A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon.
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.
Macaya
D
D
Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Katsanis
S H
SH
Hefferon
T W
TW
Audlin
S
S
Mendelsohn
N J
NJ
Roggenbuck
J
J
Cutting
G R
GR
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
D009687:Nuclear Proteins; D010750:Phosphoproteins; C105442:TCOF1 protein, human