Disruption of TWIST1 translation by 5' UTR variants in Saethre-Chotzen syndrome

Yan Zhou, Nils Koelling, Aimée L Fenwick, Simon J McGowan, Eduardo Calpena, Steven A Wall, Sarah F Smithson, Andrew O M Wilkie, Stephen R F Twigg

Research output: Contribution to journalArticle (Academic Journal)peer-review

2 Citations (Scopus)
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Saethre-Chotzen syndrome (SCS), one of the most common forms of syndromic craniosynostosis (premature fusion of the cranial sutures), results from haploinsufficiency of TWIST1, caused by deletions of the entire gene or loss-of-function variants within the coding region. To determine whether non-coding variants also contribute to SCS, we screened 14 genetically undiagnosed SCS patients using targeted capture sequencing, and identified novel single nucleotide variants (SNVs) in the 5' untranslated region (UTR) of TWIST1 in two unrelated SCS cases. We show experimentally that these variants, which create translation start sites in the TWIST1 leader sequence, reduce translation from the main open reading frame (mORF). This is the first demonstration that non-coding SNVs of TWIST1 can cause SCS, and highlights the importance of screening the 5' UTR in clinically diagnosed SCS patients without a coding mutation. Similar 5' UTR variants, particularly of haploinsufficient genes, may represent an under-ascertained cause of monogenic disease.

Original languageEnglish
Pages (from-to)1360-1365
Number of pages6
JournalHuman Mutation
Issue number10
Early online date24 Jul 2018
Publication statusPublished - Oct 2018


  • haploinsufficiency
  • Saethre-Chotzen syndrome (SCS)
  • TWIST1
  • upstream AUG (uAUG)
  • upstream open reading frame (uORF)

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