De novo mutations in epileptic encephalopathies

Andrew S. Allen, Samuel F. Berkovic, Patrick Cossette, Norman Delanty, Dennis Dlugos, Evan E. Eichler, Michael P. Epstein, Tracy Glauser, David B. Goldstein, Yujun Han, Erin L. Heinzen, Yuki Hitomi, Katherine B. Howell, Michael R. Johnson, Ruben Kuzniecky, Daniel H. Lowenstein, Yi Fan Lu, Maura R Z Madou, Anthony G. Marson, Heather C. Mefford & 51 others Sahar Esmaeeli Nieh, Terence J. O'Brien, Ruth Ottman, Slavé Petrovski, Annapurna Poduri, Elizabeth K. Ruzzo, Ingrid E. Scheffer, Elliott H. Sherr, Christopher J. Yuskaitis, Bassel Abou-Khalil, Brian K. Alldredge, Jocelyn F. Bautista, Alex Boro, Gregory D. Cascino, Damian Consalvo, Patricia Crumrine, Orrin Devinsky, Miguel Fiol, Nathan B. Fountain, Jacqueline French, Daniel Friedman, Eric B. Geller, Simon Glynn, Sheryl R. Haut, Jean Hayward, Sandra L. Helmers, Sucheta Joshi, Andres Kanner, Heidi E. Kirsch, Robert C. Knowlton, Eric H Kossoff, Rachel Kuperman, Shannon M. McGuire, Paul V. Motika, Edward J. Novotny, Juliann M. Paolicchi, Jack M. Parent, Kristen Park, Renée A. Shellhaas, Jerry J. Shih, Rani 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

Abstract

Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10 -3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10 -10 and P = 7.8 × 10 -12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P <10 -8), as has been reported previously for autism spectrum disorders.

Original languageEnglish (US)
Pages (from-to)217-221
Number of pages5
JournalNature
Volume501
Issue number7466
DOIs
StatePublished - 2013

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Brain Diseases
Mutation
Genes
Exome
Infantile Spasms
Mutation Rate
Epilepsy
Parents
Population
Proteins

ASJC Scopus subject areas

  • General

Cite this

Allen, A. S., Berkovic, S. F., Cossette, P., Delanty, N., Dlugos, D., Eichler, E. E., ... Winawer, M. R. (2013). De novo mutations in epileptic encephalopathies. Nature, 501(7466), 217-221. https://doi.org/10.1038/nature12439

De novo mutations in epileptic encephalopathies. / Allen, Andrew S.; Berkovic, Samuel F.; Cossette, Patrick; Delanty, Norman; Dlugos, Dennis; Eichler, Evan E.; Epstein, Michael P.; Glauser, Tracy; Goldstein, David B.; Han, Yujun; Heinzen, Erin L.; Hitomi, Yuki; Howell, Katherine B.; Johnson, Michael R.; Kuzniecky, Ruben; Lowenstein, Daniel H.; Lu, Yi Fan; Madou, Maura R Z; Marson, Anthony G.; Mefford, Heather C.; Esmaeeli Nieh, Sahar; O'Brien, Terence J.; Ottman, Ruth; Petrovski, Slavé; Poduri, Annapurna; Ruzzo, Elizabeth K.; Scheffer, Ingrid E.; Sherr, Elliott H.; Yuskaitis, Christopher J.; Abou-Khalil, Bassel; Alldredge, Brian K.; Bautista, Jocelyn F.; Boro, Alex; Cascino, Gregory D.; Consalvo, Damian; Crumrine, Patricia; Devinsky, Orrin; Fiol, Miguel; Fountain, Nathan B.; French, Jacqueline; Friedman, Daniel; Geller, Eric B.; Glynn, Simon; Haut, Sheryl R.; Hayward, Jean; Helmers, Sandra L.; Joshi, Sucheta; Kanner, Andres; Kirsch, Heidi E.; Knowlton, Robert C.; Kossoff, Eric H; Kuperman, Rachel; McGuire, Shannon M.; Motika, Paul V.; Novotny, Edward J.; Paolicchi, Juliann M.; Parent, Jack M.; Park, Kristen; Shellhaas, Renée A.; Shih, Jerry J.; Singh, Rani; Sirven, Joseph; Smith, Michael C.; Sullivan, Joseph; Lin Thio, Liu; Venkat, Anu; Vining, Eileen P.G.; Von Allmen, Gretchen K.; Weisenberg, Judith L.; Widdess-Walsh, Peter; Winawer, Melodie R.

In: Nature, Vol. 501, No. 7466, 2013, p. 217-221.

Research output: Contribution to journalArticle

Allen, AS, Berkovic, SF, Cossette, P, Delanty, N, Dlugos, D, Eichler, EE, Epstein, MP, Glauser, T, Goldstein, DB, Han, Y, Heinzen, EL, Hitomi, Y, Howell, KB, Johnson, MR, Kuzniecky, R, Lowenstein, DH, Lu, YF, Madou, MRZ, Marson, AG, Mefford, HC, Esmaeeli Nieh, S, O'Brien, TJ, Ottman, R, Petrovski, S, Poduri, A, Ruzzo, EK, Scheffer, IE, Sherr, EH, Yuskaitis, CJ, Abou-Khalil, B, Alldredge, BK, Bautista, JF, Boro, A, Cascino, GD, Consalvo, D, Crumrine, P, Devinsky, O, Fiol, M, Fountain, NB, French, J, Friedman, D, Geller, EB, Glynn, S, Haut, SR, Hayward, J, Helmers, SL, Joshi, S, Kanner, A, Kirsch, HE, Knowlton, RC, Kossoff, EH, Kuperman, R, McGuire, SM, Motika, PV, Novotny, EJ, Paolicchi, JM, Parent, JM, Park, K, Shellhaas, RA, Shih, JJ, Singh, R, Sirven, J, Smith, MC, Sullivan, J, Lin Thio, L, Venkat, A, Vining, EPG, Von Allmen, GK, Weisenberg, JL, Widdess-Walsh, P & Winawer, MR 2013, 'De novo mutations in epileptic encephalopathies', Nature, vol. 501, no. 7466, pp. 217-221. https://doi.org/10.1038/nature12439
Allen AS, Berkovic SF, Cossette P, Delanty N, Dlugos D, Eichler EE et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501(7466):217-221. https://doi.org/10.1038/nature12439
Allen, Andrew S. ; Berkovic, Samuel F. ; Cossette, Patrick ; Delanty, Norman ; Dlugos, Dennis ; Eichler, Evan E. ; Epstein, Michael P. ; Glauser, Tracy ; Goldstein, David B. ; Han, Yujun ; Heinzen, Erin L. ; Hitomi, Yuki ; Howell, Katherine B. ; Johnson, Michael R. ; Kuzniecky, Ruben ; Lowenstein, Daniel H. ; Lu, Yi Fan ; Madou, Maura R Z ; Marson, Anthony G. ; Mefford, Heather C. ; Esmaeeli Nieh, Sahar ; O'Brien, Terence J. ; Ottman, Ruth ; Petrovski, Slavé ; Poduri, Annapurna ; Ruzzo, Elizabeth K. ; Scheffer, Ingrid E. ; Sherr, Elliott H. ; Yuskaitis, Christopher J. ; Abou-Khalil, Bassel ; Alldredge, Brian K. ; Bautista, Jocelyn F. ; Boro, Alex ; Cascino, Gregory D. ; Consalvo, Damian ; Crumrine, Patricia ; Devinsky, Orrin ; Fiol, Miguel ; Fountain, Nathan B. ; French, Jacqueline ; Friedman, Daniel ; Geller, Eric B. ; Glynn, Simon ; Haut, Sheryl R. ; Hayward, Jean ; Helmers, Sandra L. ; Joshi, Sucheta ; Kanner, Andres ; Kirsch, Heidi E. ; Knowlton, Robert C. ; Kossoff, Eric H ; Kuperman, Rachel ; McGuire, Shannon M. ; Motika, Paul V. ; Novotny, Edward J. ; Paolicchi, Juliann M. ; Parent, Jack M. ; Park, Kristen ; Shellhaas, Renée A. ; Shih, Jerry J. ; Singh, Rani ; Sirven, Joseph ; Smith, Michael C. ; Sullivan, Joseph ; Lin Thio, Liu ; Venkat, Anu ; Vining, Eileen P.G. ; Von Allmen, Gretchen K. ; Weisenberg, Judith L. ; Widdess-Walsh, Peter ; Winawer, Melodie R. / De novo mutations in epileptic encephalopathies. In: Nature. 2013 ; Vol. 501, No. 7466. pp. 217-221.
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AU - Allen, Andrew S.

AU - Berkovic, Samuel F.

AU - Cossette, Patrick

AU - Delanty, Norman

AU - Dlugos, Dennis

AU - Eichler, Evan E.

AU - Epstein, Michael P.

AU - Glauser, Tracy

AU - Goldstein, David B.

AU - Han, Yujun

AU - Heinzen, Erin L.

AU - Hitomi, Yuki

AU - Howell, Katherine B.

AU - Johnson, Michael R.

AU - Kuzniecky, Ruben

AU - Lowenstein, Daniel H.

AU - Lu, Yi Fan

AU - Madou, Maura R Z

AU - Marson, Anthony G.

AU - Mefford, Heather C.

AU - Esmaeeli Nieh, Sahar

AU - O'Brien, Terence J.

AU - Ottman, Ruth

AU - Petrovski, Slavé

AU - Poduri, Annapurna

AU - Ruzzo, Elizabeth K.

AU - Scheffer, Ingrid E.

AU - Sherr, Elliott H.

AU - Yuskaitis, Christopher J.

AU - Abou-Khalil, Bassel

AU - Alldredge, Brian K.

AU - Bautista, Jocelyn F.

AU - Boro, Alex

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 - Glynn, Simon

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 - McGuire, Shannon M.

AU - Motika, Paul V.

AU - Novotny, Edward J.

AU - Paolicchi, Juliann M.

AU - Parent, Jack M.

AU - Park, Kristen

AU - Shellhaas, Renée A.

AU - Shih, Jerry J.

AU - Singh, Rani

AU - Sirven, Joseph

AU - Smith, Michael C.

AU - Sullivan, Joseph

AU - Lin Thio, Liu

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 - 2013

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N2 - Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10 -3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10 -10 and P = 7.8 × 10 -12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P <10 -8), as has been reported previously for autism spectrum disorders.

AB - Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10 -3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10 -10 and P = 7.8 × 10 -12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P <10 -8), as has been reported previously for autism spectrum disorders.

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