ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
11462173 van Bokhoven et al. (2001) describe TP63 mutations in a series of 43 individuals with EEC syndrome, 35 individuals with isolated SHFM, and three families with LMS. Three frameshift mutations were detected; one in an individual diagnosed with EEC, and the other two in individuals with features more consistent with LMS. All three frameshift mutations affect only the p63? isotypes, which have dominant-negative effects on transactivation, whereas the ? and ? isotypes may be normally produced. The two frameshift mutations in exon 13 are predicted to yield similar protein products with premature truncations in the SAM domain, whereas the frameshift in exon 14 does not affect the SAM domain. From the manuscript: A single nonsense mutation was reported in an individual with isolated SHFM (Q634X), "as [was] a mutation in the 3? splice site in intron 4. This splice-site mutation is likely to give rise to alternative splicing rather than to skipping of exon 5, because the latter is likely to be a loss-of-function event. Three nucleotides in front of the normal 3? splice site is a potential splice-acceptor site (fig. 2). Use of this alternative site would lead to insertion of a proline amino acid at position 233 in the DNA-binding domain. Indeed, this alternative splicing route was used for this mutation in an exon-trapping assay (fig. 2). Although unlikely, we cannot formally exclude the possibility that this mutation generates a haploinsufficiency in the patient." The authors pose that haploinsufficiency of TP63 is not believed to cause features of EEC, as a previously reported individual (Chitayat et al. 1996) with a terminal 3q27 deletion did not have features of the syndrome; these authors performed FISH on a sample from this individual to confirm the absence of TP63.

Haploinsufficiency phenotype comments:

Heterozygous TP63 mutations are associated with ADULT syndrome (103285), Ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome 3 (604292), Hay-Wells syndrome (106260), Limb-mammary syndrome (603543), Orofacial cleft 8 (129400), Rapp-Hodgkin syndrome (129400), and Split-hand/foot malformation 4 (605289). The majority of mutations reported to date are missense mutations; the mechanisms by which these mutations result in these different phenotypes is not well understood. Brunner et al. (PMID:12070241) propose a "partial loss of function in combination with dominant gain or change of function defects." Deletions/duplications of TP63 have not been reported in patient populations. Additionally, DGV has a number of relatively small CNVs that reside within the first intron of TP63.

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