1	766.0×	0.006	RBMX
membrane protein ectodomain proteolysis	1	648.1×	0.006	RBMX
positive regulation of mRNA splicing, via spliceosome	1	543.6×	0.006	RBMX
cellular response to interleukin-1	1	280.9×	0.008	RBMX
regulation of alternative mRNA splicing, via spliceosome	1	244.2×	0.008	RBMX
protein homooligomerization	1	122.1×	0.012	RBMX
osteoblast differentiation	1	121.2×	0.012	RBMX
mRNA splicing, via spliceosome	1	91.6×	0.014	RBMX
transcription by RNA polymerase II	1	70.5×	0.016	RBMX
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	RBMX

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RBMX	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RBMX	6	Binding:6

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	RBMX

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)
RBMX	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.