A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon.


Journal Article

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.

Full Text

Cited Authors

  • Macaya, D; Katsanis, SH; Hefferon, TW; Audlin, S; Mendelsohn, NJ; Roggenbuck, J; Cutting, GR

Published Date

  • August 2009

Published In

Volume / Issue

  • 149A / 8

Start / End Page

  • 1624 - 1627

PubMed ID

  • 19572402

Pubmed Central ID

  • 19572402

Electronic International Standard Serial Number (EISSN)

  • 1552-4833

International Standard Serial Number (ISSN)

  • 1552-4825

Digital Object Identifier (DOI)

  • 10.1002/ajmg.a.32834


  • eng