Human Gene Module / Chromosome X / TFE3

TFE3transcription factor binding to IGHM enhancer 3

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
18 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xp11.23
Associated Disorders
-
Relevance to Autism

Hemizygous or heterozygous mutations in the TFE3 gene are responsible for X-linked syndromic intellectual developmental disorder with pigmentary mosaicism and coarse facies (MRXSPF; OMIM 301066), a disorder characterized by a phenotypic triad of severe developmental delay, coarse facial dysmorphisms, and Blaschkoid pigmentary mosaicism; autism spectrum disorder or autistic features (frequently in the form of stereotypic movements) have been observed in a subset of affected individuals (Villegas et al., 2019; Diaz et al., 2020; Lehalle et al., 2020). A rare potentially damaging de novo missense variant in this gene was observed in a male ASD proband from the Autism Sequencing Consortium (Satterstrom et al., 2020).

Molecular Function

This gene encodes a basic helix-loop-helix domain-containing transcription factor that binds MUE3-type E-box sequences in the promoter of genes. The encoded protein promotes the expression of genes downstream of transforming growth factor beta (TGF-beta) signaling.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to TFE3 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary - Villegas F et al. (2019) No Stereotypy
2 Support - Diaz J et al. (2020) Yes Epilepsy/seizures
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Recent Recommendation - Lehalle D et al. (2020) No ASD or autistic behavior, stereotypy, epilepsy/sei
5 Support - Zhou X et al. (2022) Yes -
Rare Variants   (18)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.465+1G>A - splice_site_variant De novo - - 32409512 Lehalle D et al. (2020)
c.350G>A p.Arg117Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.465+1G>A - splice_site_variant De novo - Simplex 31833172 Diaz J et al. (2020)
c.350G>A p.Arg117Gln missense_variant De novo - - 32409512 Lehalle D et al. (2020)
c.551A>G p.Glu184Gly missense_variant De novo - - 32409512 Lehalle D et al. (2020)
c.559A>C p.Thr187Pro missense_variant De novo - - 32409512 Lehalle D et al. (2020)
c.560C>A p.Thr187Lys missense_variant De novo - - 32409512 Lehalle D et al. (2020)
c.560C>T p.Thr187Met missense_variant De novo - - 32409512 Lehalle D et al. (2020)
c.566A>G p.Tyr189Cys missense_variant De novo - - 32409512 Lehalle D et al. (2020)
c.570C>G p.His190Gln missense_variant De novo - - 32409512 Lehalle D et al. (2020)
c.572T>C p.Leu191Pro missense_variant De novo - - 32409512 Lehalle D et al. (2020)
c.245C>T p.Thr82Met missense_variant De novo - - 30595499 Villegas F et al. (2019)
c.356A>C p.Gln119Pro missense_variant De novo - - 30595499 Villegas F et al. (2019)
c.557C>T p.Pro186Leu missense_variant De novo - - 30595499 Villegas F et al. (2019)
c.560C>G p.Thr187Arg missense_variant De novo - - 30595499 Villegas F et al. (2019)
c.602A>C p.Gln201Pro missense_variant De novo - - 30595499 Villegas F et al. (2019)
c.35G>A p.Arg12Gln missense_variant De novo - Simplex 31833172 Diaz J et al. (2020)
c.563G>A p.Arg188His missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

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."

Krishnan Probability Score

Score 0.49525398437063

Ranking 3093/25841 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.
Original Source
ExAC Score

Score 0.97374220954369

Ranking 2280/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.9347379850098

Ranking 12660/18665 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).
Original Source
Zhang D Score

Score -0.010978701668164

Ranking 9033/20870 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.
Original Source
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