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Genetic diagnosis impacts medical management for pediatric epilepsies

  • Author Footnotes
    ∗ These authors contributed equally to the manuscript.
    Isabel Haviland
    Footnotes
    ∗ These authors contributed equally to the manuscript.
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
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  • Author Footnotes
    ∗ These authors contributed equally to the manuscript.
    Carolyn I. Daniels
    Footnotes
    ∗ These authors contributed equally to the manuscript.
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
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  • Author Footnotes
    ∗ These authors contributed equally to the manuscript.
    Caitlin A. Greene
    Footnotes
    ∗ These authors contributed equally to the manuscript.
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
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  • Jacqueline Drew
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Boston University Clinical Investigation Master’s Program, Boston, MA, USA
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  • Jamie A. Love-Nichols
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Department of Genetics, Seattle Children’s Hospital, Seattle, WA, USA
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  • Lindsay C. Swanson
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
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  • Lacey Smith
    Affiliations
    Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
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  • Duyu A. Nie
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Departments of Pediatrics, Neurology and Neurosurgery, Warren Alpert Medical School of Brown University, Providence, RI, USA

    Division of Pediatric Neurology and the Children's Neurodevelopment Center (CNDC), Hasbro Children’s Hospital, Providence, RI, USA
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  • Timothy Benke
    Affiliations
    Children’s Hospital Colorado, University of Colorado School of Medicine Departments of Pediatrics, Neurology, Pharmacology, and Otolaryngology, Aurora, Colorado, USA
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  • Beth R. Sheidley
    Affiliations
    Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
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  • Bo Zhang
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
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  • Author Footnotes
    # These authors contributed equally to the manuscript.
    Annapurna Poduri
    Footnotes
    # These authors contributed equally to the manuscript.
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
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  • Author Footnotes
    # These authors contributed equally to the manuscript.
    Heather E. Olson
    Correspondence
    Corresponding author: Heather Olson, MD, MS, Boston Children’s Hospital Peabody, 10 Centennial Dr., Peabody, MA 01960, Phone: 617-355-7970, Fax: 617-730-4850
    Footnotes
    # These authors contributed equally to the manuscript.
    Affiliations
    Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

    Division of Epilepsy and Clinical Neurophysiology and Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to the manuscript.
    # These authors contributed equally to the manuscript.

      Highlights

      • Genetic sequencing leads to precision diagnosis in pediatric epilepsy
      • Abnormal muscle tone predicts diagnosis by exome even after negative gene panel
      • Medical management was impacted in 72% of participants with genetic diagnosis
      • Medical management was impacted regardless of age of epilepsy onset
      • Medical management was impacted even with neurotypical development

      Abstract

      Objective

      To determine the impact of genetic diagnosis on medical management in a cohort of individuals with epilepsy.

      Methods

      We performed detailed phenotyping of individuals with epilepsy who underwent clinical genetic testing with an epilepsy panel and/or exome sequencing at Boston Children’s Hospital between June 2012 and January 2019. We assessed the impact of genetic diagnosis on medical management.

      Results

      We identified a genetic etiology in 152/602 (25%) individuals with infantile or childhood-onset epilepsy who underwent next-generation sequencing (46% F, median age of onset 6 months [IQR 2-15 months]). Diagnosis impacted medical management in at least one category for 72% of patients (110/152), and in more than one category in 34% (51/152). Treatment was impacted in 45% of individuals, including 36% with impact on anti-seizure medication choice, 7% on use of disease-specific vitamin or metabolic treatments, 3% on pathway-driven off-label use of medications, and 10% on discussion of gene-specific clinical trials. Care coordination was impacted in 48% of individuals, including surveillance for disease-associated features, disease-specific diagnostic testing, and specialist referrals or multi-disciplinary clinics. Counseling on a change in prognosis was reported in 28% of individuals, and 1% of individuals had a correction of diagnosis. Impact was documented in 13/13 individuals with neurotypical development and 55% of those with epilepsy onset >2 years.

      Interpretation

      We demonstrated meaningful impact of genetic diagnosis on medical care and prognosis in over 70% of cases, including individuals with neurotypical development and age of epilepsy onset >2 years.

      Keywords

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