Identification of the first non-Jewish mutation in familial Dysautonomia

Authors

  • Maire Leyne,

    1. Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts
    2. Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts
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  • James Mull,

    1. Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts
    2. Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts
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  • Sandra P. Gill,

    1. Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts
    2. Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts
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  • Math P. Cuajungco,

    1. Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts
    2. Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts
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  • Carole Oddoux,

    1. Human Genetics Program, Department of Pediatrics, New York University Medical Center, New York, New York
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  • Anat Blumenfeld,

    1. Department of Ophthalmology, Hadassah University Hospital, Jerusalem, Israel
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  • Channa Maayan,

    1. Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel
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  • James F. Gusella,

    1. Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts
    2. Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts
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  • Felicia B. Axelrod,

    1. Department of Pediatrics, New York University Medical School, New York, New York
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  • Susan A. Slaugenhaupt

    Corresponding author
    1. Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts
    2. Harvard Institute of Human Genetics, Harvard Medical School, Boston, Massachusetts
    • HIM Building Room 422, 4 Blackfan Circle, Boston, MA 02115.
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Abstract

Familial Dysautonomia is an autosomal recessive disease with a remarkably high carrier frequency in the Ashkenazi Jewish population. It has recently been estimated that as many as 1 in 27 Ashkenazi Jews is a carrier of FD. The FD gene has been identified as IKBKAP, and two disease-causing mutations have been identified. The most common mutation, which is present on 99.5% of all FD chromosomes, is an intronic splice site mutation that results in tissue-specific skipping of exon 20. The second mutation, R696P, is a missense mutation that has been identified in 4 unrelated patients heterozygous for the major splice mutation. Interestingly, despite the fact that FD is a recessive disease, normal mRNA and protein are expressed in patient cells. To date, the diagnosis of FD has been limited to individuals of Ashkenazi Jewish descent and identification of the gene has led to widespread diagnostic and carrier testing in this population. In this report, we describe the first non-Jewish IKBKAP mutation, a proline to leucine missense mutation in exon 26, P914L. This mutation is of particular significance because it was identified in a patient who lacks one of the cardinal diagnostic criteria for the disease–pure Ashkenazi Jewish ancestry. In light of this fact, the diagnostic criteria for FD must be expanded. Furthermore, in order to ensure carrier identification in all ethnicities, this mutation must now be considered when screening for FD. © 2003 Wiley-Liss, Inc.

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