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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