SLC25A22 is a novel gene for migrating partial seizures in infancy

Authors

  • Annapurna Poduri MD, MPH,

    1. Department of Neurology, Boston Children's Hospital, Boston, MA, USA
    2. Department of Neurology, Harvard Medical School, Boston, MA, USA
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  • Erin L. Heinzen PhD,

    1. Center for Human Genome Variation, Duke University School of Medicine, Durham, NC, USA
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  • Vida Chitsazzadeh BS,

    1. University of Texas School of Medicine, Houston, TX, USA
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  • Francesco Massimo Lasorsa PhD,

    1. Department of Biosciences and Biotechnologies, University of Bari, Bari, Italy
    2. CNR Institute of Biomembranes and Bioenergetics, Bari, Italy
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  • P. Christina Elhosary BS,

    1. Department of Neurology, Boston Children's Hospital, Boston, MA, USA
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  • Christopher M. LaCoursiere BS,

    1. Department of Neurology, Boston Children's Hospital, Boston, MA, USA
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  • Emilie Martin BS,

    1. Department of Neurology, Boston Children's Hospital, Boston, MA, USA
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  • Christopher J. Yuskaitis MD, PhD,

    1. Department of Neurology, Boston Children's Hospital, Boston, MA, USA
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  • Robert Sean Hill PhD,

    1. Division of Genetics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
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  • Kutay Deniz Atabay MS,

    1. Division of Genetics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
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  • Brenda Barry MS,

    1. Division of Genetics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
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  • Jennifer N. Partlow MS,

    1. Division of Genetics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
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  • Fahad A. Bashiri MD,

    1. Division of Pediatric Neurology, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
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  • Radwan M. Zeidan MD,

    1. Division of Neurology, Department of Medicine, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
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  • Salah A. Elmalik MD,

    1. Department of Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
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  • Mohammad M. U. Kabiraj MBBS, MPhil, PhD,

    1. Division of Clinical Neurophysiology, Department of Neuroscience, Armed Forces Hospital, Riyadh, Saudi Arabia
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  • Sanjeev Kothare MBBS,

    1. Department of Neurology, Boston Children's Hospital, Boston, MA, USA
    2. Department of Neurology, Harvard Medical School, Boston, MA, USA
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  • Tommy Stödberg MD,

    1. Department of Neuropediatrics, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden
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  • Amy McTague,

    1. Department of Neurology, Great Ormond Street Hospital, London, UK
    2. Neurosciences Unit, UCL-Institute of Child Health, London
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  • Manju A. Kurian,

    1. Department of Neurology, Great Ormond Street Hospital, London, UK
    2. Neurosciences Unit, UCL-Institute of Child Health, London
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  • Ingrid E. Scheffer MBBS, PhD, FRACP,

    1. Departments of Medicine and Paediatrics, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Australia
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  • A. James Barkovich MD,

    1. Department of Radiology, University of California San Francisco, San Francisco, CA, USA
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  • Ferdinando Palmieri PhD,

    1. Department of Biosciences and Biotechnologies, University of Bari, Bari, Italy
    2. CNR Institute of Biomembranes and Bioenergetics, Bari, Italy
    3. Center of Excellence in Comparative Genomics, University of Bari, Italy
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  • Mustafa A. Salih MD, Dr Med Sci,

    Corresponding author
    1. Division of Pediatric Neurology, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
    • Address correspondence to Dr Salih, Division of Pediatric Neurology, College of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Kingdom of Saudi Arabia. E-mail: mustafa_salih05@yahoo.com or Dr Walsh, Center for Life Sciences 15th floor, Room 15064, 300 Longwood Avenue, Boston, MA 02115. E-mail: christopher.walsh@childrens.harvard.edu

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  • Christopher A. Walsh MD, PhD

    Corresponding author
    1. Department of Neurology, Harvard Medical School, Boston, MA, USA
    2. Division of Genetics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
    • Address correspondence to Dr Salih, Division of Pediatric Neurology, College of Medicine, King Saud University, PO Box 2925, Riyadh 11461, Kingdom of Saudi Arabia. E-mail: mustafa_salih05@yahoo.com or Dr Walsh, Center for Life Sciences 15th floor, Room 15064, 300 Longwood Avenue, Boston, MA 02115. E-mail: christopher.walsh@childrens.harvard.edu

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Abstract

Objective

To identify a genetic cause for migrating partial seizures in infancy (MPSI).

Methods

We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22.

Results

In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport.

Interpretation

We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22. Ann Neurol 2013;74:873–882

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