ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000002.11) (NC_000002.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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
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.

Haploinsufficiency phenotype 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 score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There is currently no literature regarding isolated whole gene duplication.