A Synonymous Mutation in TCOF1 Causes Treacher Collins Syndrome Due to Mis-Splicing of a Constitutive Exon

作者：Macaya D; Katsanis S H; Hefferon T W; Audlin S; Mendelsohn N J; Roggenbuck J; Cutting G R^*

来源：American Journal of Medical Genetics, Part A, 2009, 149A(8): 1624-1627.

DOI：10.1002/ajmg.a.32834

• 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.

• 出版日期2009-8
• 单位河北医科大学