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A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis‐splicing of a constitutive exon
Author(s) -
Macaya D.,
Katsanis S.H.,
Hefferon T.W.,
Audlin S.,
Mendelsohn N.J.,
Roggenbuck J.,
Cutting G.R.
Publication year - 2009
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.32834
Subject(s) - haploinsufficiency , treacher collins syndrome , exon , genetics , mutation , biology , sequence (biology) , gene , rna splicing , phenotype , rna , craniofacial
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. © 2009 Wiley‐Liss, Inc.