A comprehensive screen for TWIST mutations in patients with craniosynostosis identifies a new microdeletion syndrome of chromosome band 7p21.1.
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.
Johnson
D
D
Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, OX 9DS, UK.
Horsley
S W
SW
Moloney
D M
DM
Oldridge
M
M
Twigg
S R
SR
Walsh
S
S
Barrow
M
M
Njølstad
P R
PR
Kunz
J
J
Ashworth
G J
GJ
Wall
S A
SA
Kearney
L
L
Wilkie
A O
AO
D000168:Acrocephalosyndactylia / Q000175:diagnosis / Q000235:genetics*; D002871:Chromosome Banding; D002874:Chromosome Mapping; D002897:Chromosomes, Human, Pair 7; D003398:Craniosynostoses / Q000175:diagnosis / Q000235:genetics*; D017931:DNA Primers; D005260:Female; D005819:Genetic Markers; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D007621:Karyotyping; D008297:Male; D008403:Mass Screening; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction; D017384:Sequence Deletion; D014157:Transcription Factors / Q000235:genetics*; D051879:Twist-Related Protein 1
D017931:DNA Primers; D005819:Genetic Markers; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1