De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies

Silke Appenzeller; Rudi Balling; Nina Barisic; Stéphanie Baulac; Hande Caglayan; Dana Craiu; Peter De Jonghe; Christel Depienne; Petia Dimova; Tania Djémié; Padhraig Gormley; Renzo Guerrini; Ingo Helbig; Helle Hjalgrim; Dorota Hoffman-Zacharska; Johanna Jähn; Karl Martin Klein; Bobby Koeleman; Vladimir Komarek; Roland Krause; Gregor Kuhlenbäumer; Eric Leguern; Anna Elina Lehesjoki; Johannes R. Lemke; Holger Lerche; Tarja Linnankivi; Carla Marini; Patrick May; Rikke S. Møller; Hiltrud Muhle; Deb Pal; Aarno Palotie; Manuela Pendziwiat; Angela Robbiano; Filip Roelens; Felix Rosenow; Kaja Selmer; Jose M. Serratosa; Sanjay Sisodiya; Ulrich Stephani; Katalin Sterbova; Pasquale Striano; Arvid Suls; Tiina Talvik; Sarah Von Spiczak; Yvonne Weber; Sarah Weckhuysen; Federico Zara; Bassel Abou-Khalil; Brian K. Alldredge; Eva Andermann; Frederick Andermann; Dina Amron; Jocelyn F. Bautista; Samuel F. Berkovic; Judith Bluvstein; Alex Boro; Gregory Cascino; Damian Consalvo; Patricia Crumrine; Orrin Devinsky; Dennis Dlugos; Michael P. Epstein; 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; Ruben Kuzniecky; Daniel H. Lowenstein; Shannon M. McGuire; Paul V. Motika; Edward J. Novotny; Ruth Ottman; Juliann M. Paolicchi; Jack Parent; Kristen Park; Annapurna Poduri; Lynette Sadleir; Ingrid E. Scheffer; Renée A. Shellhaas; Elliott Sherr; Jerry J. Shih; Rani Singh; Joseph Sirven; Michael C. Smith; Joe Sullivan; Liu Lin Thio; Anu Venkat; Eileen P G Vining; Gretchen K. Von Allmen; Judith L. Weisenberg; Peter Widdess-Walsh; Melodie R. Winawer; Andrew S. Allen; Patrick Cossette; Norman Delanty; Evan E. Eichler; David B. Goldstein; Yujun Han; Erin L. Heinzen; Michael R. Johnson; Anthony G. Marson; Heather C. Mefford; Sahar Esmaeeli Nieh; Terence J. O'Brien; Stephen Petrou; Slavé Petrovski; Elizabeth K. Ruzzo

doi:10.1016/j.ajhg.2014.08.013

De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies

Silke Appenzeller, Rudi Balling, Nina Barisic, Stéphanie Baulac, Hande Caglayan, Dana Craiu, Peter De Jonghe, Christel Depienne, Petia Dimova, Tania Djémié, Padhraig Gormley, Renzo Guerrini, Ingo Helbig, Helle Hjalgrim, Dorota Hoffman-Zacharska, Johanna Jähn, Karl Martin Klein, Bobby Koeleman, Vladimir Komarek, Roland KrauseGregor Kuhlenbäumer, Eric Leguern, Anna Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Tarja Linnankivi, Carla Marini, Patrick May, Rikke S. Møller, Hiltrud Muhle, Deb Pal, Aarno Palotie, Manuela Pendziwiat, Angela Robbiano, Filip Roelens, Felix Rosenow, Kaja Selmer, Jose M. Serratosa, Sanjay Sisodiya, Ulrich Stephani, Katalin Sterbova, Pasquale Striano, Arvid Suls, Tiina Talvik, Sarah Von Spiczak, Yvonne Weber, Sarah Weckhuysen, Federico Zara, Bassel Abou-Khalil, Brian K. Alldredge, Eva Andermann, Frederick Andermann, Dina Amron, Jocelyn F. Bautista, Samuel F. Berkovic, Judith Bluvstein, Alex Boro, Gregory Cascino, Damian Consalvo, Patricia Crumrine, Orrin Devinsky, Dennis Dlugos, Michael P. Epstein, 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, Ruben Kuzniecky, Daniel H. Lowenstein, Shannon M. McGuire, Paul V. Motika, Edward J. Novotny, Ruth Ottman, Juliann M. Paolicchi, Jack Parent, Kristen Park, Annapurna Poduri, Lynette Sadleir, Ingrid E. Scheffer, Renée A. Shellhaas, Elliott Sherr, Jerry J. Shih, Rani Singh, Joseph Sirven, Michael C. Smith, Joe Sullivan, Liu Lin Thio, Anu Venkat, Eileen P G Vining, Gretchen K. Von Allmen, Judith L. Weisenberg, Peter Widdess-Walsh, Melodie R. Winawer, Andrew S. Allen, Patrick Cossette, Norman Delanty, Evan E. Eichler, David B. Goldstein, Yujun Han, Erin L. Heinzen, Michael R. Johnson, Anthony G. Marson, Heather C. Mefford, Sahar Esmaeeli Nieh, Terence J. O'Brien, Stephen Petrou, Slavé Petrovski, Elizabeth K. Ruzzo

Neurology

Research output: Contribution to journal › Article › peer-review

343 Scopus citations

Abstract

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10 ^-4), supporting a prominent role for de novo mutations in epileptic encephalopathies.We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

Original language	English (US)
Pages (from-to)	360-370
Number of pages	11
Journal	American Journal of Human Genetics
Volume	95
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2014.08.013
State	Published - 2014

Bibliographical note

Publisher Copyright:
© 2014 by The American Society of Human Genetics. All rights reserved.

Access

10.1016/j.ajhg.2014.08.013

OpenUrl availability

Full text

Cite this

Appenzeller, S., Balling, R., Barisic, N., Baulac, S., Caglayan, H., Craiu, D., De Jonghe, P., Depienne, C., Dimova, P., Djémié, T., Gormley, P., Guerrini, R., Helbig, I., Hjalgrim, H., Hoffman-Zacharska, D., Jähn, J., Klein, K. M., Koeleman, B., Komarek, V., ... Ruzzo, E. K. (2014). De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. American Journal of Human Genetics, 95(4), 360-370. https://doi.org/10.1016/j.ajhg.2014.08.013

Appenzeller, S, Balling, R, Barisic, N, Baulac, S, Caglayan, H, Craiu, D, De Jonghe, P, Depienne, C, Dimova, P, Djémié, T, Gormley, P, Guerrini, R, Helbig, I, Hjalgrim, H, Hoffman-Zacharska, D, Jähn, J, Klein, KM, Koeleman, B, Komarek, V, Krause, R, Kuhlenbäumer, G, Leguern, E, Lehesjoki, AE, Lemke, JR, Lerche, H, Linnankivi, T, Marini, C, May, P, Møller, RS, Muhle, H, Pal, D, Palotie, A, Pendziwiat, M, Robbiano, A, Roelens, F, Rosenow, F, Selmer, K, Serratosa, JM, Sisodiya, S, Stephani, U, Sterbova, K, Striano, P, Suls, A, Talvik, T, Von Spiczak, S, Weber, Y, Weckhuysen, S, Zara, F, Abou-Khalil, B, Alldredge, BK, Andermann, E, Andermann, F, Amron, D, Bautista, JF, Berkovic, SF, Bluvstein, J, Boro, A, Cascino, G, Consalvo, D, Crumrine, P, Devinsky, O, Dlugos, D, Epstein, MP, 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, Kuzniecky, R, Lowenstein, DH, McGuire, SM, Motika, PV, Novotny, EJ, Ottman, R, Paolicchi, JM, Parent, J, Park, K, Poduri, A, Sadleir, L, Scheffer, IE, Shellhaas, RA, Sherr, E, Shih, JJ, Singh, R, Sirven, J, Smith, MC, Sullivan, J, Thio, LL, Venkat, A, Vining, EPG, Von Allmen, GK, Weisenberg, JL, Widdess-Walsh, P, Winawer, MR, Allen, AS, Cossette, P, Delanty, N, Eichler, EE, Goldstein, DB, Han, Y, Heinzen, EL, Johnson, MR, Marson, AG, Mefford, HC, Nieh, SE, O'Brien, TJ, Petrou, S, Petrovski, S & Ruzzo, EK 2014, 'De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies', American Journal of Human Genetics, vol. 95, no. 4, pp. 360-370. https://doi.org/10.1016/j.ajhg.2014.08.013

@article{604fb7eb477447a2a434f26ef57523c4,

title = "De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies",

abstract = "Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the {"}classical{"} epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10 -4), supporting a prominent role for de novo mutations in epileptic encephalopathies.We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.",

author = "Silke Appenzeller and Rudi Balling and Nina Barisic and St{\'e}phanie Baulac and Hande Caglayan and Dana Craiu and {De Jonghe}, Peter and Christel Depienne and Petia Dimova and Tania Dj{\'e}mi{\'e} and Padhraig Gormley and Renzo Guerrini and Ingo Helbig and Helle Hjalgrim and Dorota Hoffman-Zacharska and Johanna J{\"a}hn and Klein, {Karl Martin} and Bobby Koeleman and Vladimir Komarek and Roland Krause and Gregor Kuhlenb{\"a}umer and Eric Leguern and Lehesjoki, {Anna Elina} and Lemke, {Johannes R.} and Holger Lerche and Tarja Linnankivi and Carla Marini and Patrick May and M{\o}ller, {Rikke S.} and Hiltrud Muhle and Deb Pal and Aarno Palotie and Manuela Pendziwiat and Angela Robbiano and Filip Roelens and Felix Rosenow and Kaja Selmer and Serratosa, {Jose M.} and Sanjay Sisodiya and Ulrich Stephani and Katalin Sterbova and Pasquale Striano and Arvid Suls and Tiina Talvik and {Von Spiczak}, Sarah and Yvonne Weber and Sarah Weckhuysen and Federico Zara and Bassel Abou-Khalil and Alldredge, {Brian K.} and Eva Andermann and Frederick Andermann and Dina Amron and Bautista, {Jocelyn F.} and Berkovic, {Samuel F.} and Judith Bluvstein and Alex Boro and Gregory Cascino and Damian Consalvo and Patricia Crumrine and Orrin Devinsky and Dennis Dlugos and Epstein, {Michael P.} 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 Ruben Kuzniecky and Lowenstein, {Daniel H.} and McGuire, {Shannon M.} and Motika, {Paul V.} and Novotny, {Edward J.} and Ruth Ottman and Paolicchi, {Juliann M.} and Jack Parent and Kristen Park and Annapurna Poduri and Lynette Sadleir and Scheffer, {Ingrid E.} and Shellhaas, {Ren{\'e}e A.} and Elliott Sherr and Shih, {Jerry J.} and Rani Singh and Joseph Sirven and Smith, {Michael C.} and Joe 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.} and Allen, {Andrew S.} and Patrick Cossette and Norman Delanty and Eichler, {Evan E.} and Goldstein, {David B.} and Yujun Han and Heinzen, {Erin L.} and Johnson, {Michael R.} and Marson, {Anthony G.} and Mefford, {Heather C.} and Nieh, {Sahar Esmaeeli} and O'Brien, {Terence J.} and Stephen Petrou and Slav{\'e} Petrovski and Ruzzo, {Elizabeth K.}",

year = "2014",

doi = "10.1016/j.ajhg.2014.08.013",

language = "English (US)",

volume = "95",

pages = "360--370",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies

AU - Appenzeller, Silke

AU - Balling, Rudi

AU - Barisic, Nina

AU - Baulac, Stéphanie

AU - Caglayan, Hande

AU - Craiu, Dana

AU - De Jonghe, Peter

AU - Depienne, Christel

AU - Dimova, Petia

AU - Djémié, Tania

AU - Gormley, Padhraig

AU - Guerrini, Renzo

AU - Helbig, Ingo

AU - Hjalgrim, Helle

AU - Hoffman-Zacharska, Dorota

AU - Jähn, Johanna

AU - Klein, Karl Martin

AU - Koeleman, Bobby

AU - Komarek, Vladimir

AU - Krause, Roland

AU - Kuhlenbäumer, Gregor

AU - Leguern, Eric

AU - Lehesjoki, Anna Elina

AU - Lemke, Johannes R.

AU - Lerche, Holger

AU - Linnankivi, Tarja

AU - Marini, Carla

AU - May, Patrick

AU - Møller, Rikke S.

AU - Muhle, Hiltrud

AU - Pal, Deb

AU - Palotie, Aarno

AU - Pendziwiat, Manuela

AU - Robbiano, Angela

AU - Roelens, Filip

AU - Rosenow, Felix

AU - Selmer, Kaja

AU - Serratosa, Jose M.

AU - Sisodiya, Sanjay

AU - Stephani, Ulrich

AU - Sterbova, Katalin

AU - Striano, Pasquale

AU - Suls, Arvid

AU - Talvik, Tiina

AU - Von Spiczak, Sarah

AU - Weber, Yvonne

AU - Weckhuysen, Sarah

AU - Zara, Federico

AU - Abou-Khalil, Bassel

AU - Alldredge, Brian K.

AU - Andermann, Eva

AU - Andermann, Frederick

AU - Amron, Dina

AU - Bautista, Jocelyn F.

AU - Berkovic, Samuel F.

AU - Bluvstein, Judith

AU - Boro, Alex

AU - Cascino, Gregory

AU - Consalvo, Damian

AU - Crumrine, Patricia

AU - Devinsky, Orrin

AU - Dlugos, Dennis

AU - Epstein, Michael P.

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 - Kuzniecky, Ruben

AU - Lowenstein, Daniel H.

AU - McGuire, Shannon M.

AU - Motika, Paul V.

AU - Novotny, Edward J.

AU - Ottman, Ruth

AU - Paolicchi, Juliann M.

AU - Parent, Jack

AU - Park, Kristen

AU - Poduri, Annapurna

AU - Sadleir, Lynette

AU - Scheffer, Ingrid E.

AU - Shellhaas, Renée A.

AU - Sherr, Elliott

AU - Shih, Jerry J.

AU - Singh, Rani

AU - Sirven, Joseph

AU - Smith, Michael C.

AU - Sullivan, Joe

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.

AU - Allen, Andrew S.

AU - Cossette, Patrick

AU - Delanty, Norman

AU - Eichler, Evan E.

AU - Goldstein, David B.

AU - Han, Yujun

AU - Heinzen, Erin L.

AU - Johnson, Michael R.

AU - Marson, Anthony G.

AU - Mefford, Heather C.

AU - Nieh, Sahar Esmaeeli

AU - O'Brien, Terence J.

AU - Petrou, Stephen

AU - Petrovski, Slavé

AU - Ruzzo, Elizabeth K.

PY - 2014

Y1 - 2014

N2 - Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10 -4), supporting a prominent role for de novo mutations in epileptic encephalopathies.We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

AB - Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10 -4), supporting a prominent role for de novo mutations in epileptic encephalopathies.We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

UR - http://www.scopus.com/inward/record.url?scp=84921803785&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84921803785&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2014.08.013

DO - 10.1016/j.ajhg.2014.08.013

M3 - Article

C2 - 25262651

AN - SCOPUS:84921803785

SN - 0002-9297

VL - 95

SP - 360

EP - 370

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 4

ER -

De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies

Abstract

Bibliographical note

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this