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.
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.
Authors: Arvid Suls; Johanna A Jaehn; Angela Kecskés; Yvonne Weber; Sarah Weckhuysen; Dana C Craiu; Aleksandra Siekierska; Tania Djémié; Tatiana Afrikanova; Padhraig Gormley; Sarah von Spiczak; Gerhard Kluger; Catrinel M Iliescu; Tiina Talvik; Inga Talvik; Cihan Meral; Hande S Caglayan; Beatriz G Giraldez; José Serratosa; Johannes R Lemke; Dorota Hoffman-Zacharska; Elzbieta Szczepanik; Nina Barisic; Vladimir Komarek; Helle Hjalgrim; Rikke S Møller; Tarja Linnankivi; Petia Dimova; Pasquale Striano; Federico Zara; Carla Marini; Renzo Guerrini; Christel Depienne; Stéphanie Baulac; Gregor Kuhlenbäumer; Alexander D Crawford; Anna-Elina Lehesjoki; Peter A M de Witte; Aarno Palotie; Holger Lerche; Camila V Esguerra; Peter De Jonghe; Ingo Helbig Journal: Am J Hum Genet Date: 2013-10-24 Impact factor: 11.025
Authors: Krishna R Veeramah; Janelle E O'Brien; Miriam H Meisler; Xiaoyang Cheng; Sulayman D Dib-Hajj; Stephen G Waxman; Dinesh Talwar; Santhosh Girirajan; Evan E Eichler; Linda L Restifo; Robert P Erickson; Michael F Hammer Journal: Am J Hum Genet Date: 2012-02-23 Impact factor: 11.025
Authors: Nanda A Singh; Chris Pappas; E Jill Dahle; Lieve R F Claes; Timothy H Pruess; Peter De Jonghe; Joel Thompson; Missy Dixon; Christina Gurnett; Andy Peiffer; H Steve White; Francis Filloux; Mark F Leppert Journal: PLoS Genet Date: 2009-09-18 Impact factor: 5.917