Human Gene Module / Chromosome 2 / TRIP12

TRIP12Thyroid hormone receptor interactor 12

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
9 / 12
Rare Variants / Common Variants
34 / 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 compund 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). A de novo nonsense variant in the gene was subsequently identified by exome sequencing in an ASD case from the Simons Simplex Collection (Iossifov et al., 2012), while a second de novo loss-of-function variant in this gene was recently identified in an independent simplex ASD cohort (O'Roak et al., 2014).

Molecular Function

Component of PA700, an ATP-dependent multisubunit protein that activates the proteolytic activities of the multifunctional proteinase (20S proteasome) of the 26S complex. Specifically interacts with the ligand binding domain of the thyroid hormone receptor (in a thyroid hormone T3-independent manner) and with retinoid X receptor (RXR). Could be E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates.

Reports related to TRIP12 (12 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 (6/8 cases)
Rare Variants   (34)
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)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

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.

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."

04-01-2017
1S

Initial score established: 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.

CNVs associated with TRIP12(1 CNVs)
2q36.3 16 Deletion-Duplication 28  /  84
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
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