ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
Evidence for haploinsufficiency phenotype
PubMed ID Description
16251895 Kress et al. (2006) described nine Saethre?Chotzen syndrome patients with confirmed de novo TWIST1 nonsense / frameshift mutations. Other additional seven patients with TWIST1 LoF mutations were described but de novo origin could not be confirmed, as at least one of the parents was not available for molecular testing. They also described three patients with confirmed de novo TWIST1 entire gene deletion but only one of those patients with an exclusively TWIST1 deletion with other genes as FERD3L or HDAC9. The authors also described several families with TWIST1 mutations and Saethre?Chotzen syndrome to mild nonsyndromic phenotypes. Therefore, the authors wrote "Since different mutations like missense mutations, nonsense mutations, insertions, and whole-gene deletions result in similar phenotypes, haploinsufficiency is the likely disease causing mechanism."
15923834 de Heer et al. (2005) described a total of 34 patients with Saethre?Chotzen syndrome. Four of those patients had TWIST1 LoF confirmed de novo mutations. They also described missense mutations and two families with TWIST1 mutations but insufficient segregation data. All described patient had similar clinical phenotype excepting those with large deletions containing TWIST1 and other genes.
22544111 In a korean coronal synostosis study including 43 patients, Ko et al. (2012) described three patients with Saethre? Chotzen syndrome and TWIST1 confirmed de novo mutations (one missense, one nonsense and one frameshift deletion).

Haploinsufficiency phenotype comments:

Whole gene deletions, as well as intragenic mutations of TWIST1, are known to cause the Saethre-Chotzen syndrome by a pathogenic mechanism of haploinsufficiency. See GeneReviews for relevant primary literature and review: Additional Evidence: PMID: 24127277 Roscioli et al. (2013) described an australian craniosynostosis cohort with 630 patients with more than 20 patients with Saethre?Chotzen syndrome and TWIST1 nonsense mutations including five novel nonsense TWIST1 mutations. No segregation or inheritance information has been described by the authors as only patients with craniosynostosis underwent genetic analysis. Functional Studies: Twist1+/? mutant mice exhibit a brachycephalic skull consistent with the involvement of the coronal suture in craniofacial dysmorphism similar to Saethre-Chotzen syndrome (PMID: 24585549).

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