Volume 27, Issue 9
Research Article

Microdeletions involving the SCN1A gene may be common in SCN1A‐mutation‐negative SMEI patients

Arvid Suls

Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

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Kristl G. Claeys

Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

Department of Neurology, University Hospital Antwerp, Antwerp, Belgium

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Dirk Goossens

Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

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Boris Harding

Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

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Rob Van Luijk

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

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Stefaan Scheers

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

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Liesbet Deprez

Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

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Dominique Audenaert

Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

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Tine Van Dyck

Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

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Sabine Beeckmans

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

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Iris Smouts

Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

Department of Neurology, University Hospital Antwerp, Antwerp, Belgium

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Berten Ceulemans

Department of Neurology, University Hospital Antwerp, Antwerp, Belgium

Epilepsy Center for Children and Youth, Pulderbos, Belgium

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Lieven Lagae

Epilepsy Center for Children and Youth, Pulderbos, Belgium

Department of Child Neurology, University Hospital Gasthuisberg, Leuven, Belgium

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Gunnar Buyse

Department of Child Neurology, University Hospital Gasthuisberg, Leuven, Belgium

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Nina Barisic

Department of Pediatrics, University Medical School, Zagreb, Croatia

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Jean‐Paul Misson

Department of Neuropaediatrics, University of Liège, Liège, Belgium

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Jan Wauters

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

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Jurgen Del‐Favero

Applied Molecular Genomics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

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Peter De Jonghe

Corresponding Author

E-mail address: [email protected]

Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

Department of Neurology, University Hospital Antwerp, Antwerp, Belgium

Department of Molecular Genetics, Neurogenetics Group, University of Antwerp, Campus Drie Eiken, Parking P4, Building V, Universiteitsplein 1, BE‐2610 Antwerpen, BelgiumSearch for more papers by this author
Lieve R.F. Claes

Neurogenetics Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology (VIB), University of Antwerp, Antwerp, Belgium

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First published: 24 July 2006
Citations: 80

Communicated by Dvorah Abeliovich

Abstract

Severe myoclonic epilepsy of infancy (SMEI) or Dravet syndrome is a rare epilepsy syndrome. In 30 to 70% of SMEI patients, truncating and missense mutations in the neuronal voltage‐gated sodium‐channel α‐subunit gene (SCN1A) have been identified. The majority of patients have truncating mutations that are predicted to be loss‐of‐function alleles. Because mutation detection studies use PCR‐based sequencing or conformation sensitive gel electrophoresis (CSGE), microdeletions, which are also predicted to be loss‐of‐function alleles, can easily escape detection. We selected 11 SMEI patients with or without additional features who had no SCN1A mutation detectable with sequencing analysis. In addition, none of the patients was heterozygous for any of the SNPs in SCN1A, indicating that they were either homozygous for all SNPs or hemizygous due to a microdeletion of the gene. We subsequently analyzed these patients for the presence of microdeletions in SCN1A using a quantitative PCR method named multiplex amplicon quantification (MAQ), and observed three patients missing one copy of the SCN1A gene. All three microdeletions were confirmed by fluorescence in situ hybridization (FISH). These findings demonstrate that a substantial percentage of SCN1A‐mutation‐negative SMEI patients with or without additional features carry a chromosomal microdeletion comprising the SCN1A gene and that haploinsufficiency of the SCN1A gene is a cause of SMEI. Hum Mutat 27(9), 914–920, 2006. © 2006 Wiley‐Liss, Inc.

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