FOXG1

protein-coding

forkhead box G1, the group of Forkhead boxes

Gene summary

This locus encodes a member of the fork-head transcription factor family. The encoded protein, which functions as a transcriptional repressor, is highly expressed in neural tissues during brain development. Mutations at this locus have been associated with Rett syndrome and a diverse spectrum of neurodevelopmental disorders defined as part of the FOXG1 syndrome. This gene is disregulated in many types of cancer and is the target of multiple microRNAs that regulate the proliferation of tumor cells. [provided by RefSeq, Jul 2020]

Previous symbols:

FKHL2
FOXG1B
FKHL4
FKH2
FKHL1
FOXG1C
FKHL3
FOXG1A

MANE transcript

NM_005249.5

Inheritance

ClinVar variants

P:288U:280B:303

Top phenotype

Rett syndrome, congenital variant

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr14:28,764,329-28,770,277

External References & Databases

Ensembl (ENSG00000176165)

Transcript & Mutation Effects

hg38 • Region Span ~5.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

FOXG1 disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100040

Submitter: ClinGen

Haploinsufficiency of the FOXG1 gene causes FOXG1 disorder, a condition sometimes referred to as the congenital variant of Rett syndrome. FOXG1 disorder, however, is a clinically distinct entity characterized by onset of neurodevelopmental impairment congenitally or during early infancy, in contrast to typical Rett syndrome in which symptoms appear after a period of normal development. Patients with FOXG1 disorder can also have epilepsy, motor dysfunction, stereotypic hand movements, abnormal breathing, lack of speech development, and corpus callosum hypoplasia on MRI. Variants in FOXG1 were first reported in patients with this disorder by Ariani et al. (2008). Males and females are equally affected, and the mechanism of disease is loss of function. Both sequence and copy number loss variants have been reported in patients with FOXG1 disorder. All reported variants are presumed to have arisen de novo. Experimental evidence, including mouse models with neurological phenotypes consistent with FOXG1 disorder (Xuan et al 1995, Shen et al. 2006, Tian et al. 2012) as well as interaction with MECP2, the causative gene of classical Rett syndrome (Dastidar et al 2012, Orlic-Milacic et al 2014) support the role of FOXG1 in this disease. This disease association is not accounted for in this assessment. In summary, the association between FOXG1 and FOXG1 disorder has been classified as definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. Approved by the ClinGen Rett/Angelman Expert Panel 4/30/2018.

FOXG1 disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100040

Submitter: G2P

Rett syndrome, congenital variantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013270

Submitter: Ambry Genetics

Rett syndrome, congenital variantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013270

Submitter: Labcorp Genetics (formerly Invitae)

FOXG1 disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100040

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Rett syndrome, congenital variantAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 18571142; 19578037; 19564653; 20736978; 21441262; 21536641; 21910242; 21953941; 22091895; 22129046; 22258524; 22415763; 22670136

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FOXG1 variants in ClinVar

26 Conditions Cataloged

FOXG1 disorderTotal: 740

not providedTotal: 287

Inborn genetic diseasesTotal: 134

not specifiedTotal: 101

FOXG1-related disorderTotal: 59

Rett syndromeTotal: 16

Intellectual disabilityTotal: 3

Neurodevelopmental disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005249.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			44 clinvar	191 clinvar	22 clinvar	257
missense	32 clinvar	77 clinvar	233 clinvar	61 clinvar	29 clinvar	432
nonsense	44 clinvar	11 clinvar				55
start loss			1 clinvar			1
frameshift	91 clinvar	33 clinvar	2 clinvar			126
splice donor/acceptor (+/-2bp)						0
Total	167	121	280	252	51	871

Highest pathogenic variant AF is 0.00000985336

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005249.5	RefSeq	NP_005240.3	1	MANE Select
ENST00000313071.7	Ensembl	ENSP00000339004.3	1	MANE Select
ENST00000706482.1	Ensembl	ENSP00000516406.1	1	Standard
ENST00001125064.1	Ensembl	ENSP00000794869.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
foxg1a	Danio rerio	Structure: microvillous olfactory receptor neuron Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

foxg1a

Danio rerio

Structure: microvillous olfactory receptor neuron

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

FoxO signaling pathway - Homo sapiens (human)
Tgif disruption of Shh signaling
Regulation of nuclear SMAD2/3 signaling

Biological Process

regulation of transcription by RNA polymerase II
brain development
aging
negative regulation of transcription, DNA-templated

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
protein binding
sequence-specific DNA binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000382535
Coding exons: 1
Length: 3821
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.49	84	234	0.358	0.0000115	3156
Missense (PolyPhen)		3	62.181	0.048246		684
Synonymous	-2.38	137	106	1.29	0.00000569	1025
Loss of Function	2.79	0	9.09	0.00	3.97e-7	124

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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. {ECO:0000269|PubMed:12657635}.;

Recessive Scores

pRec: 0.696

Intolerance Scores

RVIS EVS: -0.25
RVIS percentile EVS: 35.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium