How to cite this article: Macaya D, Katsanis SH, Hefferon TW, Audlin S, Mendelsohn NJ, Roggenbuck J, Cutting GR. 2009. A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon. Am J Med Genet Part A 149A:1624–1627.
A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon†
Article first published online: 1 JUL 2009
Copyright © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A
Volume 149A, Issue 8, pages 1624–1627, August 2009
How to Cite
Macaya, D., Katsanis, S.H., Hefferon, T.W., Audlin, S., Mendelsohn, N.J., Roggenbuck, J. and Cutting, G.R. (2009), A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon. Am. J. Med. Genet., 149A: 1624–1627. doi: 10.1002/ajmg.a.32834
- Issue published online: 23 JUL 2009
- Article first published online: 1 JUL 2009
- Manuscript Accepted: 25 FEB 2009
- Manuscript Received: 26 SEP 2008
- mandibulofacial dysostosis;
- TCOF1 protein;
- RNA splicing;
- silent mutation;
- exonic splice enhancer;
- clinical molecular diagnostics
Interpretation of the pathogenicity of sequence alterations in disease-associated genes is challenging. This is especially true for novel alterations that lack obvious functional consequences. We report here on a patient with Treacher Collins syndrome (TCS) found to carry a previously reported mutation, c.122C > T, which predicts p.A41V, and a novel synonymous mutation, c.3612A > C. Pedigree analysis showed that the c.122C > T mutation segregated with normal phenotypes in multiple family members while the c.3612A > C was de novo in the patient. Analysis of TCOF1 RNA in lymphocytes showed a transcript missing exon 22. These results show that TCS in the patient is due to haploinsufficiency of TCOF1 caused by the synonymous de novo c.3612A > C mutation. This study highlights the importance of clinical and pedigree evaluation in the interpretation of known and novel sequence alterations. © 2009 Wiley-Liss, Inc.