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

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 PoduriZhong 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, Miguel E. Fiol, Epi4K Consortium, Epilepsy Phenome Genome Project, EuroEPINOMICS-RES Consortium

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


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 languageEnglish (US)
Pages (from-to)894-899
Number of pages6
JournalEuropean Journal of Human Genetics
Issue number7
StatePublished - Jun 1 2017

Bibliographical note

Funding Information:
This work was supported by grants from the National Institute of Neurological Disorders and Stroke (The Epilepsy Phenome/Genome Project NS053998; Epi4K NS077364, NS077274, NS077303, and NS077276), The Andrew's Foundation, Finding a Cure for Epilepsy and Seizures, the Richard Thalheimer Philanthropic Fund, and the Eurocores program EuroEPINOMICS-RES of the European Science Foundation. The project received further support through grants from the Fund for Scientific Research Flanders (FWO); the Academy of Finland (141549); the Folkhälsan Research Foundation; the program 'Investissements d'avenir' ANR-10- IAIHU-06; the Federal Ministry for Education and Research (IonNeurONet: 01GM1105), the German Research Foundation (DFG: HE5415/3-1; Le1030/11- 1; RO3396/2-1), the German Society for Epileptology (DGfE), the Foundation noepilep.; the Swiss National Science Foundation (SNF: 32EP30-136042/1); the Wellcome Trust (09805); intramural funds of the University of Kiel; the Popgen 2.0 network (P2N) through the German Ministry for Education and Research (01EY1103); and the European Union through Seventh Framework Programme (FP7) under the project DESIRE (N602531).

Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.


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