Human Gene Module / Chromosome 5 / TRIO

TRIOTrio Rho guanine nucleotide exchange factor

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
13 / 28
Rare Variants / Common Variants
117 / 0
Aliases
TRIO, ARHGEF23,  tgat
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
5p15.2
Associated Disorders
ADHD, ASD
Relevance to Autism

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. Barbosa et al., 2020 reported 24 individuals with confirmed pathogenic missense or nonsense variants in the TRIO gene and noted that stereotypy (27%) and autistic behavior (31%) were among the recurrent behavioral phentotypes observed in this cohort; furthermore, the authors found that while all individuals in this cohort presented with developmental delay, individuals with a pathogenic variant in the seventh spectrin repeat (which was shown by functional analysis to cause TRIO-mediated hyper-activation of RAC1) presented with a more severe intellectual disability associated with macrocephaly, whereas individuals with variants in the RAC1-activating GEFD1 domain (which were shown to cause TRIO-mediated hypo-activation of RAC1) presented with milder ID and microcephaly.

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 (28 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 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Sanders SJ , et al. (2015) Yes -
11 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
12 Recent Recommendation Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA Turner TN et al. (2016) Yes -
13 Support Mutations specific to the Rac-GEF domain of TRIO cause intellectual disability and microcephaly. Pengelly RJ , et al. (2016) No Microcephaly
14 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
15 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
16 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
17 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains. Geisheker MR , et al. (2017) No -
18 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 -
19 Recent Recommendation An autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio. Sadybekov A , et al. (2017) No -
20 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 -
21 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
22 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
23 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly. Boonsawat P , et al. (2019) No ADHD, learning disabilities
24 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing. Aspromonte MC , et al. (2019) Yes -
25 Support Mutations in ASH1L confer susceptibility to Tourette syndrome. Liu S , et al. (2019) No -
26 Recent recommendation Opposite Modulation of RAC1 by Mutations in TRIO Is Associated with Distinct, Domain-Specific Neurodevelopmental Disorders. Barbosa S , et al. (2020) No Autistic features, stereotypy
27 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
28 Support De novo variants in neurodevelopmental disorders-experiences from a tertiary care center Brunet T et al. (2021) No -
Rare Variants   (117)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 26721934 Ba W , et al. (2016)
c.347+1G>C - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1690C>T p.Gln564Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.4219G>T p.Glu1407Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.4673G>A p.Trp1558Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.5032C>T p.Arg1678Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.5497A>T p.Arg1833Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.5581G>T p.Glu1861Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.4128G>A p.Trp1376Ter stop_gained De novo NA - 26721934 Ba W , et al. (2016)
c.316A>G p.Arg106Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.697C>T p.Arg233Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
- - copy_number_gain Familial Maternal Simplex 26749308 Turner TN et al. (2016)
c.2302C>T p.Gln768Ter stop_gained Unknown - - 32109419 Barbosa S , et al. (2020)
c.3712T>C p.Tyr1238His missense_variant Unknown - - 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)
c.1072C>T p.His358Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1307C>A p.Ala436Asp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1981C>T p.Arg661Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2276C>T p.Thr759Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2365C>T p.Arg789Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2479C>T p.Arg827Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2699G>T p.Arg900Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2729G>A p.Arg910His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2956C>T p.Arg986Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4860-2A>G - splice_site_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.3256A>G p.Lys1086Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3299C>T p.Thr1100Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3695C>T p.Ser1232Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3868G>T p.Ala1290Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3869C>T p.Ala1290Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4073A>G p.Glu1358Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4759C>T p.Arg1587Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5834C>T p.Ser1945Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5855C>T p.Ser1952Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6559C>T p.Arg2187Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8131C>T p.Arg2711Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2465C>A p.Thr822Lys missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.4283G>A p.Arg1428Gln missense_variant De novo NA - 33004838 Wang T et al. (2020)
c.3224C>T p.Thr1075Ile missense_variant Unknown - - 32109419 Barbosa S , et al. (2020)
c.2848C>G p.His950Asp missense_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.2848C>T p.His950Tyr missense_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.3232C>T p.Arg1078Trp missense_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.3233G>A p.Arg1078Gln missense_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.3895G>A p.Glu1299Lys missense_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.4283G>A p.Arg1428Gln missense_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.4382C>T p.Pro1461Leu missense_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.4406A>G p.His1469Arg missense_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.748T>G p.Leu250Val missense_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.2770C>A p.Arg924Ser missense_variant Familial Paternal - 26721934 Ba W , et al. (2016)
c.433del p.Leu145CysfsTer13 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3936G>A p.Arg1312= splice_site_variant De novo NA - 28771251 Lionel AC , et al. (2017)
c.4375A>G p.Ser1459Gly missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
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.3657dup p.Cys1220MetfsTer7 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3239A>T p.Asn1080Ile missense_variant De novo NA - 27418539 Pengelly RJ , et al. (2016)
c.4283G>A p.Arg1428Gln missense_variant De novo NA - 27418539 Pengelly RJ , et al. (2016)
c.5303G>A p.Arg1768Gln missense_variant De novo NA - 28191889 Stessman HA , et al. (2017)
c.4615-2del - splice_site_variant De novo NA Simplex 30842647 Boonsawat P , et al. (2019)
c.8500C>T p.Arg2834Cys missense_variant De novo NA Simplex 31673123 Liu S , et al. (2019)
c.131C>T p.Ala44Val missense_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.3752del p.Asp1251ValfsTer11 frameshift_variant De novo NA - 26721934 Ba W , et al. (2016)
c.649A>T p.Arg217Ter stop_gained Familial Paternal Multiplex 26721934 Ba W , et al. (2016)
c.6422G>T p.Arg2141Leu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.6545G>A p.Arg2182His missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.4111C>T p.His1371Tyr missense_variant De novo NA - 31209962 Aspromonte MC , et al. (2019)
c.3232C>T p.Arg1078Trp missense_variant De novo NA Unknown 33619735 Brunet T et al. (2021)
c.463G>A p.Val155Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.925C>T p.Pro309Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.946G>A p.Asp316Asn missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7632+713G>A - stop_gained Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.2649G>T p.Glu883Asp missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.2237A>G p.Asn746Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2699G>A p.Arg900Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1061_1064del p.Asp354GlyfsTer10 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.8692G>A p.Glu2898Lys missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.7078del p.Gln2360ArgfsTer53 frameshift_variant Unknown - - 32109419 Barbosa S , et al. (2020)
c.3934C>T p.Arg1312Trp missense_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.4103A>T p.Asp1368Val missense_variant De novo NA Simplex 23033978 de Ligt J , et al. (2012)
c.7688C>T p.Thr2563Met missense_variant De novo NA Simplex 23033978 de Ligt J , et al. (2012)
c.3149A>T p.Asn1050Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3251T>A p.Phe1084Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3397C>T p.Arg1133Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3749C>T p.Ser1250Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6353C>G p.Ser2118Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6611A>G p.Lys2204Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7447G>C p.Gly2483Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7910G>A p.Arg2637His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8027A>G p.Asn2676Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9157G>A p.Gly3053Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4292A>T p.Lys1431Met missense_variant De novo NA Simplex 22495306 Sanders SJ , et al. (2012)
c.7632+731T>A - missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7632+791C>A - missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5708dup p.Pro1904ThrfsTer11 frameshift_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.6667del p.Leu2223PhefsTer16 frameshift_variant De novo NA - 32109419 Barbosa S , et al. (2020)
c.6658G>C p.Val2220Leu missense_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.6400del p.Val2134SerfsTer4 frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.8729G>A p.Arg2910Lys missense_variant Unknown Not paternal Simplex 30564305 Guo H , et al. (2018)
c.4231C>T p.Arg1411Ter stop_gained Familial Maternal Simplex 31209962 Aspromonte MC , et al. (2019)
c.440A>T p.Glu147Val missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8834C>T p.Thr2945Met missense_variant De novo NA Simplex 23934111 Epi4K Consortium , et al. (2013)
c.2533G>A p.Val845Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5671T>C p.Ser1891Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6262G>A p.Gly2088Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6274C>A p.Gln2092Lys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6274C>A p.Gln2092Lys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7079A>C p.Gln2360Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7361C>T p.Ala2454Val missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7922A>C p.Lys2641Thr missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.9157G>A p.Gly3053Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3985del p.Ile1329PhefsTer6 frameshift_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.7361C>T p.Ala2454Val missense_variant Familial Paternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.4381C>A p.Pro1461Thr missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4382C>T p.Pro1461Leu missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4090del p.Gln1364SerfsTer33 frameshift_variant Familial Paternal Extended multiplex 27418539 Pengelly RJ , et al. (2016)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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.

Score Delta: Score remained at 2

1

High Confidence

See all Category 1 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.

1/1/2021
2
icon
2

Score remained at 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.

10/1/2020
2
icon
2

Score remained at 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.

1/1/2020
2
icon
2

Score remained at 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.

10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
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.

7/1/2019
2
icon
2

Decreased from 2 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.

4/1/2019
2
icon
2

Decreased from 2 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.

1/1/2019
2
icon
2

Decreased from 2 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.

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

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.
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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