A synonymous mutation in TCOF1 causes treacher collins syndrome due to mis-splicing of a constitutive exon

D. Macaya, Sara Katsanis, T. W. Hefferon, S. Audlin, N. J. Mendelsohn, J. Roggenbuck, G. R. Cutting

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1624-1627
Number of pages4
JournalAmerican Journal of Medical Genetics, Part A
Volume149
Issue number8
DOIs
StatePublished - Aug 1 2009

Keywords

  • Clinical molecular diagnostics
  • Exonic splice enhancer
  • Mandibulofacial dysostosis
  • RNA splicing
  • Silent mutation
  • TCOF1 protein

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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