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.
Bibliographical noteFunding 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 Folkh?lsan 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).
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