Human Gene Module / Chromosome 2 / TRIP12

TRIP12Thyroid hormone receptor interactor 12

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
11 / 14
Rare Variants / Common Variants
38 / 0
Aliases
TRIP12, KIAA0045,  MGC138849,  MGC138850,  ULF
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
2q36.3
Associated Disorders
ASD
Relevance to Autism

A compound heterozygous mutation in the TRIP12 gene was identified in an ASD proband from a nonconsanguineous family that showed evidence of distant shared ancestry as identified by homozygosity analysis (Chahrour et al., 2012). Two de novo LoF variants and two de novo missense variants in the TRIP12 gene were identified in ASD probands from independent simplex cohorts (PMID 22542183, 25418537). A third de novo LoF variant in the TRIP12 gene was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A patient with intellectual disability and a de novo frameshift variant in TRIP12 that was first reported in Lelieveld et al., 2016 was subsequently reported to have a diagnosis of ASD in Bramswig et al., 2016. Two previously unreported patients that were diagnosed with ASD and intellectual disability were also found to have de novo LoF variants in the TRIP12 gene in Bramswig et al., 2016. Variants in the TRIP12 gene have also been observed in patients with intellectual disability without autism (Lelieveld et al., 2016; Bramswig et al., 2016). An additional de novo LoF variant in TRIP12 was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. Zhang et al., 2017 described nine novel patients with TRIP12 variants (five deletions, four SNVs), all of whom presented with developmental delay/intellectual disability; autistic behaviors (6/8 patients), speech delay (8/8 patients), motor delay (7/8 patients), obesity (4/7 patients), narrow palpebral fissures (4/7 patients), and downturned corners of the mouth (4/8 cases) were also frequently observed.

Molecular Function

The protein encoded by this gene is an E3 ubiquitin-protein ligase involved in the degradation of the p19ARF/ARF isoform of CDKN2A, a tumor suppressor. The encoded protein also plays a role in the DNA damage response by regulating the stability of USP7, which regulates tumor suppressor p53.

Reports related to TRIP12 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism. Chahrour MH , et al. (2012) Yes -
2 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
3 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder. Prasad A , et al. (2013) Yes -
4 Support Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Pinto D , et al. (2014) Yes -
5 Recent Recommendation Recurrent de novo mutations implicate novel genes underlying simplex autism risk. O'Roak BJ , et al. (2014) Yes -
6 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
7 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
8 Recent Recommendation Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
9 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
10 Recent Recommendation Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without au... Bramswig NC , et al. (2016) Yes -
11 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
12 Recent Recommendation Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech ... Zhang J , et al. (2017) No Autistic behaviors
13 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
14 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
Rare Variants   (38)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.130G>A p.Ala44Thr missense_variant Familial - Multiplex 22511880 Chahrour MH , et al. (2012)
c.152A>G p.Lys51Arg missense_variant Familial - Multiplex 22511880 Chahrour MH , et al. (2012)
c.1138C>T p.Arg380Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_loss De novo - Simplex 24768552 Pinto D , et al. (2014)
c.2981+1delG - splice_site_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.5519C>T p.Ser1840Leu missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.4784G>A p.Arg1595Gln missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.5900C>G p.Thr1967Ser missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.3835C>T p.Gln1279Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
TAAAA/TAA - frameshift_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.586_587del p.Ser196fs frameshift_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.5746C>T p.Gln1916Ter stop_gained De novo - - 27479843 Lelieveld SH , et al. (2016)
c.334C>T p.Arg112Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.3350G>A p.Gly1117Glu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.3356+1G>A p.Ala1061GlufsTer16 splice_site_variant De novo - - 27848077 Bramswig NC , et al. (2016)
c.2524+3dupA p.Ala791ValfsTer16 splice_site_variant De novo - - 27848077 Bramswig NC , et al. (2016)
c.1054C>T p.Arg352Ter stop_gained Unknown - - 27848077 Bramswig NC , et al. (2016)
c.4768G>C p.Asp1590His missense_variant De novo - - 27848077 Bramswig NC , et al. (2016)
c.14C>T p.Pro5Leu missense_variant Familial Maternal Simplex 27848077 Bramswig NC , et al. (2016)
- - translocation De novo - - 27848077 Bramswig NC , et al. (2016)
c.2300C>T p.Ala767Val missense_variant De novo - - 27848077 Bramswig NC , et al. (2016)
c.5920C>T p.Arg1974Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
- - copy_number_loss De novo - - 28251352 Zhang J , et al. (2017)
- - copy_number_loss Unknown - - 28251352 Zhang J , et al. (2017)
- - copy_number_loss Unknown - - 28251352 Zhang J , et al. (2017)
- - copy_number_loss De novo - - 28251352 Zhang J , et al. (2017)
- - copy_number_loss De novo - - 28251352 Zhang J , et al. (2017)
c.3446_3447delCA p.Ser1149Ter frameshift_variant De novo - - 28251352 Zhang J , et al. (2017)
c.2979dupA p.Gly994ArgfsTer5 frameshift_variant De novo - - 28251352 Zhang J , et al. (2017)
c.2282C>T p.Ala761Val missense_variant De novo - - 28251352 Zhang J , et al. (2017)
c.3743+1G>A p.? splice_site_variant De novo - - 28251352 Zhang J , et al. (2017)
c.1145-2A>C p.? splice_site_variant Unknown Not maternal - 28251352 Zhang J , et al. (2017)
- - copy_number_loss Unknown - - 28251352 Zhang J , et al. (2017)
G>A p.Thr969Ile missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.3226+1G>C p.? splice_site_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.2578delT p.Ser860fs frameshift_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.3050C>T p.Thr1017Ile missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

1S

Score Delta: Score remained at 1.1 + S

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.

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
1S
icon
1S

Score remained at 1S

Description

A compound heterozygous mutation in the TRIP12 gene was identified in an ASD proband from a nonconsanguineous family that showed evidence of distant shared ancestry as identified by homozygosity analysis (Chahrour et al., 2012). Two de novo LoF variants and two de novo missense variants in the TRIP12 gene were identified in ASD probands from independent simplex cohorts (PMID 22542183, 25418537). A third de novo LoF variant in the TRIP12 gene was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A patient with intellectual disability and a de novo frameshift variant in TRIP12 that was first reported in Lelieveld et al., 2016 was subsequently reported to have a diagnosis of ASD in Bramswig et al., 2016. Two previously unreported patients that were diagnosed with ASD and intellectual disability were also found to have de novo LoF variants in the TRIP12 gene in Bramswig et al., 2016. Variants in the TRIP12 gene have also been observed in patients with intellectual disability without autism (Lelieveld et al., 2016; Bramswig et al., 2016). An additional de novo LoF variant in TRIP12 was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. Zhang et al., 2017 described nine novel patients with TRIP12 variants (five deletions, four SNVs), all of whom presented with developmental delay/intellectual disability; autistic behaviors (6/8 patients), speech delay (8/8 patients), motor delay (7/8 patients), obesity (4/7 patients), narrow palpebral fissures (4/7 patients), and downturned corners of the mouth (4/8 cases) were also frequently observed.

1/1/2017
2
icon
1S

Decreased from 2 to 1S

Description

Two de novo LoF variants and two de novo missense variants in the TRIP12 gene have been identified in ASD probands from independent simplex cohorts (PMID 22542183, 25418537). A third de novo LoF variant in the TRIP12 gene was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A patient with intellectual disability and a de novo frameshift variant in TRIP12 that was first reported in Lelieveld et al., 2016 was subsequently reported to have a diagnosis of ASD in Bramswig et al., 2016. Two previously unreported patients that were diagnosed with ASD and intellectual disability were also found to have de novo LoF variants in the TRIP12 gene in Bramswig et al., 2016. Variants in the TRIP12 gene have also been observed in patients with intellectual disability without autism (Lelieveld et al., 2016; Bramswig et al., 2016). An additional de novo LoF variant in TRIP12 was identified in an ASD proband from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017. Zhang et al., 2017 described nine novel patients with TRIP12 variants (five deletions, four SNVs), all of whom presented with developmental delay/intellectual disability; autistic behaviors (6/8 patients), speech delay (8/8 patients), motor delay (7/8 patients), obesity (4/7 patients), narrow palpebral fissures (4/7 patients), and downturned corners of the mouth (4/8 cases) were also frequently observed.

10/1/2016
3
icon
2

Decreased from 3 to 2

Description

Two de novo LoF variants and two de novo missense variants in the TRIP12 gene have been identified in ASD probands from independent simplex cohorts (PMID 22542183, 25418537). A third de novo LoF variant in the TRIP12 gene was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. A patient with intellectual disability and a de novo frameshift variant in TRIP12 that was first reported in Lelieveld et al., 2016 was subsequently reported to have a diagnosis of ASD in Bramswig et al., 2016. Two previously unreported patients that were diagnosed with ASD and intellectual disability were also found to have de novo LoF variants in the TRIP12 gene in Bramswig et al., 2016. Variants in the TRIP12 gene have also been observed in patients with intellectual disability without autism (Lelieveld et al., 2016; Bramswig et al., 2016).

7/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants and two de novo missense variants in the TRIP12 gene have been identified in ASD probands from independent simplex cohorts (PMID 22542183, 25418537).

1/1/2015
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants and two de novo missense variants in the TRIP12 gene have been identified in ASD probands from independent simplex cohorts (PMID 22542183, 25418537).

10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants and two de novo missense variants in the TRIP12 gene have been identified in ASD probands from independent simplex cohorts (PMID 22542183, 25418537).

Krishnan Probability Score

Score 0.5016416177204

Ranking 2013/25841 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 0.99999999999948

Ranking 39/18225 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 0.818

Ranking 219/239 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 0.0019420151541799

Ranking 21/18665 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 20

Ranking 106/461 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 0.5042194288131

Ranking 494/20870 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 TRIP12(1 CNVs)
2q36.3 19 Deletion-Duplication 31  /  87
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CARNS1 carnosine synthase 1 Human Protein Binding 57571 A5YM72
TRADD TNFRSF1A-associated via death domain Human Protein Binding 8717 Q15628
UBE2DI ubiquitin-conjugating enzyme E2D 1 Human Protein Modification 7321 P51668
Submit New Gene

Report an Error