A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1

Am J Hum Genet. 1998 Nov;63(5):1282-93. doi: 10.1086/302122.


Mutations in the coding region of the TWIST gene (encoding a basic helix-loop-helix transcription factor) have been identified in some cases of Saethre-Chotzen syndrome. Haploinsufficiency appears to be the pathogenic mechanism involved. To investigate the possibility that complete deletions of the TWIST gene also contribute to this disorder, we have developed a comprehensive strategy to screen for coding-region mutations and for complete gene deletions. Heterozygous TWIST mutations were identified in 8 of 10 patients with Saethre-Chotzen syndrome and in 2 of 43 craniosynostosis patients with no clear diagnosis. In addition to six coding-region mutations, our strategy revealed four complete TWIST deletions, only one of which associated with a translocation was suspected on the basis of conventional cytogenetic analysis. This case and two interstitial deletions were detectable by analysis of polymorphic microsatellite loci, including a novel (CA)n locus 7.9 kb away from TWIST, combined with FISH; these deletions ranged in size from 3.5 Mb to >11.6 Mb. The remaining, much smaller deletion was detected by Southern blot analysis and removed 2,924 bp, with a 2-bp orphan sequence at the breakpoint. Significant learning difficulties were present in the three patients with megabase-sized deletions, which suggests that haploinsufficiency of genes neighboring TWIST contributes to developmental delay. Our results identify a new microdeletion disorder that maps to chromosome band 7p21.1 and that causes a significant proportion of Saethre-Chotzen syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acrocephalosyndactylia / diagnosis
  • Acrocephalosyndactylia / genetics*
  • Chromosome Banding
  • Chromosome Mapping
  • Chromosomes, Human, Pair 7*
  • Craniosynostoses / diagnosis
  • Craniosynostoses / genetics*
  • DNA Primers
  • Female
  • Genetic Markers
  • Helix-Loop-Helix Motifs
  • Humans
  • Karyotyping
  • Male
  • Mass Screening
  • Molecular Sequence Data
  • Nuclear Proteins*
  • Polymerase Chain Reaction
  • Sequence Deletion*
  • Transcription Factors / genetics*
  • Twist-Related Protein 1


  • DNA Primers
  • Genetic Markers
  • Nuclear Proteins
  • TWIST1 protein, human
  • Transcription Factors
  • Twist-Related Protein 1

Associated data

  • GENBANK/U80998
  • GENBANK/Y10871