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

Authors

  • D. Macaya,

    1. DNA Diagnostic Laboratory, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
    Current affiliation:
    1. Molecular Genetics Laboratory, National Children's Hospital, San José, Costa Rica.
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  • S.H. Katsanis,

    1. DNA Diagnostic Laboratory, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
    Current affiliation:
    1. Genetics and Public Policy Center, Berman Institute of Bioethics, Johns Hopkins University, Washington, DC 20036.
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  • T.W. Hefferon,

    1. Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland
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  • S. Audlin,

    1. DNA Diagnostic Laboratory, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
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  • N.J. Mendelsohn,

    1. Children's Hospitals & Clinics of Minnesota, Minneapolis, Minnesota
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  • J. Roggenbuck,

    1. Children's Hospitals & Clinics of Minnesota, Minneapolis, Minnesota
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  • G.R. Cutting

    Corresponding author
    1. DNA Diagnostic Laboratory, Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland
    • Johns Hopkins University School of Medicine, The McKusick-Nathans Institute of Genetic Medicine, 733 N. Broadway, Broadway Research Building, 559, Baltimore, MD.

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  • How to cite this article: Macaya D, Katsanis SH, Hefferon TW, Audlin S, Mendelsohn NJ, Roggenbuck J, Cutting GR. 2009. A synonymous mutation in TCOF1 causes Treacher Collins syndrome due to mis-splicing of a constitutive exon. Am J Med Genet Part A 149A:1624–1627.

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. © 2009 Wiley-Liss, Inc.

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