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

✍ Scribed by Arvid Suls; Kristl G. Claeys; Dirk Goossens; Boris Harding; Rob Van Luijk; Stefaan Scheers; Liesbet Deprez; Dominique Audenaert; Tine Van Dyck; Sabine Beeckmans; Iris Smouts; Berten Ceulemans; Lieven Lagae; Gunnar Buyse; Nina Barisic; Jean-Paul Misson; Jan Wauters; Jurgen Del-Favero; Peter De Jonghe; Lieve R.F. Claes

Publisher
John Wiley and Sons
Year
2006
Tongue
English
Weight
329 KB
Volume
27
Category
Article
ISSN
1059-7794

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✦ Synopsis

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 alpha-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.

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