atypical Rett syndrome

disease

On this page

Also known as atypical RTTRett like syndromeRett syndrome variant

Summary

atypical Rett syndrome (MONDO:0017746) is a disease with 9 cohort genes.

At a glance

Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
Cohort genes: 9
ClinVar variants: 57
Phenotypes (HPO): 54

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

54 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000713	Agitation	Very frequent (80-99%)
HP:0000729	Autistic behavior	Very frequent (80-99%)
HP:0000817	Reduced eye contact	Very frequent (80-99%)
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0002371	Loss of speech	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0002793	Abnormal pattern of respiration	Very frequent (80-99%)
HP:0004302	Functional motor deficit	Very frequent (80-99%)
HP:0004305	Involuntary movements	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0012171	Stereotypical hand wringing	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0000723	Restrictive behavior	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001773	Short foot	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002186	Apraxia	Frequent (30-79%)
HP:0002300	Mutism	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0002876	Episodic tachypnea	Frequent (30-79%)
HP:0002882	Sudden episodic apnea	Frequent (30-79%)
HP:0003808	Abnormal muscle tone	Frequent (30-79%)
HP:0005484	Secondary microcephaly	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0012719	Functional abnormality of the gastrointestinal tract	Frequent (30-79%)
HP:0032588	Hand apraxia	Frequent (30-79%)
HP:0032807	Neonatal seizure	Frequent (30-79%)
HP:0045084	Limb myoclonus	Frequent (30-79%)
HP:0100703	Tongue thrusting	Frequent (30-79%)
HP:0200055	Small hand	Frequent (30-79%)
HP:0012760	Reduced social responsiveness	Frequent (30-79%)
HP:0000748	Inappropriate laughter	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001319	Neonatal hypotonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0002123	Generalized myoclonic seizure	Occasional (5-29%)
HP:0002194	Delayed gross motor development	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002808	Kyphosis	Occasional (5-29%)
HP:0007281	Developmental stagnation	Occasional (5-29%)
HP:0007328	Impaired pain sensation	Occasional (5-29%)
HP:0012469	Infantile spasms	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	atypical Rett syndrome
Mondo ID	MONDO:0017746
Orphanet	3095
ICD-11	605088126
SNOMED CT	718393002
UMLS	C2748910
MedGen	440664
GARD	0004694
Is cancer (heuristic)	no

Also known as: atypical RTT · Rett like syndrome · Rett syndrome variant

Data availability: 57 ClinVar variants · 7 GenCC gene-disease records · 49 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › atypical Rett syndrome

Subtypes (2): developmental and epileptic encephalopathy, 2, FOXG1 disorder

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

57 retrieved; paginated sample, class counts are floors:

32 pathogenic, 13 likely pathogenic, 4 uncertain significance, 4 pathogenic/likely pathogenic, 2 benign, 1 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
11500	NM_001323289.2(CDKL5):c.2500C>T (p.Gln834Ter)	CDKL5	Pathogenic	reviewed by expert panel
11502	NM_001323289.2(CDKL5):c.119C>T (p.Ala40Val)	CDKL5	Pathogenic	reviewed by expert panel
143774	NM_001323289.2(CDKL5):c.1311dup (p.Ser438fs)	CDKL5	Pathogenic	reviewed by expert panel
143779	NM_001323289.2(CDKL5):c.163_166del (p.Glu55fs)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143780	NM_001323289.2(CDKL5):c.1648C>T (p.Arg550Ter)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
143781	NM_001323289.2(CDKL5):c.1675C>T (p.Arg559Ter)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143783	NM_001323289.2(CDKL5):c.175C>T (p.Arg59Ter)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
143785	NM_001323289.2(CDKL5):c.183del (p.Met63fs)	CDKL5	Pathogenic	criteria provided, single submitter
143787	NM_001323289.2(CDKL5):c.1892_1893dup (p.Gly632Ter)	CDKL5	Pathogenic	criteria provided, single submitter
143794	NM_003159.2(CDKL5):c.2045_2046delAGins18 (p.?)	CDKL5	Pathogenic	no assertion criteria provided
143801	NM_001323289.2(CDKL5):c.2343del (p.Arg781fs)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
143809	NM_001323289.2(CDKL5):c.2635_2636del (p.Leu879fs)	CDKL5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143817	NM_001323289.2(CDKL5):c.352C>T (p.Gln118Ter)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
143818	NM_001323289.2(CDKL5):c.380A>G (p.His127Arg)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
143823	NM_001323289.2(CDKL5):c.532C>T (p.Arg178Trp)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
143829	NM_001323289.2(CDKL5):c.607G>T (p.Glu203Ter)	CDKL5	Pathogenic	criteria provided, single submitter
143834	NM_001323289.2(CDKL5):c.838_847del (p.Asp281fs)	CDKL5	Pathogenic	criteria provided, single submitter
156074	NM_001323289.2(CDKL5):c.145+2T>C	CDKL5	Pathogenic	criteria provided, single submitter
156077	NM_001323289.2(CDKL5):c.2047-1G>A	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
156088	NM_001323289.2(CDKL5):c.463+1G>A	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
189556	NM_001323289.2(CDKL5):c.1375C>T (p.Gln459Ter)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
189560	NM_001323289.2(CDKL5):c.1550del (p.Phe517fs)	CDKL5	Pathogenic	criteria provided, single submitter
189564	NM_003159.2(CDKL5):c.-162-?_99+?del	CDKL5	Pathogenic	no assertion criteria provided
189567	NM_001323289.2(CDKL5):c.1854del (p.Asp618fs)	CDKL5	Pathogenic	criteria provided, single submitter
189568	NM_001323289.2(CDKL5):c.2046+1G>A	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
189578	NC_000023.11:g.(?18425605)(18507160_?)del	CDKL5	Pathogenic	no assertion criteria provided
189581	NC_000023.11:g.(?18425605)(18510854_?)del	CDKL5	Pathogenic	no assertion criteria provided
189585	NM_001323289.2(CDKL5):c.283-3_290del	CDKL5	Pathogenic	criteria provided, single submitter
189586	NM_001323289.2(CDKL5):c.403+1G>A	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
189587	NM_003159.2(CDKL5):c.404-?_554+?del	CDKL5	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 58 · Orphanet: 24 · 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	Rett syndrome	13
CDKL5	Supportive	Autosomal dominant	atypical Rett syndrome	9
GABBR2	Supportive	Autosomal dominant	atypical Rett syndrome	6
NTNG1	Supportive	Autosomal dominant	atypical Rett syndrome	2
NTNG2	Supportive	Autosomal dominant	atypical Rett syndrome	6
SMC1A	Supportive	Autosomal dominant	atypical Rett syndrome	8
STXBP1	Supportive	Autosomal dominant	atypical Rett syndrome	12
PDLIM7	Limited	Autosomal dominant	atypical Rett syndrome	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMC1A	Orphanet:199	Cornelia de Lange syndrome
SMC1A	Orphanet:220386	Semilobar holoprosencephaly
SMC1A	Orphanet:3095	Atypical Rett syndrome
SMC1A	Orphanet:708203	Intellectual disability-small hands and feet-drug-resistant epilepsy syndrome
CDKL5	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CDKL5	Orphanet:3095	Atypical Rett syndrome
CDKL5	Orphanet:505652	CDKL5-deficiency disorder
CDKL5	Orphanet:697160	Infantile epileptic spasms syndrome
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
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
NTNG2	Orphanet:528084	Non-specific syndromic intellectual disability
NTNG1	Orphanet:3095	Atypical Rett syndrome
NTNG1	Orphanet:528084	Non-specific syndromic intellectual disability
GABBR2	Orphanet:3095	Atypical Rett syndrome
GABBR2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GPHN	Orphanet:308400	Sulfite oxidase deficiency due to molybdenum cofactor deficiency type C
GPHN	Orphanet:3197	Hereditary hyperekplexia

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
SMC1A	HGNC:11111	ENSG00000072501	Q14683	Structural maintenance of chromosomes protein 1A	gencc,clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	gencc,clinvar
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	gencc,clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	gencc
NTNG2	HGNC:14288	ENSG00000196358	Q96CW9	Netrin-G2	gencc
PDLIM7	HGNC:22958	ENSG00000196923	Q9NR12	PDZ and LIM domain protein 7	gencc
NTNG1	HGNC:23319	ENSG00000162631	Q9Y2I2	Netrin-G1	gencc
GABBR2	HGNC:4507	ENSG00000136928	O75899	Gamma-aminobutyric acid type B receptor subunit 2	gencc
GPHN	HGNC:15465	ENSG00000171723	Q9NQX3	Gephyrin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMC1A	Structural maintenance of chromosomes protein 1A	Involved in chromosome cohesion during cell cycle and in DNA repair.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
MECP2	Methyl-CpG-binding protein 2	Chromosomal protein that binds to methylated DNA.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
NTNG2	Netrin-G2	Involved in controlling patterning and neuronal circuit formation at the laminar, cellular, subcellular and synaptic levels.
PDLIM7	PDZ and LIM domain protein 7	May function as a scaffold on which the coordinated assembly of proteins can occur.
NTNG1	Netrin-G1	Involved in controlling patterning and neuronal circuit formation at the laminar, cellular, subcellular and synaptic levels.
GABBR2	Gamma-aminobutyric acid type B receptor subunit 2	Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2.
GPHN	Gephyrin	Microtubule-associated protein involved in membrane protein-cytoskeleton interactions.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 6 · Druggable fraction: 0.22

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
Kinase	1	3.1×	0.507
GPCR	1	2.7×	0.507
Other/Unknown	6	1.2×	0.507
Transcription factor	1	0.9×	0.687

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMC1A	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
MECP2	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA-bd_dom_sf, Me_CpG-bd_MeCP2
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
NTNG2	Other/Unknown	no		EGF, LE_dom, Laminin_N
PDLIM7	Transcription factor	no		PDZ, Znf_LIM, PDZ_sf
NTNG1	Other/Unknown	no		EGF, LE_dom, Laminin_N
GABBR2	GPCR	yes		GPCR_3, ANF_lig-bd_rcpt, GPCR3_GABA-B
GPHN	Other/Unknown	no		MoaB/Mog_dom, MoeA_linker/N, MoeA_C_domain_IV

Expression context

Cohort genes with no expression data: 0.

9 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	4
lateral nuclear group of thalamus	3
sural nerve	2
middle temporal gyrus	2
embryo	1
trabecular bone tissue	1
cortical plate	1
frontal pole	1
Brodmann (1909) area 10	1
paraflocculus	1
leukocyte	1
monocyte	1
pancreatic ductal cell	1
ascending aorta	1
body of uterus	1
thoracic aorta	1
buccal mucosa cell	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMC1A	289	ubiquitous	marker	sural nerve, trabecular bone tissue, embryo
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
MECP2	277	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, sural nerve
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
NTNG2	173	broad	marker	pancreatic ductal cell, monocyte, leukocyte
PDLIM7	234	ubiquitous	marker	body of uterus, ascending aorta, thoracic aorta
NTNG1	198	broad	marker	lateral nuclear group of thalamus, buccal mucosa cell, Brodmann (1909) area 23
GABBR2	193	broad	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, middle temporal gyrus
GPHN	270	ubiquitous	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
SMC1A	5,246
STXBP1	3,003
NTNG1	2,644
GPHN	2,500
PDLIM7	2,400
GABBR2	1,980
NTNG2	1,387
CDKL5	1,357

Intra-cohort edges

A	B	Sources
CDKL5	MECP2	string_interaction
CDKL5	NTNG1	string_interaction
CDKL5	NTNG2	string_interaction
CDKL5	STXBP1	string_interaction
MECP2	NTNG1	string_interaction
MECP2	NTNG2	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABBR2	O75899	26
SMC1A	Q14683	18
MECP2	P51608	9
CDKL5	O76039	3
NTNG2	Q96CW9	3
PDLIM7	Q9NR12	2
STXBP1	P61764	1
NTNG1	Q9Y2I2	1
GPHN	Q9NQX3	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 55. Enrichment computed across 9 evidence-associated genes (8 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 8 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	1427.5×	0.026	MECP2
Post-translational modification: synthesis of GPI-anchored proteins	2	42.0×	0.026	NTNG2, NTNG1
MECP2 regulates transcription of genes involved in GABA signaling	1	475.8×	0.031	MECP2
Loss of phosphorylation of MECP2 at T308	1	356.9×	0.031	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	356.9×	0.031	MECP2
MECP2 regulates transcription factors	1	285.5×	0.031	MECP2
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	203.9×	0.031	MECP2
Molybdenum cofactor biosynthesis	1	203.9×	0.031	GPHN
Mitotic Telophase/Cytokinesis	1	178.4×	0.031	SMC1A
MECP2 regulates transcription of neuronal ligands	1	178.4×	0.031	MECP2
Cohesin Loading onto Chromatin	1	142.8×	0.035	SMC1A
Establishment of Sister Chromatid Cohesion	1	129.8×	0.035	SMC1A
Acetylcholine Neurotransmitter Release Cycle	1	84.0×	0.043	STXBP1
Serotonin Neurotransmitter Release Cycle	1	79.3×	0.043	STXBP1
Norepinephrine Neurotransmitter Release Cycle	1	79.3×	0.043	STXBP1
GABA synthesis, release, reuptake and degradation	1	79.3×	0.043	STXBP1
MECP2 regulates neuronal receptors and channels	1	75.1×	0.043	MECP2
GABA B receptor activation	1	68.0×	0.045	GABBR2
Dopamine Neurotransmitter Release Cycle	1	62.1×	0.046	STXBP1
Glutamate Neurotransmitter Release Cycle	1	57.1×	0.048	STXBP1
Activation of G protein gated Potassium channels	1	49.2×	0.050	GABBR2
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	49.2×	0.050	GABBR2
Regulation of MECP2 expression and activity	1	46.0×	0.051	MECP2
Nuclear events stimulated by ALK signaling in cancer	1	40.8×	0.055	MECP2
Transcriptional Regulation by MECP2	1	39.6×	0.055	MECP2
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	36.6×	0.056	GABBR2
Meiosis	1	35.7×	0.056	SMC1A
Protein-protein interactions at synapses	1	33.2×	0.058	STXBP1
RET signaling	1	32.4×	0.058	PDLIM7
Regulation of insulin secretion	1	27.4×	0.066	STXBP1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of neuron projection arborization	2	624.1×	5e-04	NTNG2, NTNG1
modulation of chemical synaptic transmission	3	61.1×	8e-04	CDKL5, NTNG2, NTNG1
regulation of neuron migration	2	138.7×	0.003	NTNG2, NTNG1
synaptic membrane adhesion	2	129.1×	0.003	NTNG2, NTNG1
regulation of neuron projection development	2	96.0×	0.004	NTNG2, NTNG1
catecholamine secretion	1	1872.4×	0.006	MECP2
glycine receptor clustering	1	1872.4×	0.006	GPHN
trans-synaptic signaling by BDNF	1	1872.4×	0.006	MECP2
obsolete positive regulation of vesicle docking	1	1872.4×	0.006	STXBP1
regulation of acrosomal vesicle exocytosis	1	1872.4×	0.006	STXBP1
synapse assembly	2	51.3×	0.007	MECP2, GPHN
establishment of synaptic specificity at neuromuscular junction	1	936.2×	0.009	GPHN
cardiolipin metabolic process	1	936.2×	0.009	MECP2
response to DNA damage checkpoint signaling	1	936.2×	0.009	SMC1A
positive regulation of glutamate secretion, neurotransmission	1	936.2×	0.009	STXBP1
nervous system process involved in regulation of systemic arterial blood pressure	1	624.1×	0.010	MECP2
biogenic amine metabolic process	1	624.1×	0.010	MECP2
axon target recognition	1	624.1×	0.010	STXBP1
response to other organism	1	624.1×	0.010	MECP2
axonogenesis	2	35.7×	0.010	NTNG2, NTNG1
proprioception	1	468.1×	0.010	MECP2
negative regulation of synaptic transmission, GABAergic	1	468.1×	0.010	STXBP1
establishment of meiotic sister chromatid cohesion	1	468.1×	0.010	SMC1A
postsynaptic specialization assembly	1	468.1×	0.010	NTNG2
presynaptic dense core vesicle exocytosis	1	468.1×	0.010	STXBP1
platelet degranulation	1	374.5×	0.011	STXBP1
developmental process involved in reproduction	1	374.5×	0.011	STXBP1
gamma-aminobutyric acid receptor clustering	1	374.5×	0.011	GPHN
neuron-glial cell signaling	1	374.5×	0.011	GABBR2
negative regulation of neuron apoptotic process	2	24.6×	0.011	MECP2, STXBP1

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 6

Druggability breadth: 5 of 9 evidence-associated genes (56%) 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
SMC1A	SELUMETINIB
CDKL5	FEDRATINIB
GABBR2	BACLOFEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDKL5	14	4
GABBR2	4	4
SMC1A	2	4
MECP2	0	0
STXBP1	0	0
NTNG2	0	0
PDLIM7	0	0
NTNG1	0	0
GPHN	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SELUMETINIB	4	SMC1A
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
BACLOFEN	4	GABBR2
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
ARBACLOFEN	3	GABBR2
MOLIBRESIB	2	SMC1A
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
SGS-742	2	GABBR2
BMS-387032	1	CDKL5
PF-03758309	1	CDKL5
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL5
AST-487	1	CDKL5
GAMMA-AMINOBUTYRIC ACID	1	GABBR2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDKL5	74	Binding:74
GABBR2	57	Binding:35, Functional:21, ADMET:1
SMC1A	10	Binding:10
MECP2	1	Binding:1
STXBP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDKL5	2.7.11.22	cyclin-dependent kinase

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

20 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)
SELUMETINIB	4	SMC1A
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
BACLOFEN	4	GABBR2
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
ARBACLOFEN	3	GABBR2
MOLIBRESIB	2	SMC1A
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
SGS-742	2	GABBR2
BMS-387032	1	CDKL5
PF-03758309	1	CDKL5
5-(6-BENZOTHIAZOLYLMETHYLENE)-3,5-DIHYDRO-2-(((1S)-1-(METHOXYMETHYL)-3-METHYLBUTYL)AMINO)-4H-IMIDAZOL-4-ONE, (5Z)-	1	CDKL5
AST-487	1	CDKL5
GAMMA-AMINOBUTYRIC ACID	1	GABBR2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SMC1A, CDKL5, GABBR2
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	6	MECP2, STXBP1, NTNG2, PDLIM7, NTNG1, GPHN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NTNG2	0	CDKL5
NTNG1	0	CDKL5
MECP2	1	—
STXBP1	1	—
PDLIM7	0	—
GPHN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: SMC1A, CDKL5, MECP2, STXBP1, NTNG2, PDLIM7, NTNG1, GABBR2, GPHN