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X-linked CHARGE-like Abruzzo–Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations
Version of Record online: 7 AUG 2012
© 2012 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd
Volume 83, Issue 4, pages 352–358, April 2013
How to Cite
X-linked CHARGE-like Abruzzo–Erickson syndrome and classic cleft palate with ankyloglossia result from TBX22 splicing mutations, , , , , , , , , , .
- Issue online: 12 MAR 2013
- Version of Record online: 7 AUG 2012
- Accepted manuscript online: 11 JUL 2012 12:44PM EST
- Manuscript Revised: 4 JUL 2012
- Manuscript Accepted: 4 JUL 2012
- Manuscript Received: 2 APR 2012
- Holsclaw Family Professorship
- Great Ormond Street Hospital Children's Charity
- CHARGE syndrome;
- cleft palate;
- mRNA splicing;
X-linked cleft palate (CPX) is caused by mutations in the gene encoding the TBX22 transcription factor and is known to exhibit phenotypic variability, usually involving either a complete, partial or submucous cleft palate, with or without ankyloglossia. This study hypothesized a possible involvement of TBX22 in a family with X-linked, CHARGE-like Abruzzo–Erickson syndrome, of unknown etiology. The phenotype extends to additional features including sensorineural deafness and coloboma, which are suggested by the Tbx22 developmental expression pattern but not previously associated in CPX patients. A novel TBX22 splice acceptor mutation (c.593−5T>A) was identified that tracked with the phenotype in this family. A novel splice donor variant (c.767+5G>A) and a known canonical splice donor mutation (c.767+1G>A) affecting the same exon were identified in patients with classic CPX phenotypes and were comparatively analyzed using both in silico and in vitro splicing studies. All three variants were predicted to abolish normal mRNA splicing and an in vitro assay indicated that use of alternative splice sites was a likely outcome. Collectively, the data showed the functional effect of several novel intronic splice site variants but most importantly confirms that TBX22 is the gene underlying Abruzzo–Erickson syndrome, expanding the phenotypic spectrum of TBX22 mutations.