Rett syndrome

Summary

Rett syndrome (MONDO:0010726) is a disease caused by MECP2 (GenCC Definitive), with 8 cohort genes and 88 clinical trials. Top therapeutic interventions include dextromethorphan, trofinetide, and donepezil.

At a glance

• Prevalence: 1-5 / 10 000 (Europe) [Orphanet-validated]
• Causal gene: MECP2 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 1,131
• Phenotypes (HPO): 36
• Clinical trials: 88

Clinical features

Epidemiology

Prevalence records

11 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	10	Europe	Validated
Point prevalence	1-9 / 100 000	1.6	United Kingdom	Validated
Point prevalence	1-9 / 100 000		Worldwide	Not yet validated
Prevalence at birth	1-9 / 100 000	5	Europe	Not yet validated
Point prevalence	1-9 / 100 000		France	Not yet validated
Point prevalence	1-9 / 100 000	5	Sweden	Not yet validated
Point prevalence	1-9 / 100 000		Japan	Not yet validated
Point prevalence	1-9 / 100 000		Australia	Not yet validated
Point prevalence	1-9 / 100 000		Hong Kong	Not yet validated
Prevalence at birth	1-9 / 100 000		United States	Not yet validated
Prevalence at birth	1-9 / 100 000	3.05	Australia	Not yet validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000253	Progressive microcephaly	Very frequent (80-99%)
HP:0000733	Abnormal repetitive mannerisms	Very frequent (80-99%)
HP:0001263	Global developmental delay	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001344	Absent speech	Very frequent (80-99%)
HP:0002376	Developmental regression	Very frequent (80-99%)
HP:0002793	Abnormal pattern of respiration	Very frequent (80-99%)
HP:0007064	Progressive language deterioration	Very frequent (80-99%)
HP:0012171	Stereotypical hand wringing	Very frequent (80-99%)
HP:0025430	High-pitched cry	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003763	Bruxism	Frequent (30-79%)
HP:0003808	Abnormal muscle tone	Frequent (30-79%)
HP:0030217	Limb apraxia	Frequent (30-79%)
HP:0033850	Coldness	Frequent (30-79%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0001082	Cholecystitis	Occasional (5-29%)
HP:0001987	Hyperammonemia	Occasional (5-29%)
HP:0002151	Increased circulating lactate concentration	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002490	Increased CSF lactate	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0003542	Increased serum pyruvate	Occasional (5-29%)
HP:0008947	Floppy infant	Occasional (5-29%)
HP:0012332	Abnormal autonomic nervous system physiology	Occasional (5-29%)
HP:0031793	Increased serum leptin	Occasional (5-29%)
HP:0500231	Abnormal CSF pyruvate family amino acid concentration	Occasional (5-29%)
HP:0011451	Congenital microcephaly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Rett syndrome
Mondo ID	MONDO:0010726
MeSH	D015518
OMIM	312750
Orphanet	778
DOID	DOID:1206
ICD-11	201200685
NCIT	C75488
SNOMED CT	68618008
UMLS	C0035372
MedGen	48441
GARD	0005696
MedDRA	10039000
NORD	1666
Is cancer (heuristic)	no

Also known as: Rett syndrome · Rett syndrome, atypical, X-linked dominant · Rett syndrome, preserved speech variant, X-linked dominant · Rett syndrome, X-linked dominant · Rett’s disease · RTS · RTT

Data availability: 1,131 ClinVar variants · 188 ClinGen variant curations · 6 GenCC gene-disease records · 148 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › mental disorder › developmental disorder of mental health › pervasive developmental disorder › Rett syndrome

Related subtypes (4): autism spectrum disorder, childhood disintegrative disorder, atypical autism, 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

600 retrieved; paginated sample, class counts are floors:

189 pathogenic, 99 likely pathogenic, 85 uncertain significance, 78 benign, 45 pathogenic/likely pathogenic, 45 benign/likely benign, 42 likely benign, 17 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
11503	NM_001323289.2(CDKL5):c.215T>C (p.Ile72Thr)	CDKL5	Pathogenic	reviewed by expert panel
1274	NM_173660.5(DOK7):c.1263dup (p.Ser422fs)	DOK7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1303502	NM_005249.5(FOXG1):c.923G>A (p.Trp308Ter)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1325763	NM_005249.5(FOXG1):c.974dup (p.Leu325fs)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1338970	NM_005249.5(FOXG1):c.512dup (p.Glu173fs)	FOXG1	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
1071768	NM_001110792.2(MECP2):c.74C>G (p.Ser25Ter)	MECP2	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
11818	NM_001110792.2(MECP2):c.203_204del (p.Pro68fs)	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
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
11834	NM_001110792.2(MECP2):c.1399G>T (p.Glu467Ter)	MECP2	Pathogenic	criteria provided, single submitter
11835	NM_001110792.2(MECP2):c.334C>G (p.Leu112Val)	MECP2	Pathogenic	reviewed by expert panel
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
1301354	NM_001110792.2(MECP2):c.1209_1243del (p.Pro403_Glu404insTer)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1308657	NM_001110792.2(MECP2):c.1209_*6del (p.Glu404fs)	MECP2	Pathogenic	criteria provided, single submitter
143300	NM_004992.3(MECP2):c.(?-1)(26_?)del	MECP2	Pathogenic	no assertion criteria provided
143304	NM_001110792.2(MECP2):c.136_139del (p.Asp46fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143307	NM_001110792.2(MECP2):c.1065del (p.Arg356fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143322	NM_001110792.2(MECP2):c.1115C>A (p.Ser372Ter)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143323	NM_001110792.2(MECP2):c.143_144del (p.Lys48fs)	MECP2	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 21 · 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

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
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
RHOBTB2	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
RHOBTB2	Orphanet:2131	Alternating hemiplegia of childhood
DOK7	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
DOK7	Orphanet:994	Fetal akinesia deformation sequence
FOXG1	Orphanet:261144	FOXG1 syndrome due to 14q12 microdeletion
FOXG1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
FOXG1	Orphanet:598164	FOXG1 syndrome due to intragenic alteration
GABBR2	Orphanet:3095	Atypical Rett syndrome
GABBR2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP2B3	Orphanet:314978	X-linked non progressive cerebellar ataxia

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	gencc,clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
RHOBTB2	HGNC:18756	ENSG00000008853	Q9BYZ6	Rho-related BTB domain-containing protein 2	clinvar
DOK7	HGNC:26594	ENSG00000175920	Q18PE1	Protein Dok-7	clinvar
FOXG1	HGNC:3811	ENSG00000176165	P55316	Forkhead box protein G1	clinvar
GABBR2	HGNC:4507	ENSG00000136928	O75899	Gamma-aminobutyric acid type B receptor subunit 2	clinvar
MAP2	HGNC:6839	ENSG00000078018	P11137	Microtubule-associated protein 2	clinvar
ATP2B3	HGNC:816	ENSG00000067842	Q16720	Plasma membrane calcium-transporting ATPase 3	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.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
RHOBTB2	Rho-related BTB domain-containing protein 2	Regulator of cell proliferation and apoptosis.
DOK7	Protein Dok-7	Probable muscle-intrinsic activator of MUSK that plays an essential role in neuromuscular synaptogenesis.
FOXG1	Forkhead box protein G1	Transcription repression factor which plays an important role in the establishment of the regional subdivision of the developing brain and in the development of the telencephalon.
GABBR2	Gamma-aminobutyric acid type B receptor subunit 2	Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2.
MAP2	Microtubule-associated protein 2	The exact function of MAP2 is unknown but MAPs may stabilize the microtubules against depolymerization.
ATP2B3	Plasma membrane calcium-transporting ATPase 3	ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels at the presynaptic terminals.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 3 · Druggable fraction: 0.25

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	3.5×	0.474
GPCR	1	3.0×	0.474
Scaffold/PPI	1	2.2×	0.474
Transcription factor	2	2.1×	0.474
Other/Unknown	3	0.7×	0.919

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
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
RHOBTB2	Other/Unknown	no		BTB/POZ_dom, Small_GTPase, Small_GTPase_Rho
DOK7	Scaffold/PPI	no		PH_domain, IRS_PTB, PH-like_dom_sf
FOXG1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
GABBR2	GPCR	yes		GPCR_3, ANF_lig-bd_rcpt, GPCR3_GABA-B
MAP2	Other/Unknown	no		MAP_tubulin-bd_rpt, MAP2_projctn, MAP2/MAP4/Tau
ATP2B3	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C

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	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	5
endothelial cell	3
cortical plate	2
middle temporal gyrus	2
Brodmann (1909) area 10	1
paraflocculus	1
sural nerve	1
frontal pole	1
right frontal lobe	1
upper lobe of left lung	1
upper lobe of lung	1
apex of heart	1
right atrium auricular region	1
tibialis anterior	1
lateral nuclear group of thalamus	1
superior vestibular nucleus	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
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
RHOBTB2	213	ubiquitous	marker	upper lobe of left lung, upper lobe of lung, right frontal lobe
DOK7	180	broad	yes	apex of heart, tibialis anterior, right atrium auricular region
FOXG1	100	broad	marker	cortical plate, endothelial cell, Brodmann (1909) area 23
GABBR2	193	broad	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, middle temporal gyrus
MAP2	267	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, superior vestibular nucleus
ATP2B3	145	tissue_specific	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
ATP2B3	3,203
MAP2	2,993
RHOBTB2	2,577
GABBR2	1,980
CDKL5	1,357
DOK7	704
FOXG1	106

Intra-cohort edges

A	B	Sources
CDKL5	MECP2	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GABBR2	O75899	26
MECP2	P51608	9
CDKL5	O76039	3
FOXG1	P55316	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RHOBTB2	Q9BYZ6	81.89
ATP2B3	Q16720	74.57
DOK7	Q18PE1	65.61
MAP2	P11137	40.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 28. Enrichment computed across 8 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MECP2 expression and activity	2	147.3×	0.002	MECP2, FOXG1
Loss of MECP2 binding ability to 5hmC-DNA	1	2284.0×	0.006	MECP2
MECP2 regulates transcription of genes involved in GABA signaling	1	761.3×	0.010	MECP2
Loss of phosphorylation of MECP2 at T308	1	571.0×	0.010	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	571.0×	0.010	MECP2
MECP2 regulates transcription factors	1	456.8×	0.010	MECP2
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	326.3×	0.012	MECP2
MECP2 regulates transcription of neuronal ligands	1	285.5×	0.012	MECP2
Reduction of cytosolic Ca++ levels	1	190.3×	0.016	ATP2B3
Platelet calcium homeostasis	1	142.8×	0.019	ATP2B3
FOXO-mediated transcription of cell cycle genes	1	134.3×	0.019	FOXG1
MECP2 regulates neuronal receptors and channels	1	120.2×	0.019	MECP2
GABA B receptor activation	1	108.8×	0.020	GABBR2
RHOBTB2 GTPase cycle	1	95.2×	0.021	RHOBTB2
Activation of G protein gated Potassium channels	1	78.8×	0.022	GABBR2
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	78.8×	0.022	GABBR2
Nuclear events stimulated by ALK signaling in cancer	1	65.3×	0.024	MECP2
Transcriptional Regulation by MECP2	1	63.4×	0.024	MECP2
Class C/3 (Metabotropic glutamate/pheromone receptors)	1	58.6×	0.025	GABBR2
Platelet homeostasis	1	55.7×	0.025	ATP2B3
Ion transport by P-type ATPases	1	41.5×	0.031	ATP2B3
Ion homeostasis	1	40.8×	0.031	ATP2B3
Cardiac conduction	1	21.8×	0.055	ATP2B3
Ion channel transport	1	19.2×	0.060	ATP2B3
Muscle contraction	1	15.4×	0.071	ATP2B3
G alpha (i) signalling events	1	7.8×	0.131	GABBR2
Hemostasis	1	7.2×	0.136	ATP2B3
Transport of small molecules	1	5.0×	0.184	ATP2B3

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
positive regulation of Rac protein signal transduction	2	162.0×	0.007	CDKL5, DOK7
dendrite development	2	98.0×	0.009	MECP2, MAP2
catecholamine secretion	1	2106.5×	0.012	MECP2
trans-synaptic signaling by BDNF	1	2106.5×	0.012	MECP2
cardiolipin metabolic process	1	1053.2×	0.014	MECP2
positive regulation of anterograde dense core granule transport	1	1053.2×	0.014	MAP2
positive regulation of anterograde synaptic vesicle transport	1	1053.2×	0.014	MAP2
nervous system process involved in regulation of systemic arterial blood pressure	1	702.2×	0.014	MECP2
biogenic amine metabolic process	1	702.2×	0.014	MECP2
pyramidal neuron migration to cerebral cortex	1	702.2×	0.014	FOXG1
response to other organism	1	702.2×	0.014	MECP2
proprioception	1	526.6×	0.015	MECP2
regulation of organelle transport along microtubule	1	526.6×	0.015	MAP2
axon midline choice point recognition	1	421.3×	0.017	FOXG1
neuron-glial cell signaling	1	421.3×	0.017	GABBR2
glucocorticoid metabolic process	1	351.1×	0.018	MECP2
calcium ion export across plasma membrane	1	351.1×	0.018	ATP2B3
inositol metabolic process	1	300.9×	0.019	MECP2
neuron fate determination	1	263.3×	0.019	FOXG1
positive regulation of protein tyrosine kinase activity	1	263.3×	0.019	DOK7
positive regulation of microtubule nucleation	1	263.3×	0.019	MECP2
negative regulation of smooth muscle cell differentiation	1	234.1×	0.019	MECP2
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	234.1×	0.019	DOK7
cortical cytoskeleton organization	1	210.7×	0.021	RHOBTB2
negative regulation of adenylate cyclase activity	1	175.5×	0.022	GABBR2
regulation of respiratory gaseous exchange by nervous system process	1	162.0×	0.022	MECP2
L-glutamine metabolic process	1	162.0×	0.022	MECP2
enzyme-linked receptor protein signaling pathway	1	162.0×	0.022	DOK7
negative regulation of microtubule polymerization	1	162.0×	0.022	MAP2
startle response	1	140.4×	0.024	MECP2

Therapeutics

Drugs indicated or in trials for this disease

1 approved drug — disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Status
Trofinetide	Approved (phase 4)

11 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Cannabidiol	Phase 3
Dextromethorphan	Phase 3
Risperidone	Phase 3
Desipramine	Phase 2
Glatiramer Acetate	Phase 2
Ketamine	Phase 2
Lovastatin	Phase 2
Mecasermin	Phase 2
Sarizotan	Phase 2
Triheptanoin	Phase 2
Vatiquinone	Phase 2

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 6

Druggability breadth: 4 of 8 evidence-associated genes (50%) 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
CDKL5	FEDRATINIB
GABBR2	BACLOFEN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDKL5	14	4
GABBR2	4	4
MECP2	0	0
RHOBTB2	0	0
DOK7	0	0
FOXG1	0	0
MAP2	0	0
ATP2B3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
BACLOFEN	4	GABBR2
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
ARBACLOFEN	3	GABBR2
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): 2.

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
MAP2	3	Binding:3
MECP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDKL5	2.7.11.22	cyclin-dependent kinase
ATP2B3	7.2.2.10	P-type Ca2+ transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

18 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)
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
BACLOFEN	4	GABBR2
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
ARBACLOFEN	3	GABBR2
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)	2	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, RHOBTB2, DOK7, FOXG1, MAP2, ATP2B3

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)
MECP2	1	—
RHOBTB2	0	—
DOK7	0	—
FOXG1	0	—
MAP2	3	—
ATP2B3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 88.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	47
PHASE2	15
PHASE3	13
PHASE2/PHASE3	5
PHASE1	4
PHASE1/PHASE2	2
EARLY_PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05606614	PHASE3	RECRUITING	A Phase 1/2/3 Study of TSHA-102 Gene Therapy in Females With Rett Syndrome (REVEAL Pivotal Study)
NCT05898620	PHASE3	RECRUITING	A Novel, Regulated Gene Therapy (NGN-401) Study for Females With Rett Syndrome
NCT06840496	PHASE3	RECRUITING	To Investigate the Efficacy of Treatment With Oral NA-921 (Bionetide) Versus Placebo in Females With Rett Syndrome
NCT07257978	PHASE2/PHASE3	NOT_YET_RECRUITING	Efficacy and Safety of NTI164 in Children and Young Adults With Rett Syndrome
NCT07480564	PHASE3	RECRUITING	Safety and Preliminary Efficacy of TSHA-102 Gene Therapy in Pediatric Females Aged >2 to <4 Years With Rett Syndrome
NCT07503444	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study of Fenfluramine Hydrochloride in Rett Syndrome
NCT00069550	PHASE3	UNKNOWN	Independent Studies of Dextromethorphan and of Donepezil Hydrochloride for Rett Syndrome
NCT00261508	PHASE3	COMPLETED	A Study of the Effectiveness and Safety of Risperidone Versus Placebo in the Treatment of Children With Autistic Disorder and Other Pervasive Developmental Disorders (PDD)
NCT02790034	PHASE2/PHASE3	TERMINATED	Evaluation of the Efficacy, Safety, and Tolerability of Sarizotan in Rett Syndrome With Respiratory Symptoms
NCT03848832	PHASE3	TERMINATED	Efficacy and Safety of Cannabidiol Oral Solution (GWP42003-P, CBD-OS) in Patients With Rett Syndrome
NCT03941444	PHASE3	COMPLETED	ANAVEX2-73 Study in Patients With Rett Syndrome
NCT04181723	PHASE3	COMPLETED	Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome (LAVENDER™)
NCT04252586	PHASE3	TERMINATED	A Long-term Safety Study of Cannabidiol Oral Solution (GWP42003-P, CBD-OS) in Patients With Rett Syndrome
NCT04279314	PHASE3	COMPLETED	Open-Label Extension Study of Trofinetide for the Treatment of Girls and Women With Rett Syndrome
NCT04304482	PHASE2/PHASE3	COMPLETED	ANAVEX2-73 Study in Pediatric Patients With Rett Syndrome
NCT04776746	PHASE3	TERMINATED	Open-Label Extension Study of Trofinetide for Rett Syndrome
NCT04988867	PHASE2/PHASE3	TERMINATED	An Open-Label Study of Trofinetide for the Treatment of Girls Two to Five Years of Age Who Have Rett Syndrome
NCT06849973	PHASE2/PHASE3	COMPLETED	To Study the Efficacy & Safety of Oral NA-921 (Bionetide) in Girls and Women with Rett Syndrome
NCT04041713	PHASE2	NOT_YET_RECRUITING	A Pilot Study of an Antioxidant Cocktail vs. Placebo in the Treatment of Children and Adolescents With Rett Syndrome
NCT06152237	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of TSHA-102 in Pediatric Females With Rett Syndrome (REVEAL Pediatric Study)
NCT06621043	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Assessing the Safety and Efficacy of Full-Spectrum Medicinal Cannabis Plant Extract 0.08% THC (NTI164) in the Treatment of Rett Syndrome (RTT)
NCT00593957	PHASE2	TERMINATED	Trial of Dextromethorphan in Rett Syndrome
NCT00990691	PHASE2	COMPLETED	Pilot Study of the Effects of the Desipramine on the Neurovegetative Parameters of the Child With Rett Syndrome
NCT01520363	PHASE2	COMPLETED	Placebo Controlled Trial of Dextromethorphan in Rett Syndrome
NCT01703533	PHASE2	COMPLETED	A Safety Study of NNZ-2566 in Patients With Rett Syndrome
NCT01777542	PHASE2	COMPLETED	Treatment of Rett Syndrome With Recombinant Human IGF-1
NCT01822249	PHASE2	COMPLETED	Phase 2 Study of EPI-743 for Treatment of Rett Syndrome
NCT02153723	PHASE2	COMPLETED	Pharmacological Treatment of Rett Syndrome With Glatiramer Acetate (Copaxone)
NCT02563860	PHASE2	COMPLETED	Pharmacological Treatment of Rett Syndrome With Statins
NCT02696044	PHASE2	UNKNOWN	Treatment of Mitochondrial Dysfunction in Rett Syndrome With Triheptanoin
NCT02715115	PHASE2	COMPLETED	A Safety Study of NNZ-2566 in Pediatric Rett Syndrome
NCT03059160	PHASE2	UNKNOWN	Open Label Trial of Triheptanoin (UX007) in Treatment of Rett Syndrome.
NCT03633058	PHASE2	COMPLETED	A Study to Evaluate Ketamine for the Treatment of Rett Syndrome
NCT03758924	PHASE2	COMPLETED	Study of ANAVEX2-73 in Patients With Rett Syndrome
NCT05625568	PHASE2	UNKNOWN	Study of VYNT-0126 in the Treatment of Rett Syndrome in Adult Patients
NCT07150013	PHASE1	RECRUITING	Rett REVOLUTION Trial: An Exploratory Evaluation of the Safety and Efficacy of Vorinostat in Rett Syndrome
NCT01253317	PHASE1	COMPLETED	Treatment of Rett Syndrome With rhIGF-1 (Mecasermin [rDNA]Injection)
NCT02023424	PHASE1	UNKNOWN	An Open Label, Exploratory Study to Investigate the Treatment Effect of Glatiramer Acetate on Girls Woth Rett Syndrome
NCT02562820	PHASE1	TERMINATED	An Exploratory Trial of Ketamine for the Treatment of Rett Syndrome
NCT06856759	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Single-Dose AAV-MECP2 Safety/Tolerability and Efficacy in Rett Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEXTROMETHORPHAN	4	12
TROFINETIDE	4	6
DONEPEZIL	4	3
CANNABIDIOL	4	2
ESKETAMINE HYDROCHLORIDE	4	1
FENFLURAMINE HYDROCHLORIDE	4	1
GLATIRAMER ACETATE	4	1
LOVASTATIN	4	1
TRIHEPTANOIN	4	1
ZINC OXIDE	4	1
BLARCAMESINE HYDROCHLORIDE	3	3
VATIQUINONE	3	1
LONIMECGENE RENPARVOVEC	2	3
SODIUM BUTYRATE	2	1
TRIDECANOATE	2	1
CHEMBL5275950	0	1
BOSCALID	-1	1