Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

Epi4K Consortium; Epilepsy Phenome Genome Project; EuroEPINOMICS RES Consortium; Andrew S. Allen; Samuel F. Berkovic; Joshua Bridgers; Patrick Cossette; Dennis Dlugos; Michael P. Epstein; Tracy Glauser; David B. Goldstein; Erin L. Heinzen; Yu Jiang; Michael R. Johnson; Ruben Kuzniecky; Daniel H. Lowenstein; Anthony G. Marson; Heather C. Mefford; Terence J. O'Brien; Ruth Ottman; Steven Petrou; Slavé Petrovski; Annapurna Poduri; Zhong Ren; Ingrid E. Scheffer; Elliott Sherr; Quanli Wang; Rudi Balling; Nina Barisic; Stéphanie Baulac; Hande Caglayan; Dana Craiu; Peter De Jonghe; Christel Depienne; Renzo Guerrini; Ingo Helbig; Helle Hjalgrim; Dorota Hoffman-Zacharska; Johanna Jähn; Karl Martin Klein; Bobby Koeleman; Vladimir Komarek; Roland Krause; Eric Leguern; Anna Elina Lehesjoki; Johannes R. Lemke; Holger Lerche; Tarja Linnankivi; Carla Marini; Patrick May; Rikke S. Møller; Hiltrud Muhle; Deb Pal

doi:10.1038/ejhg.2017.61

Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

Epi4K Consortium, Epilepsy Phenome Genome Project, EuroEPINOMICS RES Consortium, Andrew S. Allen, Samuel F. Berkovic, Joshua Bridgers, Patrick Cossette, Dennis Dlugos, Michael P. Epstein, Tracy Glauser, David B. Goldstein, Erin L. Heinzen, Yu Jiang, Michael R. Johnson, Ruben Kuzniecky, Daniel H. Lowenstein, Anthony G. Marson, Heather C. Mefford, Terence J. O'Brien, Ruth OttmanSteven Petrou, Slavé Petrovski, Annapurna Poduri, Zhong Ren, Ingrid E. Scheffer, Elliott Sherr, Quanli Wang, Rudi Balling, Nina Barisic, Stéphanie Baulac, Hande Caglayan, Dana Craiu, Peter De Jonghe, Christel Depienne, Renzo Guerrini, Ingo Helbig, Helle Hjalgrim, Dorota Hoffman-Zacharska, Johanna Jähn, Karl Martin Klein, Bobby Koeleman, Vladimir Komarek, Roland Krause, Eric Leguern, Anna Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Tarja Linnankivi, Carla Marini, Patrick May, Rikke S. Møller, Hiltrud Muhle, Deb Pal

Basic and Clinical Neuroscience

Research output: Book/Report › Report › peer-review

7 Citations (Scopus)

Abstract

The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population.

Original language	English
Number of pages	6
Volume	25
Edition	7
DOIs	https://doi.org/10.1038/ejhg.2017.61
Publication status	E-pub ahead of print - 17 May 2017

Publication series

Name	European Journal of Human Genetics
ISSN (Print)	1018-4813

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10.1038/ejhg.2017.61

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Epi4K Consortium, Epilepsy Phenome Genome Project, EuroEPINOMICS RES Consortium, Allen, A. S., Berkovic, S. F., Bridgers, J., Cossette, P., Dlugos, D., Epstein, M. P., Glauser, T., Goldstein, D. B., Heinzen, E. L., Jiang, Y., Johnson, M. R., Kuzniecky, R., Lowenstein, D. H., Marson, A. G., Mefford, H. C., O'Brien, T. J., ... Pal, D. (2017). Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data. (7 ed.) (European Journal of Human Genetics). Advance online publication. https://doi.org/10.1038/ejhg.2017.61

@book{5df7191fc8814183bbd7eeff5d7f4c3a,

title = "Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data",

abstract = "The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population.",

author = "{Epi4K Consortium} and {Epilepsy Phenome Genome Project} and {EuroEPINOMICS RES Consortium} and Allen, {Andrew S.} and Berkovic, {Samuel F.} and Joshua Bridgers and Patrick Cossette and Dennis Dlugos and Epstein, {Michael P.} and Tracy Glauser and Goldstein, {David B.} and Heinzen, {Erin L.} and Yu Jiang and Johnson, {Michael R.} and Ruben Kuzniecky and Lowenstein, {Daniel H.} and Marson, {Anthony G.} and Mefford, {Heather C.} and O'Brien, {Terence J.} and Ruth Ottman and Steven Petrou and Slav{\'e} Petrovski and Annapurna Poduri and Zhong Ren and Scheffer, {Ingrid E.} and Elliott Sherr and Quanli Wang 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 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 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",

year = "2017",

month = may,

day = "17",

doi = "10.1038/ejhg.2017.61",

language = "English",

volume = "25",

series = "European Journal of Human Genetics",

edition = "7",

}

Epi4K Consortium, Epilepsy Phenome Genome Project, EuroEPINOMICS RES Consortium, Allen, AS, Berkovic, SF, Bridgers, J, Cossette, P, Dlugos, D, Epstein, MP, Glauser, T, Goldstein, DB, Heinzen, EL, Jiang, Y, Johnson, MR, Kuzniecky, R, Lowenstein, DH, Marson, AG, Mefford, HC, O'Brien, TJ, Ottman, R, Petrou, S, Petrovski, S, Poduri, A, Ren, Z, Scheffer, IE, Sherr, E, Wang, Q, Balling, R, Barisic, N, Baulac, S, Caglayan, H, Craiu, D, De Jonghe, P, Depienne, C, Guerrini, R, Helbig, I, Hjalgrim, H, Hoffman-Zacharska, D, Jähn, J, Klein, KM, Koeleman, B, Komarek, V, Krause, R, Leguern, E, Lehesjoki, AE, Lemke, JR, Lerche, H, Linnankivi, T, Marini, C, May, P, Møller, RS, Muhle, H & Pal, D 2017, Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data. European Journal of Human Genetics, vol. 25, 7 edn. https://doi.org/10.1038/ejhg.2017.61

TY - BOOK

T1 - Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

AU - Epi4K Consortium

AU - Epilepsy Phenome Genome Project

AU - EuroEPINOMICS RES Consortium

AU - Allen, Andrew S.

AU - Berkovic, Samuel F.

AU - Bridgers, Joshua

AU - Cossette, Patrick

AU - Dlugos, Dennis

AU - Epstein, Michael P.

AU - Glauser, Tracy

AU - Goldstein, David B.

AU - Heinzen, Erin L.

AU - Jiang, Yu

AU - Johnson, Michael R.

AU - Kuzniecky, Ruben

AU - Lowenstein, Daniel H.

AU - Marson, Anthony G.

AU - Mefford, Heather C.

AU - O'Brien, Terence J.

AU - Ottman, Ruth

AU - Petrou, Steven

AU - Petrovski, Slavé

AU - Poduri, Annapurna

AU - Ren, Zhong

AU - Scheffer, Ingrid E.

AU - Sherr, Elliott

AU - Wang, Quanli

AU - Balling, Rudi

AU - Barisic, Nina

AU - Baulac, Stéphanie

AU - Caglayan, Hande

AU - Craiu, Dana

AU - De Jonghe, Peter

AU - Depienne, Christel

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 - 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

PY - 2017/5/17

Y1 - 2017/5/17

N2 - The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population.

AB - The classic epileptic encephalopathies, including infantile spasms (IS) and Lennox-Gastaut syndrome (LGS), are severe seizure disorders that usually arise sporadically. De novo variants in genes mainly encoding ion channel and synaptic proteins have been found to account for over 15% of patients with IS or LGS. The contribution of autosomal recessive genetic variation, however, is less well understood. We implemented a rare variant transmission disequilibrium test (TDT) to search for autosomal recessive epileptic encephalopathy genes in a cohort of 320 outbred patient-parent trios that were generally prescreened for rare metabolic disorders. In the current sample, our rare variant transmission disequilibrium test did not identify individual genes with significantly distorted transmission over expectation after correcting for the multiple tests. While the rare variant transmission disequilibrium test did not find evidence of a role for individual autosomal recessive genes, our current sample is insufficiently powered to assess the overall role of autosomal recessive genotypes in an outbred epileptic encephalopathy population.

UR - http://www.scopus.com/inward/record.url?scp=85019562360&partnerID=8YFLogxK

U2 - 10.1038/ejhg.2017.61

DO - 10.1038/ejhg.2017.61

M3 - Report

C2 - 28513609

AN - SCOPUS:85019562360

VL - 25

T3 - European Journal of Human Genetics

BT - Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

ER -

Application of rare variant transmission disequilibrium tests to epileptic encephalopathy trio sequence data

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