Human Gene Module / Chromosome 14 / FOXG1

FOXG1Forkhead box G1

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 24
Rare Variants / Common Variants
64 / 1
Aliases
FOXG1, BF1,  BF2,  QIN,  FKH2,  HBF2,  HFK1,  HFK2,  HFK3,  KHL2,  FHKL3,  FKHL1,  FKHL2,  FKHL3,  FKHL4,  HBF-1,  HBF-2,  HBF-3,  FOXG1A,  FOXG1B,  FOXG1C,  HBF-G2
Associated Syndromes
Rett syndrome, FOXG1 syndrome, West syndrome, Rett syndrome, congenital variant
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
14q12
Associated Disorders
DD/NDD, EPS
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, studies have found rare mutations in the FOXG1 gene that are associated with FOXG1 syndrome (Kortm et al., 2011) and Rett's syndrome (quite a bit of phenotypic overlap exists between these two syndromes) as well as West syndrome.

Molecular Function

Transcription factor which plays an important role in the establishment of the regional subdivision of the developing brain and in the development of the telencephalon.

Reports related to FOXG1 (24 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Hbert JM and McConnell SK (2000) No -
2 Highly Cited Foxg1 suppresses early cortical cell fate. Hanashima C , et al. (2004) No -
3 Highly Cited FOXG1 is responsible for the congenital variant of Rett syndrome. Ariani F , et al. (2008) No -
4 Recent Recommendation A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization. Le Guen T , et al. (2011) No -
5 Recent Recommendation The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels. Manuel MN , et al. (2011) No -
6 Primary The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum h... Kortm F , et al. (2011) No -
7 Recent Recommendation West syndrome associated with 14q12 duplications harboring FOXG1. Striano P , et al. (2011) No -
8 Support 14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype. Ellaway CJ , et al. (2012) No DD, epilepsy
9 Support De novo mutations in moderate or severe intellectual disability. Hamdan FF , et al. (2014) No Absent speech, microcephaly
10 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
11 Support Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome. Olson HE , et al. (2015) No -
12 Recent Recommendation FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Mariani J , et al. (2015) No -
13 Recent Recommendation Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1 patients and in foxg1 mice. Patriarchi T , et al. (2015) No -
14 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
15 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Alvarez-Mora MI , et al. (2016) Yes -
16 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
17 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No -
18 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Trujillano D , et al. (2016) No DD, epilepsy/seizures, microcephaly
19 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No -
20 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
21 Recent Recommendation FOXG1 syndrome: genotype-phenotype association in 83 patients with FOXG1 variants. Mitter D , et al. (2017) No -
22 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients. Chrot E , et al. (2017) No Microcephaly, hypotonia
23 Support Early-onset movement disorder as diagnostic marker in genetic syndromes: Three cases of FOXG1-related syndrome. Caporali C , et al. (2018) No -
24 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Pardias AF , et al. (2018) No -
Rare Variants   (64)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.765G>A p.Trp255Ter stop_gained De novo - - 18571142 Ariani F , et al. (2008)
c.969delC p.Ser323fsTer325 frameshift_variant De novo - - 18571142 Ariani F , et al. (2008)
N/A N/A translocation De novo - - 21441262 Kortm F , et al. (2011)
- - copy_number_loss De novo - - 21441262 Kortm F , et al. (2011)
- - copy_number_loss De novo - - 21441262 Kortm F , et al. (2011)
- - copy_number_loss - - - 21441262 Kortm F , et al. (2011)
c.757A>G p.Asn253Asp missense_variant De novo - - 21441262 Kortm F , et al. (2011)
c.460dupG p.Glu154GlyfsTer301 frameshift_variant De novo - - 21441262 Kortm F , et al. (2011)
c.505_506delGGinsT p.Gly168SerfsTer23 frameshift_variant De novo - - 21441262 Kortm F , et al. (2011)
c.460dupG p.Glu154GlyfsTer301 frameshift_variant - - - 21441262 Kortm F , et al. (2011)
c.256C>T p.Arg86Ter stop_gained - - - 21441262 Kortm F , et al. (2011)
c.263_278del16 p.Arg88ProfsTer99 frameshift_variant De novo - - 21441262 Kortm F , et al. (2011)
c.700T>C p.Ser234Pro missense_variant De novo - - 21441262 Kortm F , et al. (2011)
- - copy_number_gain De novo - - 21536641 Striano P , et al. (2011)
- - copy_number_gain De novo - - 21536641 Striano P , et al. (2011)
c.256dupC p.Gln86ProfsTer35 frameshift_variant De novo - Unknown 22968132 Ellaway CJ , et al. (2012)
c.506delG p.Gly169AlafsTer23 frameshift_variant De novo - Simplex 25356899 Hamdan FF , et al. (2014)
c.1139C>T p.Thr380Met missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1241C>A p.Thr414Asn missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.565C>G p.Leu189Val missense_variant Unknown Not maternal - 25914188 Olson HE , et al. (2015)
c.738C>A p.Tyr246Ter stop_gained De novo - Simplex 26544041 Zhang Y , et al. (2015)
- p.Pro486Ser missense_variant Familial Maternal Multi-generational 26845707 Alvarez-Mora MI , et al. (2016)
c.730C>T p.Arg244Cys missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
- - complex_structural_alteration De novo - - 27841880 Redin C , et al. (2016)
- - complex_structural_alteration De novo - - 27841880 Redin C , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.385G>T p.Glu129Ter stop_gained De novo - Simplex 27848944 Trujillano D , et al. (2016)
c.673T>C p.Trp225Arg missense_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.553A>T p.Ser185Cys missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.821G>A p.Arg274Gln missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.454delG p.Glu154Argfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.256delC p.Gln86ArgfsTer106 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.214C>T p.Gln72Ter stop_gained De novo - - 28661489 Mitter D , et al. (2017)
c.406G>T p.Glu136Ter stop_gained De novo - - 28661489 Mitter D , et al. (2017)
c.460dupG p.Glu154GlyfsTer301 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.385delG p.Glu129SerfsTer63 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.460delG p.Glu154ArgfsTer38 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.460dupG p.Glu154GlyfsTer301 frameshift_variant Unknown - - 28661489 Mitter D , et al. (2017)
c.460dupG p.Glu154GlyfsTer301 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.460dupG p.Glu154GlyfsTer301 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.517G>T p.Glu173Ter stop_gained De novo - - 28661489 Mitter D , et al. (2017)
c.543G>C p.Lys181Asn missense_variant De novo (paternal gonadal mosaicism) - Multiplex 28661489 Mitter D , et al. (2017)
c.545C>A p.Pro182Gln missense_variant De novo - - 28661489 Mitter D , et al. (2017)
c.553A>T p.Ser185Cys missense_variant De novo - - 28661489 Mitter D , et al. (2017)
c.561C>A p.Asn187Lys missense_variant De novo - - 28661489 Mitter D , et al. (2017)
c.561C>A p.Asn187Lys missense_variant De novo - - 28661489 Mitter D , et al. (2017)
c.565C>T p.Leu189Phe missense_variant De novo - Multiplex (monozygotic twins) 28661489 Mitter D , et al. (2017)
c.581T>G p.Ile194Ser missense_variant De novo - - 28661489 Mitter D , et al. (2017)
c.592_594delCCC p.Pro198del inframe_deletion De novo - - 28661489 Mitter D , et al. (2017)
c.609_616delGCTCAACG p.Leu204HisfsTer248 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.624C>G p.Tyr208Ter stop_gained De novo - - 28661489 Mitter D , et al. (2017)
c.730C>T p.Arg244Cys missense_variant De novo - - 28661489 Mitter D , et al. (2017)
c.732_741del p.His245ThrfsTer78 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.974dupT p.Leu325PhefsTer130 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.1082dupG p.Leu362ProfsTer93 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.1141delG p.Ala381ProfsTer4 frameshift_variant De novo - - 28661489 Mitter D , et al. (2017)
c.755G>A p.Gly252Asp missense_variant De novo - - 28661489 Mitter D , et al. (2017)
c.921C>G p.Tyr307Ter stop_gained De novo - - 28661489 Mitter D , et al. (2017)
c.590G>T p.Ser197Ile missense_variant De novo - - 28661489 Mitter D , et al. (2017)
c.545C>T p.Pro182Leu missense_variant De novo - - 28708303 Chrot E , et al. (2017)
- - copy_number_loss Unknown - Simplex 29396177 Caporali C , et al. (2018)
c.392delG p.Gly131AlafsTer60 frameshift_variant Unknown - Simplex 29396177 Caporali C , et al. (2018)
- - copy_number_loss De novo - Simplex 29396177 Caporali C , et al. (2018)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
T>C - intergenic_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
S

Syndromic

S

Score Delta: Score remained at S

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

7/1/2017
5
icon
S

Decreased from 5 to S

Description

Rare mutations in the FOX1 gene are responsible for a congenital variant of Rett syndrome (Ariani et al., 2008) and FOXG1 syndrome (Kortum et al., 2011); there is considerable phenotypic overlap between these two syndromes. 14q12 duplications harboring the FOXP1 gene are associated with West syndrome (Striano et al., 2011). Genotype-phenotype analysis of 30 new and 53 previously reported patients with a heterozygous pathogenic or likely pathogenic variant in FOXG1 demonstrated that 25% of patients exhibited poor social interaction, 52% exhibited poor eye contact, and 90% exhibited stereotypic movements (Mitter et al., 2017).

4/1/2017
5
icon
5

Decreased from 5 to 5

Description

Rare mutations in the FOXG1 gene that are associated with FOXG1 syndrome (Kort?m et al., 2011) and Rett's syndrome (quite a bit of phenotypic overlap exists between these two syndromes) as well as West syndrome. Not clearly syndromic autism.

Reports Added
[A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017] [Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.2015] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017] [Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1 patients and in foxg1 mice.2015] [Foxg1 suppresses early cortical cell fate.2004] [The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels.2011] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.2016] [West syndrome associated with 14q12 duplications harboring FOXG1.2011] [FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.2015] [The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum h...2011] [Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures.2000] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [De novo mutations in moderate or severe intellectual disability.2014] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016] [14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype.2012] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization.2011] [FOXG1 is responsible for the congenital variant of Rett syndrome.2008] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015]
10/1/2016
5
icon
5

Decreased from 5 to 5

Description

Rare mutations in the FOXG1 gene that are associated with FOXG1 syndrome (Kort?m et al., 2011) and Rett's syndrome (quite a bit of phenotypic overlap exists between these two syndromes) as well as West syndrome. Not clearly syndromic autism.

7/1/2016
5
icon
5

Decreased from 5 to 5

Description

Rare mutations in the FOXG1 gene that are associated with FOXG1 syndrome (Kort?m et al., 2011) and Rett's syndrome (quite a bit of phenotypic overlap exists between these two syndromes) as well as West syndrome. Not clearly syndromic autism.

1/1/2016
5
icon
5

Decreased from 5 to 5

Description

Rare mutations in the FOXG1 gene that are associated with FOXG1 syndrome (Kort?m et al., 2011) and Rett's syndrome (quite a bit of phenotypic overlap exists between these two syndromes) as well as West syndrome. Not clearly syndromic autism.

Reports Added
[Imbalance of excitatory/inhibitory synaptic protein expression in iPSC-derived neurons from FOXG1 patients and in foxg1 mice.2015] [Foxg1 suppresses early cortical cell fate.2004] [The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels.2011] [Comprehensive molecular testing in patients with high functioning autism spectrum disorder.2016] [West syndrome associated with 14q12 duplications harboring FOXG1.2011] [FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.2015] [The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum h...2011] [Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures.2000] [Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities.2015] [14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype.2012] [A missense mutation within the fork-head domain of the forkhead box G1 Gene (FOXG1) affects its nuclear localization.2011] [FOXG1 is responsible for the congenital variant of Rett syndrome.2008] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Mutations in epilepsy and intellectual disability genes in patients with features of Rett syndrome.2015]
7/1/2014
No data
icon
5

Increased from No data to 5

Description

Rare mutations in the FOXG1 gene that are associated with FOXG1 syndrome (Kort?m et al., 2011) and Rett's syndrome (quite a bit of phenotypic overlap exists between these two syndromes) as well as West syndrome. Not clearly syndromic autism.

4/1/2014
No data
icon
5

Increased from No data to 5

Description

Rare mutations in the FOXG1 gene that are associated with FOXG1 syndrome (Kort?m et al., 2011) and Rett's syndrome (quite a bit of phenotypic overlap exists between these two syndromes) as well as West syndrome. Not clearly syndromic autism.

Krishnan Probability Score

Score 0.59023510606973

Ranking 483/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Sanders TADA Score

Score 0.41739369886346

Ranking 302/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Zhang D Score

Score 0.24315392678539

Ranking 3568/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with FOXG1(1 CNVs)
14q12 20 Deletion-Duplication 31  /  96
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Fezf2 Fez family zinc finger 2 Mouse DNA Binding 54713 Q9ESP5
GDF9 growth differentiation factor 9 Human Protein Binding 2661 O60383
MIR9-1 microRNA 9-1 Mouse DNA Binding 387133 N/A
MIR9-2 microRNA 9-2 Mouse DNA Binding 723967 N/A
MIR9-3 microRNA 9-3 Mouse DNA Binding 723968 N/A
PROZ protein Z, vitamin K-dependent plasma glycoprotein Human Protein Binding 8858 P22891
Six3.2 transcription factor-like Medaka fish DNA Binding 100144381 B0R222
THSD4 Thrombospondin type-1 domain-containing protein 4 Human Protein Binding 79875 Q6ZMP0
TLE6 transducin-like enhancer of split 6, homolog of Drosophila E(spl) Mouse Protein Binding 114606 Q9WVB3
WNT8B wingless-type MMTV integration site family, member 8b Zebrafish DNA Binding 30144 P51029
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