Ultra-rare genetic variation in common epilepsies: a case-control sequencing study

Andrew S. Allen, Susannah T. Bellows, Samuel F. Berkovic, Joshua Bridgers, Rosemary Burgess, Gianpiero Cavalleri, Seo Kyung Chung, Patrick Cossette, Norman Delanty, Dennis Dlugos, Michael P. Epstein, Catharine Freyer, David B. Goldstein, Erin L. Heinzen, Michael S. Hildebrand, Michael R. Johnson, Ruben Kuzniecky, Daniel H. Lowenstein, Anthony G. Marson, Richard MayeuxCaroline Mebane, Heather C. Mefford, Terence J. O'Brien, Ruth Ottman, Steven Petrou, Slavé Petrovski, William O. Pickrell, Rodney A. Radtke, Mark I. Rees, Brigid M. Regan, Zhong Ren, Ingrid E. Scheffer, Graeme J. Sills, Rhys H. Thomas, Quanli Wang, Bassel Abou-Khalil, Brian K. Alldredge, Dina Amrom, Eva Andermann, Frederick Andermann, Jocelyn F. Bautista, Judith Bluvstein, Alexis D. Boro, Gregory D. Cascino, Damian Consalvo, Patricia Crumrine, Orrin Devinsky, Miguel Fiol, Nathan B. Fountain, Jacqueline French, Daniel Friedman, Eric B. Geller, Tracy Glauser, Simon Glynn, Kevin Haas, Sheryl R. Haut, Jean Hayward, Sandra L. Helmers, Sucheta Joshi, Andres Kanner, Heidi E. Kirsch, Robert C. Knowlton, Eric H. Kossoff, Rachel Kuperman, Paul V. Motika, Edward J. Novotny, Juliann M. Paolicchi, Jack M. Parent, Kristen Park, Annapurna Poduri, Lynette G. Sadleir, Renée A. Shellhaas, Elliott H. Sherr, Jerry J. Shih, Shlomo Shinnar, Rani K. Singh, Joseph Sirven, Michael C. Smith, Joseph Sullivan, Liu Lin Thio, Anu Venkat, Eileen P.G. Vining, Gretchen K. Von Allmen, Judith L. Weisenberg, Peter Widdess-Walsh, Melodie R. Winawer

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7–3·2, p=9·1 × 10−8; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10−17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10−8) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. Funding National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

Original languageEnglish (US)
Pages (from-to)135-143
Number of pages9
JournalThe Lancet Neurology
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2017

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Case-Control Studies
Epilepsy
Partial Epilepsy
Generalized Epilepsy
Genes
National Institute of Neurological Disorders and Stroke
Exome
Inborn Genetic Diseases
Genetic Association Studies
Comorbidity
Proteins

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Allen, A. S., Bellows, S. T., Berkovic, S. F., Bridgers, J., Burgess, R., Cavalleri, G., ... Winawer, M. R. (2017). Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. The Lancet Neurology, 16(2), 135-143. https://doi.org/10.1016/S1474-4422(16)30359-3

Ultra-rare genetic variation in common epilepsies : a case-control sequencing study. / Allen, Andrew S.; Bellows, Susannah T.; Berkovic, Samuel F.; Bridgers, Joshua; Burgess, Rosemary; Cavalleri, Gianpiero; Chung, Seo Kyung; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Epstein, Michael P.; Freyer, Catharine; Goldstein, David B.; Heinzen, Erin L.; Hildebrand, Michael S.; Johnson, Michael R.; Kuzniecky, Ruben; Lowenstein, Daniel H.; Marson, Anthony G.; Mayeux, Richard; Mebane, Caroline; Mefford, Heather C.; O'Brien, Terence J.; Ottman, Ruth; Petrou, Steven; Petrovski, Slavé; Pickrell, William O.; Radtke, Rodney A.; Rees, Mark I.; Regan, Brigid M.; Ren, Zhong; Scheffer, Ingrid E.; Sills, Graeme J.; Thomas, Rhys H.; Wang, Quanli; Abou-Khalil, Bassel; Alldredge, Brian K.; Amrom, Dina; Andermann, Eva; Andermann, Frederick; Bautista, Jocelyn F.; Bluvstein, Judith; Boro, Alexis D.; Cascino, Gregory D.; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Fiol, Miguel; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel; Geller, Eric B.; Glauser, Tracy; Glynn, Simon; Haas, Kevin; Haut, Sheryl R.; Hayward, Jean; Helmers, Sandra L.; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E.; Knowlton, Robert C.; Kossoff, Eric H.; Kuperman, Rachel; Motika, Paul V.; Novotny, Edward J.; Paolicchi, Juliann M.; Parent, Jack M.; Park, Kristen; Poduri, Annapurna; Sadleir, Lynette G.; Shellhaas, Renée A.; Sherr, Elliott H.; Shih, Jerry J.; Shinnar, Shlomo; Singh, Rani K.; Sirven, Joseph; Smith, Michael C.; Sullivan, Joseph; Thio, Liu Lin; Venkat, Anu; Vining, Eileen P.G.; Von Allmen, Gretchen K.; Weisenberg, Judith L.; Widdess-Walsh, Peter; Winawer, Melodie R.

In: The Lancet Neurology, Vol. 16, No. 2, 01.02.2017, p. 135-143.

Research output: Contribution to journalArticle

Allen, AS, Bellows, ST, Berkovic, SF, Bridgers, J, Burgess, R, Cavalleri, G, Chung, SK, Cossette, P, Delanty, N, Dlugos, D, Epstein, MP, Freyer, C, Goldstein, DB, Heinzen, EL, Hildebrand, MS, Johnson, MR, Kuzniecky, R, Lowenstein, DH, Marson, AG, Mayeux, R, Mebane, C, Mefford, HC, O'Brien, TJ, Ottman, R, Petrou, S, Petrovski, S, Pickrell, WO, Radtke, RA, Rees, MI, Regan, BM, Ren, Z, Scheffer, IE, Sills, GJ, Thomas, RH, Wang, Q, Abou-Khalil, B, Alldredge, BK, Amrom, D, Andermann, E, Andermann, F, Bautista, JF, Bluvstein, J, Boro, AD, Cascino, GD, Consalvo, D, Crumrine, P, Devinsky, O, Fiol, M, Fountain, NB, French, J, Friedman, D, Geller, EB, Glauser, T, Glynn, S, Haas, K, Haut, SR, Hayward, J, Helmers, SL, Joshi, S, Kanner, A, Kirsch, HE, Knowlton, RC, Kossoff, EH, Kuperman, R, Motika, PV, Novotny, EJ, Paolicchi, JM, Parent, JM, Park, K, Poduri, A, Sadleir, LG, Shellhaas, RA, Sherr, EH, Shih, JJ, Shinnar, S, Singh, RK, Sirven, J, Smith, MC, Sullivan, J, Thio, LL, Venkat, A, Vining, EPG, Von Allmen, GK, Weisenberg, JL, Widdess-Walsh, P & Winawer, MR 2017, 'Ultra-rare genetic variation in common epilepsies: a case-control sequencing study', The Lancet Neurology, vol. 16, no. 2, pp. 135-143. https://doi.org/10.1016/S1474-4422(16)30359-3
Allen AS, Bellows ST, Berkovic SF, Bridgers J, Burgess R, Cavalleri G et al. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. The Lancet Neurology. 2017 Feb 1;16(2):135-143. https://doi.org/10.1016/S1474-4422(16)30359-3
Allen, Andrew S. ; Bellows, Susannah T. ; Berkovic, Samuel F. ; Bridgers, Joshua ; Burgess, Rosemary ; Cavalleri, Gianpiero ; Chung, Seo Kyung ; Cossette, Patrick ; Delanty, Norman ; Dlugos, Dennis ; Epstein, Michael P. ; Freyer, Catharine ; Goldstein, David B. ; Heinzen, Erin L. ; Hildebrand, Michael S. ; Johnson, Michael R. ; Kuzniecky, Ruben ; Lowenstein, Daniel H. ; Marson, Anthony G. ; Mayeux, Richard ; Mebane, Caroline ; Mefford, Heather C. ; O'Brien, Terence J. ; Ottman, Ruth ; Petrou, Steven ; Petrovski, Slavé ; Pickrell, William O. ; Radtke, Rodney A. ; Rees, Mark I. ; Regan, Brigid M. ; Ren, Zhong ; Scheffer, Ingrid E. ; Sills, Graeme J. ; Thomas, Rhys H. ; Wang, Quanli ; Abou-Khalil, Bassel ; Alldredge, Brian K. ; Amrom, Dina ; Andermann, Eva ; Andermann, Frederick ; Bautista, Jocelyn F. ; Bluvstein, Judith ; Boro, Alexis D. ; Cascino, Gregory D. ; Consalvo, Damian ; Crumrine, Patricia ; Devinsky, Orrin ; Fiol, Miguel ; Fountain, Nathan B. ; French, Jacqueline ; Friedman, Daniel ; Geller, Eric B. ; Glauser, Tracy ; Glynn, Simon ; Haas, Kevin ; Haut, Sheryl R. ; Hayward, Jean ; Helmers, Sandra L. ; Joshi, Sucheta ; Kanner, Andres ; Kirsch, Heidi E. ; Knowlton, Robert C. ; Kossoff, Eric H. ; Kuperman, Rachel ; Motika, Paul V. ; Novotny, Edward J. ; Paolicchi, Juliann M. ; Parent, Jack M. ; Park, Kristen ; Poduri, Annapurna ; Sadleir, Lynette G. ; Shellhaas, Renée A. ; Sherr, Elliott H. ; Shih, Jerry J. ; Shinnar, Shlomo ; Singh, Rani K. ; Sirven, Joseph ; Smith, Michael C. ; Sullivan, Joseph ; Thio, Liu Lin ; Venkat, Anu ; Vining, Eileen P.G. ; Von Allmen, Gretchen K. ; Weisenberg, Judith L. ; Widdess-Walsh, Peter ; Winawer, Melodie R. / Ultra-rare genetic variation in common epilepsies : a case-control sequencing study. In: The Lancet Neurology. 2017 ; Vol. 16, No. 2. pp. 135-143.
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abstract = "Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95{\%} CI 1·7–3·2, p=9·1 × 10−8; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10−17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8{\%} of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10−8) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. Funding National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.",
author = "Allen, {Andrew S.} and Bellows, {Susannah T.} and Berkovic, {Samuel F.} and Joshua Bridgers and Rosemary Burgess and Gianpiero Cavalleri and Chung, {Seo Kyung} and Patrick Cossette and Norman Delanty and Dennis Dlugos and Epstein, {Michael P.} and Catharine Freyer and Goldstein, {David B.} and Heinzen, {Erin L.} and Hildebrand, {Michael S.} and Johnson, {Michael R.} and Ruben Kuzniecky and Lowenstein, {Daniel H.} and Marson, {Anthony G.} and Richard Mayeux and Caroline Mebane and Mefford, {Heather C.} and O'Brien, {Terence J.} and Ruth Ottman and Steven Petrou and Slav{\'e} Petrovski and Pickrell, {William O.} and Radtke, {Rodney A.} and Rees, {Mark I.} and Regan, {Brigid M.} and Zhong Ren and Scheffer, {Ingrid E.} and Sills, {Graeme J.} and Thomas, {Rhys H.} and Quanli Wang and Bassel Abou-Khalil and Alldredge, {Brian K.} and Dina Amrom and Eva Andermann and Frederick Andermann and Bautista, {Jocelyn F.} and Judith Bluvstein and Boro, {Alexis D.} and Cascino, {Gregory D.} and Damian Consalvo and Patricia Crumrine and Orrin Devinsky and Miguel Fiol and Fountain, {Nathan B.} and Jacqueline French and Daniel Friedman and Geller, {Eric B.} and Tracy Glauser and Simon Glynn and Kevin Haas and Haut, {Sheryl R.} and Jean Hayward and Helmers, {Sandra L.} and Sucheta Joshi and Andres Kanner and Kirsch, {Heidi E.} and Knowlton, {Robert C.} and Kossoff, {Eric H.} and Rachel Kuperman and Motika, {Paul V.} and Novotny, {Edward J.} and Paolicchi, {Juliann M.} and Parent, {Jack M.} and Kristen Park and Annapurna Poduri and Sadleir, {Lynette G.} and Shellhaas, {Ren{\'e}e A.} and Sherr, {Elliott H.} and Shih, {Jerry J.} and Shlomo Shinnar and Singh, {Rani K.} and Joseph Sirven and Smith, {Michael C.} and Joseph Sullivan and Thio, {Liu Lin} and Anu Venkat and Vining, {Eileen P.G.} and {Von Allmen}, {Gretchen K.} and Weisenberg, {Judith L.} and Peter Widdess-Walsh and Winawer, {Melodie R.}",
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TY - JOUR

T1 - Ultra-rare genetic variation in common epilepsies

T2 - a case-control sequencing study

AU - Allen, Andrew S.

AU - Bellows, Susannah T.

AU - Berkovic, Samuel F.

AU - Bridgers, Joshua

AU - Burgess, Rosemary

AU - Cavalleri, Gianpiero

AU - Chung, Seo Kyung

AU - Cossette, Patrick

AU - Delanty, Norman

AU - Dlugos, Dennis

AU - Epstein, Michael P.

AU - Freyer, Catharine

AU - Goldstein, David B.

AU - Heinzen, Erin L.

AU - Hildebrand, Michael S.

AU - Johnson, Michael R.

AU - Kuzniecky, Ruben

AU - Lowenstein, Daniel H.

AU - Marson, Anthony G.

AU - Mayeux, Richard

AU - Mebane, Caroline

AU - Mefford, Heather C.

AU - O'Brien, Terence J.

AU - Ottman, Ruth

AU - Petrou, Steven

AU - Petrovski, Slavé

AU - Pickrell, William O.

AU - Radtke, Rodney A.

AU - Rees, Mark I.

AU - Regan, Brigid M.

AU - Ren, Zhong

AU - Scheffer, Ingrid E.

AU - Sills, Graeme J.

AU - Thomas, Rhys H.

AU - Wang, Quanli

AU - Abou-Khalil, Bassel

AU - Alldredge, Brian K.

AU - Amrom, Dina

AU - Andermann, Eva

AU - Andermann, Frederick

AU - Bautista, Jocelyn F.

AU - Bluvstein, Judith

AU - Boro, Alexis D.

AU - Cascino, Gregory D.

AU - Consalvo, Damian

AU - Crumrine, Patricia

AU - Devinsky, Orrin

AU - Fiol, Miguel

AU - Fountain, Nathan B.

AU - French, Jacqueline

AU - Friedman, Daniel

AU - Geller, Eric B.

AU - Glauser, Tracy

AU - Glynn, Simon

AU - Haas, Kevin

AU - Haut, Sheryl R.

AU - Hayward, Jean

AU - Helmers, Sandra L.

AU - Joshi, Sucheta

AU - Kanner, Andres

AU - Kirsch, Heidi E.

AU - Knowlton, Robert C.

AU - Kossoff, Eric H.

AU - Kuperman, Rachel

AU - Motika, Paul V.

AU - Novotny, Edward J.

AU - Paolicchi, Juliann M.

AU - Parent, Jack M.

AU - Park, Kristen

AU - Poduri, Annapurna

AU - Sadleir, Lynette G.

AU - Shellhaas, Renée A.

AU - Sherr, Elliott H.

AU - Shih, Jerry J.

AU - Shinnar, Shlomo

AU - Singh, Rani K.

AU - Sirven, Joseph

AU - Smith, Michael C.

AU - Sullivan, Joseph

AU - Thio, Liu Lin

AU - Venkat, Anu

AU - Vining, Eileen P.G.

AU - Von Allmen, Gretchen K.

AU - Weisenberg, Judith L.

AU - Widdess-Walsh, Peter

AU - Winawer, Melodie R.

PY - 2017/2/1

Y1 - 2017/2/1

N2 - Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7–3·2, p=9·1 × 10−8; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10−17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10−8) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. Funding National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

AB - Background Despite progress in understanding the genetics of rare epilepsies, the more common epilepsies have proven less amenable to traditional gene-discovery analyses. We aimed to assess the contribution of ultra-rare genetic variation to common epilepsies. Methods We did a case-control sequencing study with exome sequence data from unrelated individuals clinically evaluated for one of the two most common epilepsy syndromes: familial genetic generalised epilepsy, or familial or sporadic non-acquired focal epilepsy. Individuals of any age were recruited between Nov 26, 2007, and Aug 2, 2013, through the multicentre Epilepsy Phenome/Genome Project and Epi4K collaborations, and samples were sequenced at the Institute for Genomic Medicine (New York, USA) between Feb 6, 2013, and Aug 18, 2015. To identify epilepsy risk signals, we tested all protein-coding genes for an excess of ultra-rare genetic variation among the cases, compared with control samples with no known epilepsy or epilepsy comorbidity sequenced through unrelated studies. Findings We separately compared the sequence data from 640 individuals with familial genetic generalised epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3877 controls, and found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalised epilepsy: odd ratio [OR] 2·3, 95% CI 1·7–3·2, p=9·1 × 10−8; familial non-acquired focal epilepsy 3·6, 2·7–4·9, p=1·1 × 10−17). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals. For the individuals with familial non-acquired focal epilepsy, we found that five known epilepsy genes ranked as the top five genes enriched for ultra-rare deleterious variation. After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy. Our analyses showed that no individual gene was significantly associated with familial genetic generalised epilepsy; however, known epilepsy genes had lower p values relative to the rest of the protein-coding genes (p=5·8 × 10−8) that were lower than expected from a random sampling of genes. Interpretation We identified excess ultra-rare variation in known epilepsy genes, which establishes a clear connection between the genetics of common and rare, severe epilepsies, and shows that the variants responsible for epilepsy risk are exceptionally rare in the general population. Our results suggest that the emerging paradigm of targeting of treatments to the genetic cause in rare devastating epilepsies might also extend to a proportion of common epilepsies. These findings might allow clinicians to broadly explain the cause of these syndromes to patients, and lay the foundation for possible precision treatments in the future. Funding National Institute of Neurological Disorders and Stroke (NINDS), and Epilepsy Research UK.

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