ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000015.9) (NC_000015.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23354436 Sharma et al. (2013) report 38 heterozygous TCF12 mutations in 347 samples from unrelated individuals with coronal or multisuture (including coronal) craniosynostosis, including 14 nonsense, 15 frameshift, 7 splicing and 2 missense changes. The authors report that "in cases with frameshift or splice site mutations, analyses of mRNA extracted from various cell types demonstrated relative under-expression of the mutant compared to the wild-type allele, consistent with nonsense-mediated decay leading to haploinsufficiency." Of 36 families with additional family members available for testing, 14 TCF12 variants were found to be de novo, and 22 were found to be inherited. Of the 34 additional family members found to carry TCF12 variants, only 16 were considered affected, suggesting a high rate of non-penetrance (47%).
25271085 Paumard-Hern?ndez et al. (2014) screened for variants in common craniosynostosis genes (FGFR2, FGFR3, FGFR1, TWIST1 and EFNB1) in a cohort of 182 Spanish individuals with craniosynostosis, identifying variants in 113. The authors then screened for mutations in TCF12 in the remaining 69 individual, identifying 5 variants (4 novel, 1 previously reported in Sharma et al. (2013)). The previously reported variant, p.Ser281*, was found to be de novo in the individual in this cohort. Of the remaining 4 variants, the authors report that 3 are "clearly pathogenic" and 1 is of "uncertain significance." The three "clearly pathogenic" variants are all predicted to result in premature truncation of the protein. A minigene assay was performed for one of the variants to determine its effects on splicing. The authors state: "The de novo splice site alteration, TCF12 variant c.826-2A4G, identified in proband 3, affects one of the two highly conserved splice site nucleotides in the intron 10 splice site acceptor. A minigene assay confirmed experimentally the predicted splicing effects of the TCF12 variant c.826-2A4G: the mutation had a dual effect on splicing, leading to exon 11 skipping and also generating an alternative transcript with the recognition of a cryptic acceptor site (c.826_827del), leading to the premature termination(p.Ser276-Leufs*61). In both events, the mutant transcripts are predicted to be non-functional as they either affect the activation domain 2 of TCF12 or result in a prematurely truncated protein, which may be degraded by nonsense mediated decay." In both families in which a TCF12 variant was known to be inherited, incomplete penetrance was observed. The authors note that the p.Leu507Arg variant classified as being of uncertain significance was "absent in 400 Spanish healthy controls but present in 11/2184 (MAF=0.005) European Americans in the EVS database. As the EVS population has not been excluded for craniosynostosis and incomplete penetrance is a common phenomenon, functional analysis will be required to definitely determine the pathogenicity of this variant."

Haploinsufficiency phenotype comments:

Several large deletions of 15q21.3 that include TCF12 in addition to other genes have been reported in patients with craniosynostosis. For example, Le Tanno et al. (2014) (PMID: 24648389) report a 33-month-old male with coronal craniosynostosis, developmental delay, and dysmorphic features, and a 3.64Mb de novo deletion of 15q21.3q22.2 in the context of a maternally inherited translocation between chromosomes 2 and 15 (t(2;15)(q21;q21.3). See also PMIDs 2368808, 18449934.

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