TRIP12

Gene Facts

• HGNC Symbol: TRIP12 (HGNC:12306)
• HGNC Name: thyroid hormone receptor interactor 12
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: KIAA0045, ULF, TRIPC
• %HI: 3.78
• pLI: 1
• LOEUF: 0.15
• Cytoband: 2q36.3
• Genomic Coordinates:

  GRCh37/hg19:	chr2:230628553-230787902
  GRCh38/hg38:	chr2:229763837-229923186

• MANE Select Transcript: NM_001348323.3 ENST00000675903.1
• Function: E3 ubiquitin-protein ligase involved in ubiquitin fusion degradation (UFD) pathway and regulation of DNA repair (PubMed:19028681, PubMed:22884692). Part of the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination of protein at their N-terminus, regardless of the presence of lysine residues in target proteins (PubMed:19028681). Acts as a key regulator of DNA damage response by acting as a suppressor of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-6772
• ClinGen Curation ID: CCID:008045
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 04/02/2018

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Clark-Baraitser syndrome

HI Evidence

• PUBMED: 27848077
  Bramswig et al [2017] present "seven individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene" and review the clinical findings of four previously published individuals. Eleven of 12 subjects demonstrated intellectual disability and 8/12 had autism. With the exception of subject 6, all mutations were de novo. There is no clinical information provided for the maternal carrier of subject 6. The authors propose haploinsufficiency as the mechanism for disease. Previously published individuals are found in: Iossifov I et al (2014) The contribution of de novo coding mutations to autism spectrum disorder. Nature 515:216–221. doi:10.1038/nature13908 Lelieveld SH et al (2016) Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat Neurosci. doi:10.1038/nn.4352 O’Roak BJ et al (2014) Recurrent de novo mutations implicate novel genes underlying simplex autism risk Nat Commun 5:5595. doi:10.1038/ncomms6595
• PUBMED: 28251352
  Zhang et al [2017] identified five "deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families" with deletions. Subject 8 of this study was also enrolled in the Bramswig study. The cohort in Zhang demonstrated severe language impairment, mildly dysmorphic features, and four demonstrated obesity. The authors note that two subjects in Bramswig were also obese. The deletions in subjects 1-3 are isolated to TRIP12, while deletions in subjects 4 and 5 spanned the entire gene and included other genes.

• HI Evidence Comments: Oikonomakis [2016, PMID: 26777411] studied a cohort of individuals with autism and found one subject with a partial duplication of TRIP12. There is no information provided for inheritance or whether the duplication disrupts the gene function. Based on the number of subjects reported in multiple studies that are all reviewed in Bramswig, deletion of this interval is currently assigned a haploinsufficiency score of 3.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: There is currently no literature regarding isolated whole gene duplication.