Identification of genomic deletions spanning the PCDH19 gene in two unrelated girls with intellectual disability and seizures

Authors

  • AK Vincent,

    1. Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    2. Division of Urology, Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
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    • These authors contributed equally to this work.

  • A Noor,

    1. Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
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    • These authors contributed equally to this work.

  • A Janson,

    1. The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, Ontario, Canada
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  • BA Minassian,

    1. Program in Genetics and Genomic Biology
    2. Division of Neurology, Department of Paediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
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  • M Ayub,

    1. Tees, Esk and Wear Valleys NHS Foundation Trust, Darlington, UK
    2. School for Health and Medicine, University of Durham, Stockton-On-Tees, UK
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  • JB Vincent,

    Corresponding author
    1. Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    2. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
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  • CF Morel

    1. The Fred A. Litwin Family Centre in Genetic Medicine, University Health Network, Toronto, Ontario, Canada
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Dr John B. Vincent, Neurogenetics Section, R-30, Centre for Addiction and Mental Health, 250 College Street, Toronto, ON M5T 1R8, Canada.
Tel.: +1 416 535 8501x6487;
fax: +1 416 979 4666;
e-mail: john_vincent@camh.net

Abstract

Vincent AK, Noor A, Janson A, Minassian BA, Ayub M, Vincent JB, Morel CF. Identification of genomic deletions spanning the PCDH19 gene in two unrelated girls with intellectual disability and seizures.

Recently, missense and truncating mutations in the gene PCDH19 have been reported to cause female-restricted epilepsy with mental retardation (EFMR). EFMR (MIM#300088) is an X-linked disorder characterized by early onset seizures and intellectual disability (ID). Interestingly, unlike typical X-linked mode of inheritance, the phenotype is restricted to females, and males are unaffected carriers. PCDH19 is highly expressed in brain, and the encoded protein belongs to the cadherin superfamily. Here we report two unrelated female patients with deletions spanning PCDH19 identified by copy number variation (CNV) analysis and validated by qPCR. In one, we have identified a 3 Mb interstitial deletion at Xq21.33-q22.1 which spans PCDH19, LOC442459 & TNMD. This patient had her first seizure at 8 months old, and also has ID and aggressive behavior. In another female patient we identified a de novo 603 kb heterozygous deletion in a female patient with fits (since 1 year of age), ID, hyperactivity and aggressive behavior. The deletion spans the entire PCDH19 gene (also TNMD, SRPX2, TSPAN6 and SYTL4). In conclusion, our results suggest that deletions at PCDH19 also cause EFMR.

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