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. 2009 Mar;46(3):183-91.
doi: 10.1136/jmg.2008.062323. Epub 2008 Oct 17.

Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients

C Depienne, O Trouillard, C Saint-Martin, I Gourfinkel-An, D Bouteiller, W Carpentier, B Keren, B Abert, A Gautier, S Baulac, A Arzimanoglou, C Cazeneuve, R Nabbout, E LeGuern

Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients

C Depienne et al. J Med Genet. 2009 Mar.

Abstract

Introduction: Mutations in the voltage-gated sodium channel SCN1A gene are the main genetic cause of Dravet syndrome (previously called severe myoclonic epilepsy of infancy or SMEI).

Objective: To characterise in more detail the mutation spectrum associated with Dravet syndrome.

Methods: A large series of 333 patients was screened using both direct sequencing and multiplex ligation-dependent probe amplification (MLPA). Non-coding regions of the gene that are usually not investigated were also screened.

Results: SCN1A point mutations were identified in 228 patients, 161 of which had not been previously reported. Missense mutations, either (1) altering a highly conserved amino acid of the protein, (2) transforming this conserved residue into a chemically dissimilar amino acid and/or (3) belonging to ion-transport sequences, were the most common mutation type. MLPA analysis of the 105 patients without point mutation detected a heterozygous microrearrangement of SCN1A in 14 additional patients; 8 were private, partial deletions and six corresponded to whole gene deletions, 0.15-2.9 Mb in size, deleting nearby genes. Finally, mutations in exon 5N and in untranslated regions of the SCN1A gene that were conserved during evolution were excluded in the remaining negative patients.

Conclusion: These findings widely expand the SCN1A mutation spectrum identified and highlight the importance of screening the coding regions with both direct sequencing and a quantitative method. This mutation spectrum, including whole gene deletions, argues in favour of haploinsufficiency as the main mechanism responsible for Dravet syndrome.

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