ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
22495309 In O?Roak et al.'s (2012) article "Multiplex Targeted Sequencing Identifies Recurrently Mutated Genes in Autism Spectrum Disorders" they used used molecular inversion probe. They found 44 ASD candidate genes in 2446 probands from the Simons Simplex Collection. TBL1XR1 had a borderline significant mutation burden in this cohort. There was one de novo frameshift in TBL1XR1 in a male with autism. It is important to note that there was de novo missense (p.Leu282Pro) also reported by O'Rouk et al for this gene; that patient did not appear to have Pierpont syndrome, just ID.
25425123 Pons et al (2014) A New Syndrome of Intellectual Disability with Dysmorphism Due to TBL1XR1 Deletion Case study. CMA. 708kb deletion of TBL1XR1 alone in child and mother, both affected by mild to moderate ID and facial dysmorphism. De novo in mother.
26740553 Laskowski et al (2016) Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain. Study of mainly missense cases in Decipher but includes one de novo indel frameshift. Current Decipher (public access, March 2019) lists: 6 ID/DD cases (DecipherID's: 260965, 262871, 273964, 277213, 302011, 305000) with de novo LOF in TBL1XR1 (4 LOF indels, 1 stop, 1 canonical splice site). Also, 1 neonate (DecipherID 307444) with de novo LOF in TBL1XR1 (indels), too young to assess for ID (small, dysmorphic)

Haploinsufficiency phenotype comments:

Additional papers: Tabet et al (2014) describe a de novo 1.6Mb deletion of TBL1XR1 + last coding exon of NAALADL2 in girl with non-specific, mild to moderate intellectual deficiency but no autistic behavior. Vaqueiro et al (2017) deletion of TBL1XR1 in a girl with ID, cardiac & brain malformations but family studies incomplete (mum does not carry the del but dad not tested). Other evidence: HI predictors: gnomad pLI 1, Decipher HI 6.87 No LOF in gnomad, no LOF in DGV gold (some UTR dels in DGV gold) Gene is already associated with disease (Pierpont syndrome). Overall, there are appears to be sufficient evidence for a haploinsufficiency score of 3.

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
28574232 Riehmer et al (2017) A heritable microduplication encompassing TBL1XR1 causes a genomic sister-disorder for the 3q26.32 microdeletion syndrome. Case study, CMA, four patients from two unrelated non?consanguineous families with intellectual disability carrying duplications of TBL1XR1 only and showing similar phenotypic features as the previously described patients with a TBL1XR1 deletion. The two familial dups are slightly different. No other CNVs detected. In one family, the dup is de novo. In second family, dup inherited from affected mother and also present in an affect half-sib, and not in an unaffected half-sib.

Triplosensitivity phenotype comment:

One de novo duplication One other family but not enough segregations (2) to be counted as evidence.