Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

Dennis Lal, Eva M. Reinthaler, Borislav Dejanovic, Patrick May, Holger Thiele, Anna Elina Lehesjoki, Günter Schwarz, Erik Riesch, M. Arfan Ikram, Cornelia M. Van Duijn, Andre G. Uitterlinden, Albert Hofman, Hannelore Steinböck, Ursula Gruber-Sedlmayr, Birgit Neophytou, Federico Zara, Andreas Hahn, Padhraig Gormley, Felicitas Becker, Yvonne G. WeberMaria Roberta Cilio, Wolfram S. Kunz, Roland Krause, Fritz Zimprich, Johannes R. Lemke, Peter Nürnberg, Thomas Sander, Holger Lerche, Bernd A. Neubauer, Aarno Palotie, Ann Kathrin Ruppert, Arvid Suls, Auli Siren, Bobby Koeleman, Edda Haberlandt, Gabriel M. Ronen, Hande Caglayan, Helle Hjalgrim, Hiltrud Muhle, Herbert Schulz, Ingo Helbig, Janine Altmüller, Julia Geldner, Julian Schubert, Kamel Jabbari, Kate Everett, Martha Feucht, Martina Balestri, Michael Nothnagel, Pasquale Striano, Rikke S. Møller, Rima Nabbout, Rudi Balling, Stephanie Baulac, Wolfram Kunz, Amedeo Bianchi, Angela La Neve, Carlo Minetti, Capovilla Giuseppe

Research output: Contribution to journalArticlepeer-review


Objective: The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods: We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation: We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP-001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 × 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

Original languageEnglish
Article numbere0150426
JournalPLoS One
Issue number3
Publication statusPublished - Mar 1 2016

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)


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