X-linked intellectual disability-psychosis-macroorchidism syndrome

Summary

X-linked intellectual disability-psychosis-macroorchidism syndrome (MONDO:0010235) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 110
• Phenotypes (HPO): 27

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		6	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0006801	Hyperactive deep tendon reflexes	Very frequent (80-99%)
HP:0000053	Macroorchidism	Very frequent (80-99%)
HP:0000718	Aggressive behavior	Very frequent (80-99%)
HP:0000737	Irritability	Very frequent (80-99%)
HP:0000752	Hyperactivity	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0001635	Congestive heart failure	Frequent (30-79%)
HP:0002039	Anorexia	Frequent (30-79%)
HP:0002061	Lower limb spasticity	Frequent (30-79%)
HP:0002342	Intellectual disability, moderate	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0007302	Bipolar affective disorder	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0011188	Focal EEG discharges with secondary generalization	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0001297	Stroke	Occasional (5-29%)
HP:0001300	Parkinsonism	Occasional (5-29%)
HP:0001513	Obesity	Occasional (5-29%)
HP:0002136	Broad-based gait	Occasional (5-29%)
HP:0002322	Resting tremor	Occasional (5-29%)
HP:0002362	Shuffling gait	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0025403	Stooped posture	Occasional (5-29%)
HP:0100852	Abnormal fear/anxiety-related behavior	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked intellectual disability-psychosis-macroorchidism syndrome
Mondo ID	MONDO:0010235
OMIM	300055
Orphanet	3077
DOID	DOID:0060827
SNOMED CT	702356009
UMLS	C0796222
MedGen	163232
GARD	0003506
Is cancer (heuristic)	no

Also known as: intellectual deficit, X-linked - psychosis - macroorchidism · intellectual developmental disorder, X-linked, syndromic 13, X-linked recessive · intellectual disability psychosis macroorchidism · intellectual disability with psychosis, pyramidal signs, and macroorchidism · intellectual disability, X-linked, syndromic 13 · intellectual disability, X-linked, syndromic type 13 · Lindsay-Burn syndrome · mental retardation psychosis macroorchidism · mental retardation with psychosis, pyramidal signs, and macroorchidism · mental retardation, X-linked 16 · mental retardation, X-linked 79 · mental retardation, X-linked, syndromic 13 · mental retardation, X-linked, syndromic type 13 · mental retardation, X-linked, with spasticity · MRXS13 · PPM-X · PPM-X syndrome · X-linked intellectual disability 79 · X-linked intellectual disability with spasticity

Data availability: 110 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 › X-linked intellectual disability-psychosis-macroorchidism syndrome

Related subtypes (80): 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, 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

110 retrieved; paginated sample, class counts are floors:

32 pathogenic, 22 uncertain significance, 13 benign, 11 pathogenic/likely pathogenic, 11 benign/likely benign, 9 likely pathogenic, 8 likely benign, 4 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1207096	NM_001110792.2(MECP2):c.3G>A (p.Met1Ile)	LOC130068854	Pathogenic	criteria provided, multiple submitters, no conflicts
11809	NM_001110792.2(MECP2):c.433C>T (p.Arg145Cys)	MECP2	Pathogenic	reviewed by expert panel
11811	NM_001110792.2(MECP2):c.509C>T (p.Thr170Met)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11814	NM_001110792.2(MECP2):c.352C>T (p.Arg118Trp)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11815	NM_001110792.2(MECP2):c.844C>T (p.Arg282Ter)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
11817	NM_001110792.2(MECP2):c.1216G>T (p.Glu406Ter)	MECP2	Pathogenic	criteria provided, single submitter
11819	NM_001110792.2(MECP2):c.916C>T (p.Arg306Ter)	MECP2	Pathogenic	reviewed by expert panel
11823	NM_001110792.2(MECP2):c.455C>T (p.Ala152Val)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11824	NM_001110792.2(MECP2):c.952C>T (p.Arg318Cys)	MECP2	Pathogenic	reviewed by expert panel
11825	NM_001110792.2(MECP2):c.446A>G (p.Glu149Gly)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11829	NM_001110792.2(MECP2):c.799C>T (p.Arg267Ter)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143328	NM_001110792.2(MECP2):c.144_147del (p.Glu49fs)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143342	NM_001110792.2(MECP2):c.1171_1178del (p.Pro391fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143369	NM_001110792.2(MECP2):c.1193_1233del (p.Leu398fs)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143379	NM_001110792.2(MECP2):c.1195_1196delinsT (p.Pro399fs)	MECP2	Pathogenic	criteria provided, single submitter
143395	NM_001110792.2(MECP2):c.1198_1199delinsTA (p.Pro400Ter)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143406	NM_001110792.2(MECP2):c.1200_1243del (p.Pro400_Pro401insTer)	MECP2	Pathogenic	reviewed by expert panel
143441	NM_001110792.2(MECP2):c.1252C>T (p.Gln418Ter)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143474	NM_001110792.2(MECP2):c.1451_1452del (p.Glu484fs)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143492	NM_001110792.2(MECP2):c.182C>G (p.Ser61Ter)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143534	NM_001110792.2(MECP2):c.353G>A (p.Arg118Gln)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143562	NM_001110792.2(MECP2):c.437C>G (p.Ser146Cys)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143579	NM_001110792.2(MECP2):c.491C>G (p.Pro164Arg)	MECP2	Pathogenic	reviewed by expert panel
143603	NM_001110792.2(MECP2):c.535C>T (p.Arg179Trp)	MECP2	Pathogenic	reviewed by expert panel
143695	NM_001110792.2(MECP2):c.112del (p.Leu38fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143702	NM_001110792.2(MECP2):c.844del (p.Arg282fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143734	NM_001110792.2(MECP2):c.940C>G (p.Pro314Ala)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143749	NM_001110792.2(MECP2):c.961C>T (p.Arg321Trp)	MECP2	Pathogenic	reviewed by expert panel
143754	NM_001110792.2(MECP2):c.1001C>T (p.Pro334Leu)	MECP2	Pathogenic	reviewed by expert panel
156068	NM_001110792.2(MECP2):c.414-3C>G	MECP2	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 7 · 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
MECP2	Definitive	X-linked	syndromic X-linked intellectual disability Lubs type	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MECP2	Orphanet:1762	Proximal Xq28 duplication syndrome
MECP2	Orphanet:209370	MECP2-related severe neonatal encephalopathy
MECP2	Orphanet:3077	X-linked intellectual disability-psychosis-macroorchidism syndrome
MECP2	Orphanet:3095	Atypical Rett syndrome
MECP2	Orphanet:536	Systemic lupus erythematosus
MECP2	Orphanet:777	X-linked non-syndromic intellectual disability
MECP2	Orphanet:778	Rett syndrome

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
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MECP2	Methyl-CpG-binding protein 2	Chromosomal protein that binds to methylated DNA.

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)
MECP2	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA-bd_dom_sf, Me_CpG-bd_MeCP2

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 10	1
paraflocculus	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MECP2	277	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MECP2	P51608	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. 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
Loss of MECP2 binding ability to 5hmC-DNA	1	11420.0×	1e-03	MECP2
MECP2 regulates transcription of genes involved in GABA signaling	1	3806.7×	1e-03	MECP2
Loss of phosphorylation of MECP2 at T308	1	2855.0×	1e-03	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	2855.0×	1e-03	MECP2
MECP2 regulates transcription factors	1	2284.0×	1e-03	MECP2
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	1631.4×	0.001	MECP2
MECP2 regulates transcription of neuronal ligands	1	1427.5×	0.001	MECP2
MECP2 regulates neuronal receptors and channels	1	601.0×	0.002	MECP2
Regulation of MECP2 expression and activity	1	368.4×	0.003	MECP2
Nuclear events stimulated by ALK signaling in cancer	1	326.3×	0.003	MECP2
Transcriptional Regulation by MECP2	1	317.2×	0.003	MECP2

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
catecholamine secretion	1	16852.0×	0.001	MECP2
trans-synaptic signaling by BDNF	1	16852.0×	0.001	MECP2
cardiolipin metabolic process	1	8426.0×	0.001	MECP2
nervous system process involved in regulation of systemic arterial blood pressure	1	5617.3×	0.001	MECP2
biogenic amine metabolic process	1	5617.3×	0.001	MECP2
response to other organism	1	5617.3×	0.001	MECP2
proprioception	1	4213.0×	0.002	MECP2
glucocorticoid metabolic process	1	2808.7×	0.002	MECP2
inositol metabolic process	1	2407.4×	0.002	MECP2
positive regulation of microtubule nucleation	1	2106.5×	0.002	MECP2
negative regulation of smooth muscle cell differentiation	1	1872.4×	0.002	MECP2
regulation of respiratory gaseous exchange by nervous system process	1	1296.3×	0.003	MECP2
L-glutamine metabolic process	1	1296.3×	0.003	MECP2
startle response	1	1123.5×	0.003	MECP2
negative regulation of gene expression via chromosomal CpG island methylation	1	1053.2×	0.003	MECP2
genomic imprinting	1	991.3×	0.003	MECP2
glial cell proliferation	1	887.0×	0.003	MECP2
ventricular system development	1	842.6×	0.003	MECP2
neuron maturation	1	802.5×	0.003	MECP2
phosphatidylcholine metabolic process	1	802.5×	0.003	MECP2
negative regulation of blood vessel endothelial cell migration	1	732.7×	0.003	MECP2
positive regulation of glial cell proliferation	1	702.2×	0.003	MECP2
respiratory gaseous exchange by respiratory system	1	624.1×	0.003	MECP2
excitatory postsynaptic potential	1	443.5×	0.004	MECP2
behavioral fear response	1	432.1×	0.004	MECP2
long-term memory	1	421.3×	0.004	MECP2
dendrite development	1	391.9×	0.004	MECP2
sensory perception of pain	1	374.5×	0.004	MECP2
cerebellum development	1	358.6×	0.004	MECP2
visual learning	1	306.4×	0.005	MECP2

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
MECP2	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
MECP2	1	Binding:1

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	MECP2

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)
MECP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.