Human Gene Module / Chromosome 2 / TRIP12

TRIP12Thyroid hormone receptor interactor 12

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
24 / 39
Rare Variants / Common Variants
124 / 0
EAGLE Score
27
Strong Learn More
Aliases
TRIP12, KIAA0045,  MGC138849,  MGC138850,  ULF
Associated Syndromes
Clark-Baraitser syndrome (CLABARS), ASD
Chromosome Band
2q36.3
Associated Disorders
ID, EP, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic
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). Transmission and de novo association (TADA) analysis of ASD cases and controls from the Autism Sequencing Consortium and the Simons Simplex Collection in Sanders et al., 2015 identified TRIP12 as an ASD candidate gene with a false discovery rate (FDR) 0.01. 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. Two additional de novo LoF variants in TRIP12 were identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified TRIP12 as a gene reaching exome-wide significance (P < 2.5E-06).

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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
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Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TRIP12 (39 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 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
9 Recent Recommendation Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
10 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
11 Recent Recommendation Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism Bramswig NC , et al. (2016) Yes -
12 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
13 Recent Recommendation Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features Zhang J , et al. (2017) No Autistic behaviors
14 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
15 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
16 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
17 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
18 Recent recommendation The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability Larrieu D , et al. (2020) No -
19 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
20 Support Novel de novo TRIP12 mutation reveals variable phenotypic presentation while emphasizing core features of TRIP12 variations Donoghue T et al. (2020) Yes Epilepsy/seizures
21 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
22 Support - Pode-Shakked B et al. (2021) No -
23 Support - Li D et al. (2022) Yes -
24 Support - Woodbury-Smith M et al. (2022) Yes -
25 Support - Marcogliese PC et al. (2022) Yes -
26 Support - Hu C et al. (2022) Yes -
27 Support - Krgovic D et al. (2022) No Autistic behavior
28 Support - Levchenko O et al. (2022) No -
29 Support - Zhou X et al. (2022) Yes -
30 Support - Yi S et al. (2022) No Epilepsy/seizures
31 Support - Shimelis H et al. (2023) No -
32 Recent Recommendation - Aerden M et al. (2023) No ASD or autistic features, ADHD, epilepsy/seizures,
33 Support - Spataro N et al. (2023) No ADHD, autistic features
34 Support - Hu C et al. (2023) Yes -
35 Support - Sanchis-Juan A et al. (2023) No -
36 Support - Sheth F et al. (2023) Yes DD, ID
37 Support - Amerh S Alqahtani et al. (2023) No -
38 Support - Tamam Khalaf et al. (2024) No -
39 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (124)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 28251352 Zhang J , et al. (2017)
- - copy_number_loss Unknown - - 28251352 Zhang J , et al. (2017)
- - translocation De novo - - 27848077 Bramswig NC , et al. (2016)
- - copy_number_loss De novo - Simplex 24768552 Pinto D , et al. (2014)
- - copy_number_loss De novo - Simplex 36747006 Aerden M et al. (2023)
c.40C>T p.Arg14Ter stop_gained De novo - - 35741772 Hu C et al. (2022)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
c.2500-2A>T - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.3226+2T>C - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.5128+1G>T - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.5613+1del - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.334C>T p.Arg112Ter stop_gained De novo - - 27824329 Wang T , et al. (2016)
c.3887+1G>A - splice_site_variant De novo - - 28251352 Zhang J , et al. (2017)
c.64G>A p.Gly22Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1336G>T p.Glu446Ter stop_gained De novo - - 36747006 Aerden M et al. (2023)
c.1A>G p.Met1? initiator_codon_variant De novo - - 37007974 Hu C et al. (2023)
c.5947C>T p.Pro1983Ser missense_variant Unknown - - 34968013 Li D et al. (2022)
c.1408C>T p.Arg470Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1522G>A p.Glu508Lys missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1795C>T p.Arg599Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2026C>T p.Arg676Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2234C>T p.Thr745Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2834C>T p.Ala945Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2923G>A p.Val975Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2945C>A p.Ala982Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2991C>G p.Phe997Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3335C>T p.Ser1112Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3908G>T p.Ser1303Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5065C>T p.Arg1689Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5237G>A p.Arg1746His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5321G>A p.Arg1774His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3182A>T p.Asp1061Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3797T>C p.Leu1266Pro missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4936C>G p.Pro1646Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.5188G>A p.Glu1730Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.342G>A p.Val114%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Unknown Not maternal Simplex 36747006 Aerden M et al. (2023)
c.1054C>T p.Arg352Ter stop_gained Unknown - - 27848077 Bramswig NC , et al. (2016)
c.2282C>T p.Ala761Val missense_variant De novo - - 28251352 Zhang J , et al. (2017)
c.5746C>T p.Gln1916Ter stop_gained De novo - - 27479843 Lelieveld SH et al. (2016)
c.5920C>T p.Arg1974Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.2917+1G>A - splice_site_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.40C>T p.Arg14Ter stop_gained De novo - Simplex 36475376 Shimelis H et al. (2023)
c.1507C>T p.Leu503Phe stop_gained De novo - Simplex 36747006 Aerden M et al. (2023)
c.2683C>T p.Arg895Ter stop_gained De novo - Simplex 36747006 Aerden M et al. (2023)
c.3226+1G>C - splice_site_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.1790_1792del p.Leu597del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.3586C>T p.Gln1196Ter stop_gained De novo - Simplex 36747006 Aerden M et al. (2023)
c.5284-25A>G - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1258C>T p.Gln420Ter stop_gained Familial Paternal - 36747006 Aerden M et al. (2023)
c.2300C>T p.Ala767Val missense_variant De novo - - 27848077 Bramswig NC , et al. (2016)
c.1842G>A p.Gln614%3D synonymous_variant De novo - Simplex 36275919 Yi S et al. (2022)
c.1732-3_1732-1delinsTAT - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1685G>A p.Arg562Gln missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.1138C>T p.Arg380Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.4768G>C p.Asp1590His missense_variant De novo - - 27848077 Bramswig NC , et al. (2016)
c.5213T>C p.Leu1738Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5368G>A p.Val1790Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1952A>G p.Asn651Ser missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
c.314T>G p.Val105Gly missense_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.3175A>T p.Arg1059Ter splice_site_variant De novo - - 32424948 Donoghue T et al. (2020)
c.3050C>T p.Thr1017Ile missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.3125+1del - splice_site_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.4828G>A p.Gly1610Ser missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1195dup p.Ala399GlyfsTer4 frameshift_variant De novo - - 36747006 Aerden M et al. (2023)
c.3901C>T p.Leu1301Phe missense_variant Unknown - Simplex 36747006 Aerden M et al. (2023)
c.5687A>G p.Tyr1896Cys missense_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.5801C>G p.Pro1934Arg missense_variant De novo - Unknown 36747006 Aerden M et al. (2023)
c.3350G>A p.Gly1117Glu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.2980dup p.Ala994GlyfsTer29 frameshift_variant De novo - - 28251352 Zhang J , et al. (2017)
c.2707C>G p.Pro903Ala missense_variant De novo - Multiplex 36747006 Aerden M et al. (2023)
c.4421_4443del p.Tyr1474Ter frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.3050C>T p.Thr1017Ile missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.4678C>T p.Arg1560Ter stop_gained Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.543G>T p.Gly181%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.4813dup p.Trp1605LeufsTer4 frameshift_variant De novo - - 35813072 Krgovic D et al. (2022)
c.4784G>A p.Arg1595Gln missense_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.273dup p.Pro92ThrfsTer8 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.2875dup p.Gln959ProfsTer5 frameshift_variant De novo - Simplex 36275919 Yi S et al. (2022)
c.5503G>A p.Val1835Ile splice_site_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.5050del p.Ala1684ArgfsTer20 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
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.1441del p.Ser481ValfsTer53 frameshift_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.2527dup p.Ala843GlyfsTer7 splice_site_variant De novo - - 27848077 Bramswig NC , et al. (2016)
c.1863C>G p.Phe621Leu missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.2297G>A p.Arg766His missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.3446_3447del p.Val1149GlyfsTer7 frameshift_variant De novo - - 28251352 Zhang J , et al. (2017)
c.2065C>T p.Gln689Ter stop_gained Unknown Not maternal Simplex 36747006 Aerden M et al. (2023)
c.486del p.Gln162HisfsTer3 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.5696del p.Leu1899CysfsTer20 frameshift_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.3050C>T p.Thr1017Ile missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.5027T>C p.Leu1676Pro missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.3334G>A p.Gly1112Arg missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.1983del p.Gln662ArgfsTer6 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.2532del p.Gln845ArgfsTer7 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.273dup p.Asp92ArgfsTer16 frameshift_variant Familial Maternal - 36747006 Aerden M et al. (2023)
c.2702del p.Glu901GlyfsTer40 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.3370del p.Thr1124HisfsTer5 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.4628del p.Ser1543TyrfsTer2 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.5293del p.Ile1765SerfsTer6 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.586_587del p.Ser196PhefsTer10 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.14C>T p.Pro5Leu missense_variant Familial Maternal Simplex 27848077 Bramswig NC , et al. (2016)
c.3583del p.Leu1195PhefsTer23 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.5331dup p.Glu1778ArgfsTer11 frameshift_variant Unknown - Simplex 36747006 Aerden M et al. (2023)
c.2578del p.Ser860GlnfsTer13 frameshift_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.3691_3710del p.Glu1231SerfsTer23 frameshift_variant De novo - - 32424948 Donoghue T et al. (2020)
c.3356+1G>A p.Ala1061GlufsTer16 splice_site_variant De novo - - 27848077 Bramswig NC , et al. (2016)
NM_004238:c.1145-2A>C p.? splice_site_variant Unknown Not maternal - 28251352 Zhang J , et al. (2017)
c.1503_1511del p.Gln502_Gln504del inframe_deletion De novo - Simplex 36747006 Aerden M et al. (2023)
c.2982del p.Cys995ValfsTer42 splice_site_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.2363_2364del p.Lys788ArgfsTer7 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.3749_3750del p.Glu1250AlafsTer10 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.1896_1941del p.Ile632MetfsTer9 frameshift_variant De novo - Multiplex 36747006 Aerden M et al. (2023)
TAAAA>TAA - frameshift_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1462C>T p.Gln488Ter stop_gained De novo - Multiplex (monozygotic twins) 31398340 Ruzzo EK , et al. (2019)
c.3759_3760del p.Asp1254CysfsTer34 frameshift_variant De novo - Simplex 35887114 Levchenko O et al. (2022)
c.273dup p.Asp92ArgfsTer16 frameshift_variant Unknown Not maternal Simplex 36747006 Aerden M et al. (2023)
c.2378_2379insT p.Val794SerfsTer2 frameshift_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.3835C>T p.Gln1279Ter stop_gained De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.2682_2688del p.Asp894GlufsTer5 frameshift_variant De novo - Multiplex 37799141 Amerh S Alqahtani et al. (2023)
c.5913_5914insTCTCAATATGC p.Lys1972SerfsTer26 frameshift_variant De novo - Simplex 36747006 Aerden M et al. (2023)
c.5900C>G p.Thr1967Ser missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
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.

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."

10/1/2020
1
icon
1

Score remained at 1

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. Two additional de novo LoF variants in TRIP12 were identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
4/1/2020
1
icon
1

Score remained at 1

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. Two additional de novo LoF variants in TRIP12 were identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort.

Reports Added
[Novel de novo TRIP12 mutation reveals variable phenotypic presentation while emphasizing core features of TRIP12 variations2020]
1/1/2020
1
icon
1

Score remained at 1

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. Two additional de novo LoF variants in TRIP12 were identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort.

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [The E3 ubiquitin ligase TRIP12 participates in cell cycle progression and chromosome stability.2020] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
1S
icon
1

Score remained at 1

New Scoring Scheme
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. Two additional de novo LoF variants in TRIP12 were identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort.

Reports Added
[New Scoring Scheme]
7/1/2019
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. Two additional de novo LoF variants in TRIP12 were identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2019
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. Two additional de novo LoF variants in TRIP12 were identified in ASD probands from a cohort of 262 Japanese trios in Takata et al., 2018; TADA-Denovo analysis demonstrated that this gene was significantly enriched for damaging de novo mutations in the Japanese ASD cohort, as well as in a combined dataset consisting of previously published cohorts from the Simons Simplex Collection and the Autism Sequencing Consortium in addition to the Japanese ASD cohort.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
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.

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
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.

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech ...2017]
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).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without au...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).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
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).

Reports Added
[Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.2012] [De novo gene disruptions in children on the autistic spectrum.2012] [A discovery resource of rare copy number variations in individuals with autism spectrum disorder.2013] [Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.2014] [Recurrent de novo mutations implicate novel genes underlying simplex autism risk.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
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).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
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).

Reports Added
[Recurrent de novo mutations implicate novel genes underlying simplex autism risk.2014]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
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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