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. Weber & 39 others Maria 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 journalArticle

6 Citations (Scopus)

Abstract

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
Volume11
Issue number3
DOIs
Publication statusPublished - Mar 1 2016

Fingerprint

epilepsy
NAV1.1 Voltage-Gated Sodium Channel
Epilepsy
Genes
Clinical laboratories
Throughput
Virulence
Electric potential
pathogenicity
mutation
penetrance
Mutation
missense mutation
counseling
Penetrance
Genetic Counseling
Missense Mutation
Gene Frequency
Computer Simulation
gene frequency

ASJC Scopus subject areas

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

Cite this

Lal, D., Reinthaler, E. M., Dejanovic, B., May, P., Thiele, H., Lehesjoki, A. E., ... Giuseppe, C. (2016). Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes. PLoS One, 11(3), [e0150426]. https://doi.org/10.1371/journal.pone.0150426

Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes. / Lal, Dennis; Reinthaler, Eva M.; Dejanovic, Borislav; May, Patrick; Thiele, Holger; Lehesjoki, Anna Elina; Schwarz, Günter; Riesch, Erik; Ikram, M. Arfan; Van Duijn, Cornelia M.; Uitterlinden, Andre G.; Hofman, Albert; Steinböck, Hannelore; Gruber-Sedlmayr, Ursula; Neophytou, Birgit; Zara, Federico; Hahn, Andreas; Gormley, Padhraig; Becker, Felicitas; Weber, Yvonne G.; Cilio, Maria Roberta; Kunz, Wolfram S.; Krause, Roland; Zimprich, Fritz; Lemke, Johannes R.; Nürnberg, Peter; Sander, Thomas; Lerche, Holger; Neubauer, Bernd A.; Palotie, Aarno; Ruppert, Ann Kathrin; Suls, Arvid; Siren, Auli; Koeleman, Bobby; Haberlandt, Edda; Ronen, Gabriel M.; Caglayan, Hande; Hjalgrim, Helle; Muhle, Hiltrud; Schulz, Herbert; Helbig, Ingo; Altmüller, Janine; Geldner, Julia; Schubert, Julian; Jabbari, Kamel; Everett, Kate; Feucht, Martha; Balestri, Martina; Nothnagel, Michael; Striano, Pasquale; Møller, Rikke S.; Nabbout, Rima; Balling, Rudi; Baulac, Stephanie; Kunz, Wolfram; Bianchi, Amedeo; La Neve, Angela; Minetti, Carlo; Giuseppe, Capovilla.

In: PLoS One, Vol. 11, No. 3, e0150426, 01.03.2016.

Research output: Contribution to journalArticle

Lal, D, Reinthaler, EM, Dejanovic, B, May, P, Thiele, H, Lehesjoki, AE, Schwarz, G, Riesch, E, Ikram, MA, Van Duijn, CM, Uitterlinden, AG, Hofman, A, Steinböck, H, Gruber-Sedlmayr, U, Neophytou, B, Zara, F, Hahn, A, Gormley, P, Becker, F, Weber, YG, Cilio, MR, Kunz, WS, Krause, R, Zimprich, F, Lemke, JR, Nürnberg, P, Sander, T, Lerche, H, Neubauer, BA, Palotie, A, Ruppert, AK, Suls, A, Siren, A, Koeleman, B, Haberlandt, E, Ronen, GM, Caglayan, H, Hjalgrim, H, Muhle, H, Schulz, H, Helbig, I, Altmüller, J, Geldner, J, Schubert, J, Jabbari, K, Everett, K, Feucht, M, Balestri, M, Nothnagel, M, Striano, P, Møller, RS, Nabbout, R, Balling, R, Baulac, S, Kunz, W, Bianchi, A, La Neve, A, Minetti, C & Giuseppe, C 2016, 'Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes', PLoS One, vol. 11, no. 3, e0150426. https://doi.org/10.1371/journal.pone.0150426
Lal D, Reinthaler EM, Dejanovic B, May P, Thiele H, Lehesjoki AE et al. Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes. PLoS One. 2016 Mar 1;11(3). e0150426. https://doi.org/10.1371/journal.pone.0150426
Lal, Dennis ; Reinthaler, Eva M. ; Dejanovic, Borislav ; May, Patrick ; Thiele, Holger ; Lehesjoki, Anna Elina ; Schwarz, Günter ; Riesch, Erik ; Ikram, M. Arfan ; Van Duijn, Cornelia M. ; Uitterlinden, Andre G. ; Hofman, Albert ; Steinböck, Hannelore ; Gruber-Sedlmayr, Ursula ; Neophytou, Birgit ; Zara, Federico ; Hahn, Andreas ; Gormley, Padhraig ; Becker, Felicitas ; Weber, Yvonne G. ; Cilio, Maria Roberta ; Kunz, Wolfram S. ; Krause, Roland ; Zimprich, Fritz ; Lemke, Johannes R. ; Nürnberg, Peter ; Sander, Thomas ; Lerche, Holger ; Neubauer, Bernd A. ; Palotie, Aarno ; Ruppert, Ann Kathrin ; Suls, Arvid ; Siren, Auli ; Koeleman, Bobby ; Haberlandt, Edda ; Ronen, Gabriel M. ; Caglayan, Hande ; Hjalgrim, Helle ; Muhle, Hiltrud ; Schulz, Herbert ; Helbig, Ingo ; Altmüller, Janine ; Geldner, Julia ; Schubert, Julian ; Jabbari, Kamel ; Everett, Kate ; Feucht, Martha ; Balestri, Martina ; Nothnagel, Michael ; Striano, Pasquale ; Møller, Rikke S. ; Nabbout, Rima ; Balling, Rudi ; Baulac, Stephanie ; Kunz, Wolfram ; Bianchi, Amedeo ; La Neve, Angela ; Minetti, Carlo ; Giuseppe, Capovilla. / Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes. In: PLoS One. 2016 ; Vol. 11, No. 3.
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abstract = "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.",
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T1 - Evaluation of presumably disease causing SCN1A variants in a cohort of common epilepsy syndromes

AU - Lal, Dennis

AU - Reinthaler, Eva M.

AU - Dejanovic, Borislav

AU - May, Patrick

AU - Thiele, Holger

AU - Lehesjoki, Anna Elina

AU - Schwarz, Günter

AU - Riesch, Erik

AU - Ikram, M. Arfan

AU - Van Duijn, Cornelia M.

AU - Uitterlinden, Andre G.

AU - Hofman, Albert

AU - Steinböck, Hannelore

AU - Gruber-Sedlmayr, Ursula

AU - Neophytou, Birgit

AU - Zara, Federico

AU - Hahn, Andreas

AU - Gormley, Padhraig

AU - Becker, Felicitas

AU - Weber, Yvonne G.

AU - Cilio, Maria Roberta

AU - Kunz, Wolfram S.

AU - Krause, Roland

AU - Zimprich, Fritz

AU - Lemke, Johannes R.

AU - Nürnberg, Peter

AU - Sander, Thomas

AU - Lerche, Holger

AU - Neubauer, Bernd A.

AU - Palotie, Aarno

AU - Ruppert, Ann Kathrin

AU - Suls, Arvid

AU - Siren, Auli

AU - Koeleman, Bobby

AU - Haberlandt, Edda

AU - Ronen, Gabriel M.

AU - Caglayan, Hande

AU - Hjalgrim, Helle

AU - Muhle, Hiltrud

AU - Schulz, Herbert

AU - Helbig, Ingo

AU - Altmüller, Janine

AU - Geldner, Julia

AU - Schubert, Julian

AU - Jabbari, Kamel

AU - Everett, Kate

AU - Feucht, Martha

AU - Balestri, Martina

AU - Nothnagel, Michael

AU - Striano, Pasquale

AU - Møller, Rikke S.

AU - Nabbout, Rima

AU - Balling, Rudi

AU - Baulac, Stephanie

AU - Kunz, Wolfram

AU - Bianchi, Amedeo

AU - La Neve, Angela

AU - Minetti, Carlo

AU - Giuseppe, Capovilla

PY - 2016/3/1

Y1 - 2016/3/1

N2 - 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.

AB - 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.

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