Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy

Authors

  • Annapurna Poduri,

    1. Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
    2. Harvard Medical School, Boston, Massachusetts, U.S.A.
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    • These authors contributed equally to the manuscript.

  • Sameer S. Chopra,

    1. Harvard Medical School, Boston, Massachusetts, U.S.A.
    2. Department of Internal Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, U.S.A.
    3. Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
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    • These authors contributed equally to the manuscript.

  • Edward G. Neilan,

    1. Harvard Medical School, Boston, Massachusetts, U.S.A.
    2. Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
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  • P. Christina Elhosary,

    1. Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
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  • Manju A. Kurian,

    1. Neurosciences Unit, Institute of Child Health, University College London, London, United Kingdom
    2. Department of Neurology, Great Ormond Street Hospital, London, United Kingdom
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  • Esther Meyer,

    1. Neurosciences Unit, Institute of Child Health, University College London, London, United Kingdom
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  • Brenda J. Barry,

    1. Howard Hughes Medical Institute, Chevy Chase, MD, U.S.A.
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  • Omar S. Khwaja,

    1. Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
    2. Harvard Medical School, Boston, Massachusetts, U.S.A.
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    • Present address: F. Hoffmann-La Roche AG, Basel, Switzerland.

  • Mustafa A. M. Salih,

    1. Division of Pediatric Neurology, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
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  • Tommy Stödberg,

    1. Department of Neuropediatrics, Astrid Lindgren Children’s Hospital, Karolinska Hospital, Stockholm, Sweden
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  • Ingrid E. Scheffer,

    1. Department of Medicine and Paediatrics, University of Melbourne, Austin Health and Royal Children’s Hospital, Melbourne, Victoria, Australia
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  • Eamonn R. Maher,

    1. Department of Medical and Molecular Genetics, Centre for Rare Diseases and Personalised Medicine, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham, United Kingdom
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  • Mustafa Sahin,

    1. Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
    2. Harvard Medical School, Boston, Massachusetts, U.S.A.
    3. Manton Center for Orphan Disease Research, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
    4. F.M. Kirby Neurobiology Center, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
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  • Bai-Lin Wu,

    1. Department of Laboratory Medicine, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
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  • Gerard T. Berry,

    1. Harvard Medical School, Boston, Massachusetts, U.S.A.
    2. Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
    3. Manton Center for Orphan Disease Research, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
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  • Christopher A. Walsh,

    1. Harvard Medical School, Boston, Massachusetts, U.S.A.
    2. Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
    3. Howard Hughes Medical Institute, Chevy Chase, MD, U.S.A.
    4. Manton Center for Orphan Disease Research, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
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  • Jonathan Picker,

    1. Harvard Medical School, Boston, Massachusetts, U.S.A.
    2. Division of Genetics, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
    3. Department of Child and Adolescent Psychiatry, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
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    • These senior authors contributed equally to the manuscript.

  • Sanjeev V. Kothare

    1. Department of Neurology, Children’s Hospital Boston, Boston, Massachusetts, U.S.A.
    2. Harvard Medical School, Boston, Massachusetts, U.S.A.
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    • These senior authors contributed equally to the manuscript.


Address correspondence to Annapurna Poduri, Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Fegan 9, Children’s Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, U.S.A. E-mail: annapurna.poduri@childrens.harvard.edu

Summary

Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants genome-wide and long-range polymerase chain reaction to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCβ1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.

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