Severe neonatal-onset encephalopathy with microcephaly

Summary

Severe neonatal-onset encephalopathy with microcephaly (MONDO:0010397) is a disease caused by MECP2 (GenCC Definitive), with 11 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MECP2 (GenCC Definitive)
• Cohort genes: 11
• ClinVar variants: 1,103
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0001298	Encephalopathy	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0002104	Apnea	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002033	Poor suck	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0008935	Generalized neonatal hypotonia	Frequent (30-79%)
HP:0010843	EEG with focal slow activity	Frequent (30-79%)
HP:0011471	Gastrostomy tube feeding in infancy	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002126	Polymicrogyria	Occasional (5-29%)
HP:0010841	Multifocal epileptiform discharges	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	severe neonatal-onset encephalopathy with microcephaly
Mondo ID	MONDO:0010397
MeSH	C566878
OMIM	300673
Orphanet	209370
DOID	DOID:0111932
ICD-11	240602582
NCIT	C132293
UMLS	C1968556
MedGen	409616
GARD	0017103
Is cancer (heuristic)	no

Also known as: encephalopathy, neonatal severe, X-linked recessive · severe congenital encephalopathy due to MECP2 mutation · severe neonatal encephalopathy due to MECP2 mutations

Data availability: 1,103 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › monogenic epilepsy › severe neonatal-onset encephalopathy with microcephaly

Related subtypes (17): Mowat-Wilson syndrome, developmental and epileptic encephalopathy, 2, familial infantile myoclonic epilepsy, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, polyhydramnios, megalencephaly, and symptomatic epilepsy, neonatal-onset encephalopathy with rigidity and seizures, developmental and epileptic encephalopathy, 23, spastic paraplegia-severe developmental delay-epilepsy syndrome, X-linked intellectual disability-epilepsy syndrome, focal epilepsy-intellectual disability-cerebro-cerebellar malformation, infantile-onset mesial temporal lobe epilepsy with severe cognitive regression, autosomal recessive cerebellar ataxia - epilepsy - intellectual disability syndrome, developmental and epileptic encephalopathy, 73, neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, epilepsy, X-linked, with or without impaired intellectual development and dysmorphic features, neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

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

600 retrieved; paginated sample, class counts are floors:

153 likely benign, 128 pathogenic, 112 uncertain significance, 78 benign, 49 benign/likely benign, 33 conflicting classifications of pathogenicity, 31 pathogenic/likely pathogenic, 16 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425261	NC_000023.10:g.(?153279389)(153296228_?)del	IRAK1	Pathogenic	criteria provided, single submitter
1006548	NM_001110792.2(MECP2):c.933_968del (p.Leu313_Val324del)	MECP2	Pathogenic	criteria provided, single submitter
1027605	NM_001110792.2(MECP2):c.507C>A (p.Phe169Leu)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069856	NC_000023.10:g.(?_153296154)_153302832del	MECP2	Pathogenic	criteria provided, single submitter
1071768	NM_001110792.2(MECP2):c.74C>G (p.Ser25Ter)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1071811	NM_001110792.2(MECP2):c.674dup (p.Glu226fs)	MECP2	Pathogenic	criteria provided, single submitter
1073280	NM_001110792.2(MECP2):c.984_1023del (p.Lys329fs)	MECP2	Pathogenic	criteria provided, single submitter
1075736	NC_000023.10:g.(?153292375)(153296122_?)del	MECP2	Pathogenic	criteria provided, single submitter
1075737	NC_000023.10:g.(?153357622)(153363142_?)del	MECP2	Pathogenic	criteria provided, single submitter
1076185	NM_001110792.2(MECP2):c.231del (p.Glu78fs)	MECP2	Pathogenic	criteria provided, single submitter
1076937	NM_001110792.2(MECP2):c.954_962del (p.Lys319_Arg321del)	MECP2	Pathogenic	criteria provided, single submitter
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
11825	NM_001110792.2(MECP2):c.446A>G (p.Glu149Gly)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
11833	NM_001110792.2(MECP2):c.459C>G (p.Tyr153Ter)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
11842	NM_001110792.2(MECP2):c.1192_1224del (p.Leu398_Ser408del)	MECP2	Pathogenic	no assertion criteria provided
11845	NM_001110792.2(MECP2):c.5C>T (p.Ala2Val)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11846	NM_001110792.2(MECP2):c.746del (p.Gly249fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1354117	NM_001110792.2(MECP2):c.140_144del (p.Lys47fs)	MECP2	Pathogenic	criteria provided, single submitter
1386387	NC_000023.10:g.(?153296109)(153297633_?)del	MECP2	Pathogenic	criteria provided, single submitter
1389127	NM_001110792.2(MECP2):c.1201_1237del (p.Pro401fs)	MECP2	Pathogenic	criteria provided, single submitter
1401512	NM_001110792.2(MECP2):c.1199del (p.Pro400fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1402665	NM_001110792.2(MECP2):c.573_574insT (p.Lys192Ter)	MECP2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 34 · 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	severe neonatal-onset encephalopathy with microcephaly	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
NAA10	Orphanet:276432	Ogden syndrome
NAA10	Orphanet:568	Microphthalmia, Lenz type
FLNA	Orphanet:1826	Frontometaphyseal dysplasia
FLNA	Orphanet:2301	Congenital short bowel syndrome
FLNA	Orphanet:2484	Melnick-Needles syndrome
FLNA	Orphanet:482606	X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome
FLNA	Orphanet:555877	FLNA-related X-linked myxomatous valvular dysplasia
FLNA	Orphanet:75497	X-linked Ehlers-Danlos syndrome
FLNA	Orphanet:88630	Terminal osseous dysplasia-pigmentary defects syndrome
FLNA	Orphanet:90650	Otopalatodigital syndrome type 1
FLNA	Orphanet:90652	Otopalatodigital syndrome type 2
FLNA	Orphanet:98892	Periventricular nodular heterotopia
FLNA	Orphanet:99811	Neuronal intestinal pseudoobstruction
HCFC1	Orphanet:369962	Methylmalonic acidemia with homocystinuria, type cblX
HCFC1	Orphanet:777	X-linked non-syndromic intellectual disability
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
L1CAM	Orphanet:1497	X-linked complicated corpus callosum dysgenesis
L1CAM	Orphanet:2182	Hydrocephalus with stenosis of the aqueduct of Sylvius
L1CAM	Orphanet:2466	MASA syndrome
L1CAM	Orphanet:306617	X-linked complicated spastic paraplegia type 1
AVPR2	Orphanet:223	Arginine vasopressin resistance
AVPR2	Orphanet:93606	Nephrogenic syndrome of inappropriate antidiuresis

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	gencc,clinvar
NAA10	HGNC:18704	ENSG00000102030	P41227	N-alpha-acetyltransferase 10	clinvar
OPN1MW2	HGNC:26952	ENSG00000166160	P0DN77	Medium-wave-sensitive opsin 2	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
HCFC1	HGNC:4839	ENSG00000172534	P51610	Host cell factor 1	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
L1CAM	HGNC:6470	ENSG00000198910	P32004	Neural cell adhesion molecule L1	clinvar
AVPR2	HGNC:897	ENSG00000126895	P30518	Vasopressin V2 receptor	clinvar
PLXNB3	HGNC:9105	ENSG00000198753	Q9ULL4	Plexin-B3	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.
NAA10	N-alpha-acetyltransferase 10	Catalytic subunit of N-terminal acetyltransferase complexes which display alpha (N-terminal) acetyltransferase activity.
OPN1MW2	Medium-wave-sensitive opsin 2	Visual pigments are the light-absorbing molecules that mediate vision.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
HCFC1	Host cell factor 1	Transcriptional coregulator.
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.
L1CAM	Neural cell adhesion molecule L1	Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors.
AVPR2	Vasopressin V2 receptor	G-protein-coupled receptor for arginine vasopressin, an antidiuretic that promotes renal water reabsorption.
PLXNB3	Plexin-B3	Receptor for SEMA5A that plays a role in axon guidance, invasive growth and cell migration.
RENBP	N-acylglucosamine 2-epimerase	Catalyzes the interconversion of N-acetylglucosamine to N-acetylmannosamine.

Protein-family classification

Druggable: 10 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.91

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
Antibody/Immunoglobulin	4	10.6×	0.002
GPCR	2	4.3×	0.224
Transporter	1	7.1×	0.265
Enzyme (other)	2	2.2×	0.348
Kinase	1	2.5×	0.399
Other/Unknown	1	0.2×	1.000

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
NAA10	Enzyme (other)	yes	2.3.1.255	GNAT_dom, Acyl_CoA_acyltransferase, Ard1-like
OPN1MW2	GPCR	yes		GPCR_Rhodpsn, Opsin_red/grn, Opsin
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
HCFC1	Antibody/Immunoglobulin	yes		FN3_dom, Ig-like_fold, Kelch-typ_b-propeller
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
L1CAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
AVPR2	GPCR	yes		Vprsn_rcpt_V2, GPCR_Rhodpsn, Vasoprsn_rcpt
PLXNB3	Antibody/Immunoglobulin	yes		Semap_dom, Plexin_repeat, IPT_dom
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.

8 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	1
moderate (6-20)	0
broad (>20)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right hemisphere of cerebellum	3
apex of heart	2
parotid gland	2
Brodmann (1909) area 10	1
paraflocculus	1
sural nerve	1
lower esophagus muscularis layer	1
colonic epithelium	1
primordial germ cell in gonad	1
ventricular zone	1
popliteal artery	1
right coronary artery	1
tibial artery	1
skeletal muscle tissue of rectus abdominis	1
tendon of biceps brachii	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
cervix squamous epithelium	1
pancreatic ductal cell	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
NAA10	288	ubiquitous	marker	right hemisphere of cerebellum, apex of heart, lower esophagus muscularis layer
OPN1MW2	4		yes	primordial germ cell in gonad, colonic epithelium, ventricular zone
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
HCFC1	274	ubiquitous	marker	tendon of biceps brachii, parotid gland, skeletal muscle tissue of rectus abdominis
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
L1CAM	239	ubiquitous	marker	cortical plate, right hemisphere of cerebellum, cerebellar hemisphere
AVPR2	146		yes	apex of heart, type B pancreatic cell, olfactory bulb
PLXNB3	133	ubiquitous	yes	C1 segment of cervical spinal cord, tibial nerve, right hemisphere of cerebellum
RENBP	172	ubiquitous	marker	monocyte, spleen, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
FLNA	5,321
IRAK1	4,382
L1CAM	2,937
HCFC1	2,637
NAA10	2,579
AVPR2	1,734
ABCD1	1,181
PLXNB3	1,117
RENBP	670

Intra-cohort edges

A	B	Sources
ABCD1	PLXNB3	string_interaction
AVPR2	L1CAM	string_interaction
AVPR2	NAA10	string_interaction
AVPR2	RENBP	string_interaction
HCFC1	RENBP	string_interaction
L1CAM	NAA10	string_interaction
L1CAM	PLXNB3	string_interaction
L1CAM	RENBP	string_interaction
NAA10	RENBP	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AVPR2	P30518	42
FLNA	P21333	26
ABCD1	P33897	14
NAA10	P41227	12
HCFC1	P51610	11
MECP2	P51608	9
L1CAM	P32004	2
IRAK1	P51617	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RENBP	P51606	94.97
OPN1MW2	P0DN77	82.82
PLXNB3	Q9ULL4	81.47

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 106. Enrichment computed across 11 evidence-associated genes (9 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 9 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	70.5×	0.036	MECP2, IRAK1
Loss of MECP2 binding ability to 5hmC-DNA	1	1268.9×	0.042	MECP2
Defective ABCD1 causes ALD	1	634.4×	0.042	ABCD1
Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI)	1	634.4×	0.042	AVPR2
MECP2 regulates transcription of genes involved in GABA signaling	1	423.0×	0.045	MECP2
Loss of phosphorylation of MECP2 at T308	1	317.2×	0.045	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	317.2×	0.045	MECP2
MECP2 regulates transcription factors	1	253.8×	0.045	MECP2
p75NTR signals via NF-kB	1	211.5×	0.045	IRAK1
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	211.5×	0.045	ABCD1
Vasopressin-like receptors	1	211.5×	0.045	AVPR2
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	181.3×	0.048	MECP2
Synthesis of UDP-N-acetyl-glucosamine	1	158.6×	0.048	RENBP
MECP2 regulates transcription of neuronal ligands	1	158.6×	0.048	MECP2
OAS antiviral response	1	141.0×	0.050	FLNA
Linoleic acid (LA) metabolism	1	126.9×	0.051	ABCD1
GP1b-IX-V activation signalling	1	105.7×	0.051	FLNA
p75NTR recruits signalling complexes	1	97.6×	0.051	IRAK1
NF-kB is activated and signals survival	1	97.6×	0.051	IRAK1
Beta-oxidation of very long chain fatty acids	1	97.6×	0.051	ABCD1
TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling	1	97.6×	0.051	IRAK1
IRAK1 recruits IKK complex	1	90.6×	0.051	IRAK1
IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation	1	90.6×	0.051	IRAK1
alpha-linolenic acid (ALA) metabolism	1	79.3×	0.054	ABCD1
Peroxisomal lipid metabolism	1	74.6×	0.054	ABCD1
Cell-extracellular matrix interactions	1	74.6×	0.054	FLNA
ABC transporters in lipid homeostasis	1	66.8×	0.054	ABCD1
Other semaphorin interactions	1	66.8×	0.054	PLXNB3
MECP2 regulates neuronal receptors and channels	1	66.8×	0.054	MECP2
RHO GTPases activate PAKs	1	60.4×	0.055	FLNA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
renal water retention	1	1532.0×	0.016	AVPR2
catecholamine secretion	1	1532.0×	0.016	MECP2
trans-synaptic signaling by BDNF	1	1532.0×	0.016	MECP2
positive regulation of protein refolding	1	1532.0×	0.016	NAA10
regulation of membrane repolarization during atrial cardiac muscle cell action potential	1	1532.0×	0.016	FLNA
regulation of membrane repolarization during cardiac muscle cell action potential	1	1532.0×	0.016	FLNA
negative regulation of maintenance of mitotic sister chromatid cohesion, centromeric	1	1532.0×	0.016	NAA10
semaphorin-plexin signaling pathway	2	73.0×	0.016	FLNA, PLXNB3
N-acetylmannosamine metabolic process	1	766.0×	0.019	RENBP
peroxisomal membrane transport	1	766.0×	0.019	ABCD1
cardiolipin metabolic process	1	766.0×	0.019	MECP2
very long-chain fatty-acyl-CoA catabolic process	1	766.0×	0.019	ABCD1
regulation of cytokine-mediated signaling pathway	1	510.7×	0.019	IRAK1
nervous system process involved in regulation of systemic arterial blood pressure	1	510.7×	0.019	MECP2
biogenic amine metabolic process	1	510.7×	0.019	MECP2
release from viral latency	1	510.7×	0.019	HCFC1
response to other organism	1	510.7×	0.019	MECP2
tubulin deacetylation	1	510.7×	0.019	FLNA
positive regulation of unsaturated fatty acid biosynthetic process	1	510.7×	0.019	ABCD1
synapse assembly	2	42.0×	0.019	MECP2, PLXNB3
proprioception	1	383.0×	0.020	MECP2
formation of radial glial scaffolds	1	383.0×	0.020	FLNA
sterol homeostasis	1	383.0×	0.020	ABCD1
regulation of systemic arterial blood pressure by vasopressin	1	306.4×	0.020	AVPR2
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	306.4×	0.020	FLNA
negative regulation of lamellipodium assembly	1	306.4×	0.020	PLXNB3
long-chain fatty acid import into peroxisome	1	306.4×	0.020	ABCD1
toll-like receptor 2 signaling pathway	1	306.4×	0.020	IRAK1
establishment of Sertoli cell barrier	1	306.4×	0.020	FLNA
glucocorticoid metabolic process	1	255.3×	0.020	MECP2

Therapeutics

Drug target analysis

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

Druggability breadth: 7 of 11 evidence-associated genes (64%) 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
IRAK1	PONATINIB
AVPR2	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AVPR2	51	4
IRAK1	50	4
FLNA	1	2
HCFC1	1	2
MECP2	0	0
NAA10	0	0
OPN1MW2	0	0
ABCD1	0	0
L1CAM	0	0
PLXNB3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	IRAK1
AFATINIB	4	IRAK1
FEDRATINIB	4	IRAK1
AXITINIB	4	IRAK1
SORAFENIB	4	IRAK1
RUXOLITINIB	4	IRAK1
NERATINIB	4	AVPR2, IRAK1
DABRAFENIB	4	IRAK1
PACRITINIB	4	IRAK1
AFATINIB DIMALEATE	4	IRAK1
VANDETANIB	4	IRAK1
BOSUTINIB	4	AVPR2, IRAK1
FILGOTINIB	4	IRAK1
ABEMACICLIB	4	IRAK1
ENCORAFENIB	4	IRAK1
PAZOPANIB	4	IRAK1
NINTEDANIB	4	IRAK1
SUNITINIB	4	AVPR2, IRAK1
QUIZARTINIB	4	IRAK1
CRIZOTINIB	4	IRAK1
GEFITINIB	4	IRAK1
IMATINIB	4	IRAK1
CLOTRIMAZOLE	4	AVPR2
AMOXAPINE	4	AVPR2
THIOTHIXENE	4	AVPR2
CINACALCET	4	AVPR2
PYRVINIUM	4	AVPR2
BALSALAZIDE	4	AVPR2
IPRINDOLE	4	AVPR2
SERTINDOLE	4	AVPR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
IRAK1	363	Binding:361, Functional:1, ADMET:1
AVPR2	309	Binding:208, Functional:100, ADMET:1
HCFC1	8	Binding:8
FLNA	7	Binding:7
NAA10	2	Binding:2
L1CAM	2	Binding:2
MECP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NAA10	2.3.1.255, 2.3.1.258, 2.3.1.48	N-terminal amino-acid Nalpha-acetyltransferase NatA, N-terminal methionine Nalpha-acetyltransferase NatE, histone acetyltransferase
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
IRAK1	363
AVPR2	309

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; 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)
PONATINIB	4	IRAK1
AFATINIB	4	IRAK1
FEDRATINIB	4	IRAK1
AXITINIB	4	IRAK1
SORAFENIB	4	IRAK1
RUXOLITINIB	4	IRAK1
NERATINIB	4	AVPR2, IRAK1
DABRAFENIB	4	IRAK1
PACRITINIB	4	IRAK1
AFATINIB DIMALEATE	4	IRAK1
VANDETANIB	4	IRAK1
BOSUTINIB	4	AVPR2, IRAK1
FILGOTINIB	4	IRAK1
ABEMACICLIB	4	IRAK1
ENCORAFENIB	4	IRAK1
PAZOPANIB	4	IRAK1
NINTEDANIB	4	IRAK1
SUNITINIB	4	AVPR2, IRAK1
QUIZARTINIB	4	IRAK1
CRIZOTINIB	4	IRAK1
GEFITINIB	4	IRAK1
IMATINIB	4	IRAK1
CLOTRIMAZOLE	4	AVPR2
AMOXAPINE	4	AVPR2
THIOTHIXENE	4	AVPR2
CINACALCET	4	AVPR2
PYRVINIUM	4	AVPR2
BALSALAZIDE	4	AVPR2
IPRINDOLE	4	AVPR2
SERTINDOLE	4	AVPR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	IRAK1, AVPR2
B	Phased (≥1) drug, not yet approved	2	FLNA, HCFC1
C	Druggable family + PDB, no drug	3	NAA10, ABCD1, L1CAM
D	Druggable family + AlphaFold only, no drug	3	OPN1MW2, PLXNB3, RENBP
E	Difficult family or no structure, no drug	1	MECP2

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)
RENBP	0	AVPR2, HCFC1
MECP2	1	—
NAA10	2	—
OPN1MW2	0	—
ABCD1	0	—
L1CAM	2	—
PLXNB3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.