syndromic X-linked intellectual disability Lubs type

Summary

syndromic X-linked intellectual disability Lubs type (MONDO:0010283) is a disease caused by MECP2 (GenCC Definitive), with 9 cohort genes and 2 clinical trials.

At a glance

• Prevalence: Unknown (Europe) [Orphanet-validated]
• Causal gene: MECP2 (GenCC Definitive)
• Cohort genes: 9
• ClinVar variants: 75
• Phenotypes (HPO): 18
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.07	Australia	Validated
Prevalence at birth	1-9 / 1 000 000	0.65	Australia	Validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0000028	Cryptorchidism	Very frequent (80-99%)
HP:0000047	Hypospadias	Very frequent (80-99%)
HP:0000508	Ptosis	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002750	Delayed skeletal maturation	Very frequent (80-99%)
HP:0002916	Abnormality of chromosome segregation	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0000232	Everted lower lip vermilion	Very frequent (80-99%)
HP:0000286	Epicanthus	Very frequent (80-99%)
HP:0000581	Blepharophimosis	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0010804	Tented upper lip vermilion	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0000767	Pectus excavatum	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0004299	Hernia of the abdominal wall	Frequent (30-79%)
HP:0001387	Joint stiffness	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	syndromic X-linked intellectual disability Lubs type
Mondo ID	MONDO:0010283
MeSH	C537723
OMIM	300260
Orphanet	1762
DOID	DOID:0060799
NCIT	C126747
SNOMED CT	702816000
UMLS	C1846058
MedGen	337496
GARD	0009781
Is cancer (heuristic)	no

Also known as: distal duplication Xq · intellectual developmental disorder, X-linked syndromic, Lubs type, X-linked recessive · intellectual disability, X-linked, Lubs type (formerly) · intellectual disability, X-linked, syndromic, Lubs type · intellectual disability, X-linked, with recurrent respiratory infections · Lubs X-linked intellectual disability syndrome · Lubs X-linked intellectual disability syndrome (formerly) · Lubs X-linked mental retardation syndrome · Lubs X-linked mental retardation syndrome (formerly) · MECP2 duplication syndrome · mental retardation, X-linked, Lubs type (formerly) · mental retardation, X-linked, with recurrent respiratory infections · MRXSL · syndromic X-linked intellectual disability Lubs type · telomeric duplication Xq · XLMR syndrome, Lubs type · Xq28 (MECP2) duplication

Data availability: 75 ClinVar variants · 1 GenCC gene-disease record · 9 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

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

Subtypes (1): chromosome Xq28 duplication 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

75 retrieved; paginated sample, class counts are floors:

29 pathogenic, 10 uncertain significance, 9 benign/likely benign, 8 pathogenic/likely pathogenic, 7 benign, 5 likely pathogenic, 4 conflicting classifications of pathogenicity, 3 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703536	GRCh37/hg19 Xq28(chrX:152372767-155233731)	ABCD1	Pathogenic	no assertion criteria provided
2497748	GRCh37/hg19 Xq27.1-28(chrX:139586015-154774957)	ABCD1	Pathogenic	criteria provided, single submitter
3767252	Single allele	ABCD1	Pathogenic	no assertion criteria provided
1077181	Single allele	ARHGAP4	Pathogenic	criteria provided, single submitter
626291	Single allele	CSAG1	Pathogenic	no assertion criteria provided
4073611	GRCh37/hg19 Xq28(chrX:152788477-155226944)x2	F8A1	Pathogenic	no assertion criteria provided
1342311	Single allele	GABRA3	Pathogenic	criteria provided, single submitter
2580294	GRCh37/hg19 Xq28(chrX:153217915-153618382)x2	IRAK1	Pathogenic	criteria provided, single submitter
11838	GRCh38/hg38 Xq28(chrX:153905292-154361918)	LOC130068843	Pathogenic	no assertion criteria provided
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
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
11828	NM_001110792.2(MECP2):c.538C>T (p.Arg180Ter)	MECP2	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
143406	NM_001110792.2(MECP2):c.1200_1243del (p.Pro400_Pro401insTer)	MECP2	Pathogenic	reviewed by expert panel
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
143702	NM_001110792.2(MECP2):c.844del (p.Arg282fs)	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
1684655	NM_001110792.2(MECP2):c.337_1247del911 (p.Pro113fs)	MECP2	Pathogenic	criteria provided, single submitter
189648	NM_001110792.2(MECP2):c.1137_1237del (p.His379fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
242861	Single allele	MECP2	Pathogenic	criteria provided, single submitter
242862	Single allele	MECP2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 14 · 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
GABRA3	Orphanet:79102	Thyrotoxic periodic paralysis
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease
IRAK1	Orphanet:536	Systemic lupus erythematosus
IRAK1	Orphanet:93552	Pediatric systemic lupus erythematosus

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	gencc,clinvar
TMEM187	HGNC:13705	ENSG00000177854	Q14656	Transmembrane protein 187	clinvar
CSAG1	HGNC:24294	ENSG00000198930	Q6PB30	Chondrosarcoma-associated gene 1 protein	clinvar
F8A1	HGNC:3547	ENSG00000288722	P23610	40-kDa huntingtin-associated protein	clinvar
GABRA3	HGNC:4077	ENSG00000011677	P34903	Gamma-aminobutyric acid receptor subunit alpha-3	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar
IRAK1	HGNC:6112	ENSG00000184216	P51617	Interleukin-1 receptor-associated kinase 1	clinvar
ARHGAP4	HGNC:674	ENSG00000089820	P98171	Rho GTPase-activating protein 4	clinvar
RENBP	HGNC:9959	ENSG00000102032	P51606	N-acylglucosamine 2-epimerase	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.
CSAG1	Chondrosarcoma-associated gene 1 protein	May play an important role in maintaining centrosome integrity during mitosis.
F8A1	40-kDa huntingtin-associated protein	RAB5A effector molecule that is involved in vesicular trafficking of early endosomes.
GABRA3	Gamma-aminobutyric acid receptor subunit alpha-3	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
IRAK1	Interleukin-1 receptor-associated kinase 1	Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens.
ARHGAP4	Rho GTPase-activating protein 4	Inhibitory effect on stress fiber organization.
RENBP	N-acylglucosamine 2-epimerase	Catalyzes the interconversion of N-acetylglucosamine to N-acetylmannosamine.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 5 · Druggable fraction: 0.33

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
Transporter	1	8.6×	0.550
Kinase	1	3.1×	0.641
Scaffold/PPI	1	1.9×	0.641
Enzyme (other)	1	1.3×	0.641
Other/Unknown	5	1.0×	0.641

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
TMEM187	Other/Unknown	no		TMEM187
CSAG1	Other/Unknown	no
F8A1	Other/Unknown	no		TPR-like_helical_dom_sf, F8A
GABRA3	Other/Unknown	no		GABAAa_rcpt, GABBAa3_rcpt, GABAA/Glycine_rcpt
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
IRAK1	Kinase	yes	2.7.10.2	Death_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
ARHGAP4	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain
RENBP	Enzyme (other)	yes	5.1.3.8	6-hairpin_glycosidase_sf, AGE/CE, 6hp_glycosidase-like_sf

Expression context

Cohort genes with no expression data: 0.

6 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)	8
unknown	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
monocyte	2
spleen	2
Brodmann (1909) area 10	1
paraflocculus	1
sural nerve	1
body of pancreas	1
endometrium epithelium	1
amygdala	1
putamen	1
cingulate cortex	1
cortical plate	1
prefrontal cortex	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
cervix squamous epithelium	1
pancreatic ductal cell	1
parotid gland	1
granulocyte	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
TMEM187	240	ubiquitous	marker	endometrium epithelium, male germ line stem cell (sensu Vertebrata) in testis, body of pancreas
CSAG1	67	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, putamen, amygdala
F8A1		tissue_specific
GABRA3	106	broad	yes	cortical plate, prefrontal cortex, cingulate cortex
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
IRAK1	288	ubiquitous	marker	parotid gland, pancreatic ductal cell, cervix squamous epithelium
ARHGAP4	229	broad	marker	granulocyte, spleen, monocyte
RENBP	172	ubiquitous	marker	monocyte, spleen, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
IRAK1	4,382
GABRA3	1,295
ABCD1	1,181
ARHGAP4	1,088
RENBP	670
CSAG1	412
TMEM187	390
F8A1	337

Intra-cohort edges

A	B	Sources
ARHGAP4	RENBP	string_interaction
ARHGAP4	TMEM187	string_interaction
IRAK1	TMEM187	string_interaction
MECP2	TMEM187	string_interaction
RENBP	TMEM187	string_interaction

Structural data

PDB: 6 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ABCD1	P33897	14
F8A1	P23610	10
MECP2	P51608	9
GABRA3	P34903	1
IRAK1	P51617	1
ARHGAP4	P98171	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RENBP	P51606	94.97
TMEM187	Q14656	92.12
CSAG1	Q6PB30	63.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 84. Enrichment computed across 9 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transcriptional Regulation by MECP2	2	105.7×	0.012	MECP2, IRAK1
Loss of MECP2 binding ability to 5hmC-DNA	1	1903.3×	0.022	MECP2
Defective ABCD1 causes ALD	1	951.7×	0.029	ABCD1
MECP2 regulates transcription of genes involved in GABA signaling	1	634.4×	0.029	MECP2
Loss of phosphorylation of MECP2 at T308	1	475.8×	0.029	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	475.8×	0.029	MECP2
MECP2 regulates transcription factors	1	380.7×	0.029	MECP2
p75NTR signals via NF-kB	1	317.2×	0.029	IRAK1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	317.2×	0.029	ABCD1
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	271.9×	0.029	MECP2
Synthesis of UDP-N-acetyl-glucosamine	1	237.9×	0.029	RENBP
MECP2 regulates transcription of neuronal ligands	1	237.9×	0.029	MECP2
Linoleic acid (LA) metabolism	1	190.3×	0.032	ABCD1
p75NTR recruits signalling complexes	1	146.4×	0.032	IRAK1
NF-kB is activated and signals survival	1	146.4×	0.032	IRAK1
Beta-oxidation of very long chain fatty acids	1	146.4×	0.032	ABCD1
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling	1	146.4×	0.032	IRAK1
IRAK1 recruits IKK complex	1	135.9×	0.032	IRAK1
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation	1	135.9×	0.032	IRAK1
alpha-linolenic acid (ALA) metabolism	1	119.0×	0.035	ABCD1
Peroxisomal lipid metabolism	1	112.0×	0.036	ABCD1
ABC transporters in lipid homeostasis	1	100.2×	0.036	ABCD1
MECP2 regulates neuronal receptors and channels	1	100.2×	0.036	MECP2
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	1	86.5×	0.039	IRAK1
Class I peroxisomal membrane protein import	1	86.5×	0.039	ABCD1
activated TAK1 mediates p38 MAPK activation	1	82.8×	0.039	IRAK1
ABC transporter disorders	1	73.2×	0.042	ABCD1
Regulation of MECP2 expression and activity	1	61.4×	0.048	MECP2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1	59.5×	0.048	IRAK1
Nuclear events stimulated by ALK signaling in cancer	1	54.4×	0.049	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 8 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	2106.5×	0.015	MECP2
trans-synaptic signaling by BDNF	1	2106.5×	0.015	MECP2
N-acetylmannosamine metabolic process	1	1053.2×	0.015	RENBP
peroxisomal membrane transport	1	1053.2×	0.015	ABCD1
cardiolipin metabolic process	1	1053.2×	0.015	MECP2
very long-chain fatty-acyl-CoA catabolic process	1	1053.2×	0.015	ABCD1
regulation of cytokine-mediated signaling pathway	1	702.2×	0.015	IRAK1
nervous system process involved in regulation of systemic arterial blood pressure	1	702.2×	0.015	MECP2
biogenic amine metabolic process	1	702.2×	0.015	MECP2
response to other organism	1	702.2×	0.015	MECP2
positive regulation of unsaturated fatty acid biosynthetic process	1	702.2×	0.015	ABCD1
proprioception	1	526.6×	0.015	MECP2
sterol homeostasis	1	526.6×	0.015	ABCD1
vesicle cytoskeletal trafficking	1	526.6×	0.015	F8A1
long-chain fatty acid import into peroxisome	1	421.3×	0.015	ABCD1
toll-like receptor 2 signaling pathway	1	421.3×	0.015	IRAK1
glucocorticoid metabolic process	1	351.1×	0.015	MECP2
regulation of fatty acid beta-oxidation	1	351.1×	0.015	ABCD1
long-chain fatty acid catabolic process	1	351.1×	0.015	ABCD1
myelin maintenance	1	351.1×	0.015	ABCD1
regulation of mitochondrial depolarization	1	351.1×	0.015	ABCD1
inositol metabolic process	1	300.9×	0.015	MECP2
Toll signaling pathway	1	300.9×	0.015	IRAK1
N-acetylneuraminate catabolic process	1	300.9×	0.015	RENBP
fatty acid elongation	1	300.9×	0.015	ABCD1
very long-chain fatty acid catabolic process	1	300.9×	0.015	ABCD1
interleukin-33-mediated signaling pathway	1	263.3×	0.016	IRAK1
positive regulation of microtubule nucleation	1	263.3×	0.016	MECP2
toll-like receptor 9 signaling pathway	1	234.1×	0.017	IRAK1
negative regulation of smooth muscle cell differentiation	1	234.1×	0.017	MECP2

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 7

Druggability breadth: 3 of 9 evidence-associated genes (33%) 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
GABRA3	ENZALUTAMIDE
IRAK1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
IRAK1	50	4
GABRA3	29	4
MECP2	0	0
TMEM187	0	0
CSAG1	0	0
F8A1	0	0
ABCD1	0	0
ARHGAP4	0	0
RENBP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ENZALUTAMIDE	4	GABRA3
DIAZEPAM	4	GABRA3
LIOTHYRONINE	4	GABRA3
GANAXOLONE	4	GABRA3
BREXANOLONE	4	GABRA3
APALUTAMIDE	4	GABRA3
FLUMAZENIL	4	GABRA3
CLONAZEPAM	4	GABRA3
FLUNITRAZEPAM	4	GABRA3
CHLORDIAZEPOXIDE	4	GABRA3
TRIAZOLAM	4	GABRA3
ZOLPIDEM	4	GABRA3
PROPOFOL	4	GABRA3
ESZOPICLONE	4	GABRA3
ALPRAZOLAM	4	GABRA3
PONATINIB	4	IRAK1
AFATINIB	4	IRAK1
FEDRATINIB	4	IRAK1
AXITINIB	4	IRAK1
SORAFENIB	4	IRAK1
RUXOLITINIB	4	IRAK1
NERATINIB	4	IRAK1
DABRAFENIB	4	IRAK1
PACRITINIB	4	IRAK1
AFATINIB DIMALEATE	4	IRAK1
VANDETANIB	4	IRAK1
BOSUTINIB	4	IRAK1
FILGOTINIB	4	IRAK1
ABEMACICLIB	4	IRAK1
ENCORAFENIB	4	IRAK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
GABRA3	400	Binding:324, Functional:70, ADMET:3, Toxicity:3
IRAK1	363	Binding:361, Functional:1, ADMET:1
MECP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter
IRAK1	2.7.10.2	non-specific protein-tyrosine kinase
RENBP	5.1.3.8	N-acylglucosamine 2-epimerase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GABRA3	400
IRAK1	363

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
ENZALUTAMIDE	4	GABRA3
DIAZEPAM	4	GABRA3
LIOTHYRONINE	4	GABRA3
GANAXOLONE	4	GABRA3
BREXANOLONE	4	GABRA3
APALUTAMIDE	4	GABRA3
FLUMAZENIL	4	GABRA3
CLONAZEPAM	4	GABRA3
FLUNITRAZEPAM	4	GABRA3
CHLORDIAZEPOXIDE	4	GABRA3
TRIAZOLAM	4	GABRA3
ZOLPIDEM	4	GABRA3
PROPOFOL	4	GABRA3
ESZOPICLONE	4	GABRA3
ALPRAZOLAM	4	GABRA3
PONATINIB	4	IRAK1
AFATINIB	4	IRAK1
FEDRATINIB	4	IRAK1
AXITINIB	4	IRAK1
SORAFENIB	4	IRAK1
RUXOLITINIB	4	IRAK1
NERATINIB	4	IRAK1
DABRAFENIB	4	IRAK1
PACRITINIB	4	IRAK1
AFATINIB DIMALEATE	4	IRAK1
VANDETANIB	4	IRAK1
BOSUTINIB	4	IRAK1
FILGOTINIB	4	IRAK1
ABEMACICLIB	4	IRAK1
ENCORAFENIB	4	IRAK1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	GABRA3, IRAK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ABCD1
D	Druggable family + AlphaFold only, no drug	1	RENBP
E	Difficult family or no structure, no drug	5	MECP2, TMEM187, CSAG1, F8A1, ARHGAP4

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MECP2	1	—
TMEM187	0	—
CSAG1	0	—
F8A1	0	—
ABCD1	0	—
ARHGAP4	0	—
RENBP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06615206	Not specified	RECRUITING	A First-in-Human Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of a Novel CRISPR RNA-editing Therapy in Patients with Mecp2 Duplication Syndrome, a Rare Orphan Disease (HERO)
NCT03077308	Not specified	COMPLETED	Rare Diseases Clinical Research Network: Neurophysiological Correlates