syndromic X-linked intellectual disability Shashi type

Summary

syndromic X-linked intellectual disability Shashi type (MONDO:0010277) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 12
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		9	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0000053	Macroorchidism	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Very frequent (80-99%)
HP:0000280	Coarse facial features	Very frequent (80-99%)
HP:0000336	Prominent supraorbital ridges	Very frequent (80-99%)
HP:0000400	Macrotia	Very frequent (80-99%)
HP:0000414	Bulbous nose	Very frequent (80-99%)
HP:0000581	Blepharophimosis	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001513	Obesity	Very frequent (80-99%)
HP:0002342	Intellectual disability, moderate	Very frequent (80-99%)
HP:0100540	Palpebral edema	Very frequent (80-99%)
HP:0001250	Seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability Shashi type
Mondo ID	MONDO:0010277
MeSH	C537135
OMIM	300238
Orphanet	85286
DOID	DOID:0060826
SNOMED CT	718900002
UMLS	C1846145
MedGen	335348
GARD	0004119
Is cancer (heuristic)	no

Also known as: intellectual developmental disorder, syndromic 11, Shashi type, X-linked recessive · intellectual disability X-linked Shashi type · intellectual disability X-linked syndromic 11 · intellectual disability, X-linked, syndromic 11 · intellectual disability, X-linked, syndromic 11, Shashi type · mental retardation X-linked Shashi type · mental retardation X-linked syndromic 11 · mental retardation, X-linked, Shashi type · mental retardation, X-linked, syndromic 11 · MRXS11 · Shashi X-linked intellectual disability syndrome · Shashi X-linked mental retardation syndrome · SMRXS · syndromic X-linked intellectual disability type 11 · X-linked intellectual disability Shashi type

Data availability: 12 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › syndromic X-linked intellectual disability Shashi type

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, 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-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

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

12 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 1 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
372147	NM_002139.4(RBMX):c.1037_1059del (p.Glu346fs)	LOC126863330	Pathogenic	no assertion criteria provided
4086215	NM_006565.4(CTCF):c.107A>G (p.Asp36Gly)	CTCF	Uncertain significance	criteria provided, single submitter
1184408	NM_002139.4(RBMX):c.997G>T (p.Asp333Tyr)	LOC126863330	Uncertain significance	criteria provided, single submitter
3376257	NM_002139.4(RBMX):c.1031G>A (p.Arg344Lys)	LOC126863330	Uncertain significance	criteria provided, single submitter
1027782	NM_002139.4(RBMX):c.591A>G (p.Glu197=)	RBMX	Uncertain significance	criteria provided, single submitter
1683586	NM_002139.4(RBMX):c.101T>C (p.Ile34Thr)	RBMX	Uncertain significance	criteria provided, single submitter
1701790	NM_002139.4(RBMX):c.296C>T (p.Pro99Leu)	RBMX	Uncertain significance	criteria provided, single submitter
2435385	NM_002139.4(RBMX):c.217-2dup	RBMX	Uncertain significance	criteria provided, single submitter
2570689	NM_002139.4(RBMX):c.287C>T (p.Pro96Leu)	RBMX	Uncertain significance	criteria provided, single submitter
4076368	NM_002139.4(RBMX):c.764A>G (p.Tyr255Cys)	RBMX	Uncertain significance	criteria provided, single submitter
522685	NM_002139.4(RBMX):c.389-8T>C	RBMX	Uncertain significance	criteria provided, single submitter
1327942	NM_002139.4(RBMX):c.-1C>A	RBMX	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
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
CTCF	Orphanet:363611	CTCF-related neurodevelopmental disorder

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
RBMX	HGNC:9910	ENSG00000147274	P38159	RNA-binding motif protein, X chromosome	gencc,clinvar
CTCF	HGNC:13723	ENSG00000102974	P49711	Transcriptional repressor CTCF	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.
CTCF	Transcriptional repressor CTCF	Chromatin binding factor that binds to DNA sequence specific sites and regulates the 3D structure of chromatin.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RBMX	Other/Unknown	no		RRM_dom, RRM_euk-type, RBM1CTR
CTCF	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger_PRDM4/PRDM1/PRDM14

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
ganglionic eminence	2
ventricular zone	2
cortical plate	1
endometrium epithelium	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
CTCF	297	ubiquitous	marker	ventricular zone, ganglionic eminence, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTCF	5,713
RBMX	4,460

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CTCF	P49711	21
RBMX	P38159	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
RHOBTB2 GTPase cycle	1	237.9×	0.017	RBMX
RHOBTB1 GTPase cycle	1	237.9×	0.017	RBMX
RND1 GTPase cycle	1	132.8×	0.017	RBMX
RND3 GTPase cycle	1	129.8×	0.017	RBMX
RND2 GTPase cycle	1	129.8×	0.017	RBMX
CHD6, CHD7, CHD8, CHD9 subfamily	1	74.2×	0.025	CTCF
Activation of anterior HOX genes in hindbrain development during early embryogenesis	1	45.7×	0.030	CTCF
mRNA Polyadenylation	1	43.9×	0.030	RBMX
Processing of Capped Intron-Containing Pre-mRNA	1	41.1×	0.030	RBMX
mRNA Splicing - Major Pathway	1	27.3×	0.040	RBMX
Dengue Virus-Host Interactions	1	22.8×	0.043	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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of centromeric sister chromatid cohesion	1	2808.7×	0.010	CTCF
protein localization to chromosome, centromeric region	1	1053.2×	0.010	CTCF
chromatin looping	1	601.9×	0.010	CTCF
negative regulation of gene expression via chromosomal CpG island methylation	1	526.6×	0.010	CTCF
genomic imprinting	1	495.6×	0.010	CTCF
negative regulation of mRNA splicing, via spliceosome	1	383.0×	0.010	RBMX
membrane protein ectodomain proteolysis	1	324.1×	0.010	RBMX
cardiac muscle cell development	1	312.1×	0.010	CTCF
DNA methylation-dependent constitutive heterochromatin formation	1	271.8×	0.010	CTCF
positive regulation of mRNA splicing, via spliceosome	1	271.8×	0.010	RBMX
positive regulation of transcription by RNA polymerase II	2	14.9×	0.011	RBMX, CTCF
epigenetic regulation of gene expression	1	191.5×	0.012	CTCF
cellular response to interleukin-1	1	140.4×	0.015	RBMX
regulation of alternative mRNA splicing, via spliceosome	1	122.1×	0.016	RBMX
chromosome segregation	1	86.9×	0.021	CTCF
mitochondrion organization	1	75.9×	0.023	CTCF
protein homooligomerization	1	61.1×	0.026	RBMX
osteoblast differentiation	1	60.6×	0.026	RBMX
mRNA splicing, via spliceosome	1	45.8×	0.032	RBMX
gene expression	1	39.9×	0.035	CTCF
in utero embryonic development	1	36.0×	0.036	CTCF
transcription by RNA polymerase II	1	35.3×	0.036	RBMX
negative regulation of cell population proliferation	1	21.1×	0.057	CTCF
positive regulation of gene expression	1	19.4×	0.059	CTCF
negative regulation of DNA-templated transcription	1	15.8×	0.070	CTCF
positive regulation of DNA-templated transcription	1	14.0×	0.076	CTCF
negative regulation of transcription by RNA polymerase II	1	8.9×	0.114	CTCF
regulation of transcription by RNA polymerase II	1	5.8×	0.164	CTCF

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 2 of 2 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
CTCF	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
CTCF	2	Binding:2

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

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	2	RBMX, CTCF

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RBMX	6	—
CTCF	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.