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. 1998 Nov;63(5):1282–1293. doi: 10.1086/302122

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

D Johnson 1, S W Horsley 1, D M Moloney 1, M Oldridge 1, S R Twigg 1, S Walsh 1, M Barrow 1, P R Njølstad 1, J Kunz 1, G J Ashworth 1, S A Wall 1, L Kearney 1, A O Wilkie 1
PMCID: PMC1377539  PMID: 9792856

Abstract

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.

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Selected References

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