FOXG1 disorder

Summary

FOXG1 disorder (MONDO:0100040) is a disease caused by FOXG1 (GenCC Definitive), with 5 cohort genes and 4 clinical trials.

At a glance

• Causal gene: FOXG1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 744
• Phenotypes (HPO): 49
• Clinical trials: 4

Clinical features

Signs & symptoms

Clinical features (HPO)

49 HPO clinical features (Orphanet curated; top 49 by frequency):

HPO ID	Term	Frequency
HP:0000253	Progressive microcephaly	Very frequent (80-99%)
HP:0000486	Strabismus	Very frequent (80-99%)
HP:0000733	Abnormal repetitive mannerisms	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0011968	Feeding difficulties	Very frequent (80-99%)
HP:0100660	Dyskinesia	Very frequent (80-99%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000729	Autistic behavior	Frequent (30-79%)
HP:0000749	Paroxysmal bursts of laughter	Frequent (30-79%)
HP:0000817	Reduced eye contact	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001273	Abnormal corpus callosum morphology	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001344	Absent speech	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Frequent (30-79%)
HP:0002310	Orofacial dyskinesia	Frequent (30-79%)
HP:0002360	Sleep abnormality	Frequent (30-79%)
HP:0002487	Hyperkinetic movements	Frequent (30-79%)
HP:0003763	Bruxism	Frequent (30-79%)
HP:0003781	Excessive salivation	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0004325	Decreased body weight	Frequent (30-79%)
HP:0007359	Focal-onset seizure	Frequent (30-79%)
HP:0008850	Severe postnatal growth retardation	Frequent (30-79%)
HP:0011344	Severe global developmental delay	Frequent (30-79%)
HP:0012448	Delayed myelination	Frequent (30-79%)
HP:0012469	Infantile spasms	Frequent (30-79%)
HP:0030215	Inappropriate crying	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Occasional (5-29%)
HP:0001302	Pachygyria	Occasional (5-29%)
HP:0002079	Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0002376	Developmental regression	Occasional (5-29%)
HP:0002465	Poor speech	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0002795	Abnormal respiratory system physiology	Occasional (5-29%)
HP:0007766	Optic disc hypoplasia	Occasional (5-29%)
HP:0012760	Reduced social responsiveness	Occasional (5-29%)
HP:0002133	Status epilepticus	Very rare (<1-4%)
HP:0012171	Stereotypical hand wringing	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	FOXG1 disorder
Mondo ID	MONDO:0100040
OMIM	613454
Orphanet	561854, 598164
DOID	DOID:0070657
ICD-10-CM	F84.8
NCIT	C176903
UMLS	C3150705
MedGen	462055
GARD	0026022
Is cancer (heuristic)	no

Also known as: FOXG1 disorder · FOXG1 inherited genetic disease · FOXG1 syndrome · FOXG1 syndrome due to intragenic alteration · FOXG1-related epileptic-dyskinetic encephalopathy · inherited genetic disease caused by mutation in FOXG1 · Rett syndrome, congenital variant

Data availability: 744 ClinVar variants · 68 ClinGen variant curations · 3 GenCC gene-disease records · 49 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 › FOXG1 disorder

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

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:

170 likely benign, 165 uncertain significance, 110 pathogenic, 57 benign, 50 likely pathogenic, 18 pathogenic/likely pathogenic, 16 conflicting classifications of pathogenicity, 13 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
426095	t(4;14)(q26;q12)	ARSJ	Pathogenic	no assertion criteria provided
1068106	NM_005249.5(FOXG1):c.645C>A (p.Phe215Leu)	FOXG1	Pathogenic	criteria provided, single submitter
1070076	NM_005249.5(FOXG1):c.943_949dup (p.His317fs)	FOXG1	Pathogenic	criteria provided, single submitter
1070476	NM_005249.5(FOXG1):c.469A>T (p.Lys157Ter)	FOXG1	Pathogenic	criteria provided, single submitter
1073524	NM_005249.5(FOXG1):c.654C>A (p.Tyr218Ter)	FOXG1	Pathogenic	criteria provided, single submitter
1073841	NC_000014.8:g.(?29236486)(29237955_?)del	FOXG1	Pathogenic	criteria provided, single submitter
1074213	NM_005249.5(FOXG1):c.1410del (p.Leu471fs)	FOXG1	Pathogenic	criteria provided, single submitter
1320045	NM_005249.5(FOXG1):c.559A>G (p.Asn187Asp)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1322933	NM_005249.5(FOXG1):c.1095_1114del (p.Arg366fs)	FOXG1	Pathogenic	criteria provided, single submitter
1324422	NM_005249.5(FOXG1):c.634del (p.Ile211_Met212insTer)	FOXG1	Pathogenic	criteria provided, single submitter
1325744	NM_005249.5(FOXG1):c.222_223dup (p.Pro75fs)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1325746	NM_005249.5(FOXG1):c.385del (p.Glu129fs)	FOXG1	Pathogenic	criteria provided, single submitter
1325747	NM_005249.5(FOXG1):c.430G>T (p.Glu144Ter)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1325750	NM_005249.5(FOXG1):c.517G>T (p.Glu173Ter)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1325751	NM_005249.5(FOXG1):c.543G>C (p.Lys181Asn)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1325752	NM_005249.5(FOXG1):c.545C>A (p.Pro182Gln)	FOXG1	Pathogenic	criteria provided, single submitter
1325754	NM_005249.5(FOXG1):c.565C>T (p.Leu189Phe)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1325757	NM_005249.5(FOXG1):c.592_594del (p.Pro198del)	FOXG1	Pathogenic	criteria provided, single submitter
1325758	NM_005249.5(FOXG1):c.611_618del (p.Leu204fs)	FOXG1	Pathogenic	criteria provided, single submitter
1325759	NM_005249.5(FOXG1):c.735del (p.Tyr246fs)	FOXG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1325762	NM_005249.5(FOXG1):c.921C>G (p.Tyr307Ter)	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
1325764	NM_005249.5(FOXG1):c.1141del (p.Ala381fs)	FOXG1	Pathogenic	criteria provided, single submitter
1332866	NM_005249.5(FOXG1):c.602G>C (p.Arg201Pro)	FOXG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343076	NM_005249.5(FOXG1):c.748G>C (p.Gly250Arg)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1350942	NM_005249.5(FOXG1):c.692A>G (p.His231Arg)	FOXG1	Pathogenic	criteria provided, single submitter
13867	NM_005249.5(FOXG1):c.765G>A (p.Trp255Ter)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13869	NM_005249.5(FOXG1):c.624C>G (p.Tyr208Ter)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
13870	NM_005249.5(FOXG1):c.643T>C (p.Phe215Leu)	FOXG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13871	NM_005249.5(FOXG1):c.924G>A (p.Trp308Ter)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
FOXG1	Definitive	Autosomal dominant	FOXG1 disorder	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FOXG1	HGNC:3811	ENSG00000176165	P55316	Forkhead box protein G1	gencc,clinvar
LINC01551	HGNC:19828	ENSG00000186960	Q86U37	Uncharacterized protein encoded by LINC01551	clinvar
WDFY1	HGNC:20451	ENSG00000085449	Q8IWB7	WD repeat and FYVE domain-containing protein 1	clinvar
ARSJ	HGNC:26286	ENSG00000180801	Q5FYB0	Arylsulfatase J	clinvar
LINC02327	HGNC:53247	ENSG00000258038		long intergenic non-protein coding RNA 2327	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
WDFY1	WD repeat and FYVE domain-containing protein 1	Positively regulates TLR3- and TLR4-mediated signaling pathways by bridging the interaction between TLR3 or TLR4 and TICAM1.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 2 · Druggable fraction: 0.2

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
Phosphatase	1	16.8×	0.171
Transcription factor	2	3.3×	0.171
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FOXG1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_1, TF_fork_head_CS_2
LINC01551	Other/Unknown	no
WDFY1	Transcription factor	no		Znf_FYVE, WD40_rpt, Znf_FYVE_PHD
ARSJ	Phosphatase	yes		Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
LINC02327	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	2
Brodmann (1909) area 23	1
endothelial cell	1
ganglionic eminence	1
ventricular zone	1
ileal mucosa	1
oocyte	1
secondary oocyte	1
calcaneal tendon	1
cartilage tissue	1
stromal cell of endometrium	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
quadriceps femoris	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FOXG1	100	broad	marker	cortical plate, endothelial cell, Brodmann (1909) area 23
LINC01551	129	tissue_specific	marker	ganglionic eminence, cortical plate, ventricular zone
WDFY1	260	ubiquitous	marker	secondary oocyte, oocyte, ileal mucosa
ARSJ	186	ubiquitous	marker	stromal cell of endometrium, cartilage tissue, calcaneal tendon
LINC02327	130	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, quadriceps femoris

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WDFY1	2,281
ARSJ	964
FOXG1	106
LINC01551	0
LINC02327	0

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FOXG1	P55316	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WDFY1	Q8IWB7	92.33
ARSJ	Q5FYB0	87.34
LINC01551	Q86U37	35.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 5 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
The activation of arylsulfatases	1	439.2×	0.013	ARSJ
FOXO-mediated transcription of cell cycle genes	1	335.9×	0.013	FOXG1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	211.5×	0.013	ARSJ
Regulation of MECP2 expression and activity	1	184.2×	0.013	FOXG1
Glycosphingolipid metabolism	1	150.3×	0.013	ARSJ
Glycosphingolipid catabolism	1	146.4×	0.013	ARSJ
Sphingolipid metabolism	1	84.0×	0.019	ARSJ
Metabolism of lipids	1	15.8×	0.086	ARSJ
Post-translational protein modification	1	9.6×	0.124	ARSJ
Metabolism of proteins	1	6.2×	0.165	ARSJ
Metabolism	1	5.8×	0.165	ARSJ

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyramidal neuron migration to cerebral cortex	1	2808.7×	0.004	FOXG1
axon midline choice point recognition	1	1685.2×	0.004	FOXG1
positive regulation of toll-like receptor 3 signaling pathway	1	1203.7×	0.004	WDFY1
neuron fate determination	1	1053.2×	0.004	FOXG1
positive regulation of toll-like receptor 4 signaling pathway	1	495.6×	0.007	WDFY1
positive regulation of neuroblast proliferation	1	290.6×	0.010	FOXG1
positive regulation of cell cycle	1	221.7×	0.010	FOXG1
dorsal/ventral pattern formation	1	210.7×	0.010	FOXG1
neuroblast proliferation	1	183.2×	0.010	FOXG1
inner ear morphogenesis	1	150.5×	0.011	FOXG1
negative regulation of neuron differentiation	1	135.9×	0.011	FOXG1
regulation of mitotic cell cycle	1	120.4×	0.012	FOXG1
positive regulation of neuron differentiation	1	99.1×	0.013	FOXG1
brain development	1	39.8×	0.030	FOXG1
negative regulation of DNA-templated transcription	1	15.8×	0.071	FOXG1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.117	FOXG1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	FOXG1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FOXG1	0	0
LINC01551	0	0
WDFY1	0	0
ARSJ	0	0
LINC02327	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ARSJ
E	Difficult family or no structure, no drug	4	FOXG1, LINC01551, WDFY1, LINC02327

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FOXG1	0	—
LINC01551	0	—
WDFY1	0	—
ARSJ	0	—
LINC02327	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07293546	PHASE1/PHASE2	NOT_YET_RECRUITING	Phase 1/2 Study of FRF-001, an AAV-9 Gene Therapy, in Patients With FOXG1 Syndrome (FS)
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT02705677	Not specified	COMPLETED	Biobanking of Rett Syndrome and Related Disorders
NCT02738281	Not specified	COMPLETED	Natural History of Rett Syndrome & Related Disorders