Human Gene Module / Chromosome 5 / TRIO

TRIOTrio Rho guanine nucleotide exchange factor

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 20
Rare Variants / Common Variants
61 / 0
Aliases
TRIO, ARHGEF23,  tgat
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
5p15.2
Associated Disorders
ASD, ADHD
Relevance to Autism

This gene was identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).

Molecular Function

Promotes the exchange of GDP by GTP. Together with leukocyte antigen-related (LAR) protein, it could play a role in coordinating cell-matrix and cytoskeletal rearrangements necessary for cell migration and cell growth.

Reports related to TRIO (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
2 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
3 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No -
4 Support De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No -
5 Primary Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
6 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
8 Recent Recommendation Incorporating Functional Information in Tests of Excess De Novo Mutational Load. Jiang Y , et al. (2015) No -
9 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
10 Recent Recommendation TRIO loss of function is associated with mild intellectual disability and affects dendritic branching and synapse function. Ba W , et al. (2016) No ADHD, autistic behaviors
11 Recent Recommendation Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. Turner TN , et al. (2016) Yes -
12 Support Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly. Pengelly RJ , et al. (2016) No Microcephaly
13 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
14 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
15 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
16 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Geisheker MR , et al. (2017) No -
17 Support Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Lionel AC , et al. (2017) No -
18 Recent Recommendation An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio. Sadybekov A , et al. (2017) No -
19 Recent Recommendation Neurodevelopmental disease-associated de novo mutations and rare sequence variants affect TRIO GDP/GTP exchange factor activity. Katrancha SM , et al. (2017) No -
20 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
Rare Variants   (61)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4292A>T p.Lys1431Met missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.3934C>T p.Arg1312Trp missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.4103A>T p.Asp1368Val missense_variant De novo - Simplex 23033978 de Ligt J , et al. (2012)
c.7688C>T p.Thr2563Met missense_variant De novo - Simplex 23033978 de Ligt J , et al. (2012)
c.8834C>T p.Thr2945Met missense_variant De novo - Simplex 23934111 Epi4K Consortium , et al. (2013)
c.3985delA p.Ile1329fs frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.6658G>C p.Val2220Leu missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
G>A p.Trp11Ter stop_gained Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.1594G>A p.Val532Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.502G>A p.Gly168Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.514C>A p.Gln172Lys missense_variant Familial Paternal (n=1), maternal (n=1) Simplex 25363760 De Rubeis S , et al. (2014)
c.51T>A p.Phe17Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.111C>A p.Asn37Lys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8629G>A p.Gly2877Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4732T>C p.Ser1578Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6140A>C p.Gln2047Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.419A>C p.Lys140Thr missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.440A>T p.Lys147Met missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7361C>T p.Ser2454Leu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7361C>T p.Ser2454Leu missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.925C>T p.His309Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1298A>G p.Asn433Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3002A>T p.Asn1001Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5414C>G p.Ser1805Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5673A>G p.Lys1891Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6508G>C p.Gly2170Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.407G>A p.Arg136His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.463G>A p.Glu155Lys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.524A>G p.Asn175Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2699G>A p.Arg2700His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.946G>A p.Glu316Lys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3104T>A p.Phe1035Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3250C>T p.Arg1084Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3602C>T p.Ser1201Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8629G>A p.Gly2877Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2649G>T p.Glu883Asp missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.4381C>A p.Pro1461Thr missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4382C>T p.Pro1461Leu missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
- - copy_number_loss De novo - - 26721934 Ba W , et al. (2016)
c.649A>T p.Arg217Ter stop_gained Familial Paternal Multi-generational 26721934 Ba W , et al. (2016)
c.3752del p.Asp1252ValfsTer11 frameshift_variant De novo - - 26721934 Ba W , et al. (2016)
c.4128G>A p.Trp1376Ter stop_gained De novo - - 26721934 Ba W , et al. (2016)
c.2770C>A p.Arg924Ser missense_variant Familial Paternal - 26721934 Ba W , et al. (2016)
c.3712T>C p.Tyr1238His missense_variant Unknown - - 26721934 Ba W , et al. (2016)
c.5764G>A p.Ala1922Thr missense_variant Familial Maternal - 26721934 Ba W , et al. (2016)
c.5816G>A p.Ser1939Asn missense_variant Familial Paternal - 26721934 Ba W , et al. (2016)
c.6601C>G p.Leu2201Val missense_variant Unknown - - 26721934 Ba W , et al. (2016)
c.6741G>C p.Glu2247Asp missense_variant Unknown - - 26721934 Ba W , et al. (2016)
c.8120G>A p.Arg2707Gln missense_variant Unknown - - 26721934 Ba W , et al. (2016)
- - copy_number_gain Familial Maternal Simplex 26749308 Turner TN , et al. (2016)
c.4466delA p.Gln1489ArgfsTer11 frameshift_variant Familial - Multi-generational 27418539 Pengelly RJ , et al. (2016)
c.4283G>A p.Arg1428Gln missense_variant De novo - - 27418539 Pengelly RJ , et al. (2016)
c.3239A>T p.Asn1080Ile missense_variant De novo - - 27418539 Pengelly RJ , et al. (2016)
c.748T>G p.Leu250Val missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.6545G>A p.Arg2182His missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.6422G>T p.Arg2141Leu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.8692G>A p.Glu2898Lys missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.5303G>A p.Arg1768Gln missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.4375A>G p.Ser1459Gly missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.4311+1G>A p.? splice_site_variant De novo - - 28771251 Lionel AC , et al. (2017)
c.131C>T p.Ala44Val missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2017
3
icon
2

Decreased from 3 to 2

Description

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05 < FDR ? 0.1, meaning that this gene had a ? 90% chance of being a true autism gene (PMID 25363760). De novo likely damaging missense variants in this gene have also been identified in patients presenting with intellectual disability (PMID 23033978) and epilepsy (PMID 23934111). An additional de novo likely damaging missense variant in TRIO was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. Sadybekov et al., 2017 identified an enrichment of ASD- and NDD-associated missense and loss-of-function (LoF) variants in the GEF1/DH1 subdomain of TRIO; no missense or LoF variants in this domain were observed in 9,937 control exomes. Additional functional analysis of one frameshift variant and three missense variants residing in the Trio GEF1/DH1 subdomain in this report demonstrated effects on Rac1 activation and synaptic function; one of the missense variants that exhibited reduced Rac1 activation and impaired synaptic function, suggestive of a loss-of-function effect, had previously been observed de novo in an ASD proband from the Simons Simplex Collection in Sanders et al., 2012.

7/1/2017
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05 < FDR ? 0.1, meaning that this gene had a ? 90% chance of being a true autism gene (PMID 25363760). De novo likely damaging missense variants in this gene have also been identified in patients presenting with intellectual disability (PMID 23033978) and epilepsy (PMID 23934111). An additional de novo likely damaging missense variant in TRIO was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

1/1/2017
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05 < FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). De novo likely damaging missense variants in this gene have also been identified in patients presenting with intellectual disability (PMID 23033978) and epilepsy (PMID 23934111). An additional de novo likely damaging missense variant in TRIO was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

10/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05

7/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05

7/1/2015
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05

1/1/2015
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05

10/1/2014
icon
3

Increased from to 3

Description

A de novo LoF variant and two de novo missense variants that were predicted to be damaging were observed in ASD probands (PMID 22495306, 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified TRIO as a gene meeting high statistical significance with a 0.05

Krishnan Probability Score

Score 0.60982948894912

Ranking 246/25841 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.
ExAC Score

Score 0.99999999999991

Ranking 28/18225 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
Iossifov Probability Score

Score 0.993

Ranking 21/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.05253748316185

Ranking 47/18665 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).
Larsen Cumulative Evidence Score

Score 48.5

Ranking 33/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.28609087699252

Ranking 2936/20870 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 TRIO(1 CNVs)
5p15.2 27 Deletion-Duplication 43  /  253
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ZNF232 Zinc finger protein 232 Human Protein Binding 7775 Q9UNY5-2
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