title: A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon.
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.
authors: Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
authors: D
authors: D
authors: Macaya
authors: S H
authors: SH
authors: Katsanis
authors: T W
authors: TW
authors: Hefferon
authors: S
authors: S
authors: Audlin
authors: N J
authors: NJ
authors: Mendelsohn
authors: J
authors: J
authors: Roggenbuck
authors: G R
authors: GR
authors: Cutting
mesh_terms: D004742:Enhancer Elements, Genetic / Q000235:genetics; D005091:Exons / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010750:Phosphoproteins / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics*; D035781:Siblings
chemical_list: D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human