Medicine (Austin & Northern Health) - Research Publications

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Author: O'Brien, Terence × Author: Petrovski, Slave × End date: 2013 × Start date: 2012 ×

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    De novo mutations in epileptic encephalopathies
    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, Y-F ; Madou, MRZ ; Marson, AG ; Mefford, HC ; Nieh, SE ; O'Brien, TJ ; Ottman, R ; Petrovski, S ; Poduri, A ; Ruzzo, EK ; Scheffer, IE ; Sherr, EH ; Yuskaitis, CJ ; Abou-Khalil, B ; Alldredge, BK ; Bautista, JF ; Berkovic, SF ; Boro, A ; Cascino, GD ; Consalvo, D ; Crumrine, P ; Devinsky, O ; Dlugos, D ; Epstein, MP ; Fiol, M ; Fountain, NB ; French, J ; Friedman, D ; Geller, EB ; Glauser, T ; Glynn, S ; Haut, SR ; Hayward, J ; Helmers, SL ; Joshi, S ; Kanner, A ; Kirsch, HE ; Knowlton, RC ; Kossoff, E ; Kuperman, R ; Kuzniecky, R ; Lowenstein, DH ; McGuire, SM ; Motika, PV ; Novotny, EJ ; Ottman, R ; Paolicchi, JM ; Parent, JM ; Park, K ; Poduri, A ; Scheffer, IE ; Shellhaas, RA ; Sherr, EH ; 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 (NATURE PUBLISHING GROUP, 2013-09-12)
    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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    Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A
    Kasperaviciute, D ; Catarino, CB ; Matarin, M ; Leu, C ; Novy, J ; Tostevin, A ; Leal, B ; Hessel, EVS ; Hallmann, K ; Hildebrand, MS ; Dahl, H-HM ; Ryten, M ; Trabzuni, D ; Ramasamy, A ; Alhusaini, S ; Doherty, CP ; Dorn, T ; Hansen, J ; Kraemer, G ; Steinhoff, BJ ; Zumsteg, D ; Duncan, S ; Kaelviaeinen, RK ; Eriksson, KJ ; Kantanen, A-M ; Pandolfo, M ; Gruber-Sedlmayr, U ; Schlachter, K ; Reinthaler, EM ; Stogmann, E ; Zimprich, F ; Theatre, E ; Smith, C ; O'Brien, TJ ; Tan, KM ; Petrovski, S ; Robbiano, A ; Paravidino, R ; Zara, F ; Striano, P ; Sperling, MR ; Buono, RJ ; Hakonarson, H ; Chaves, J ; Costa, PP ; Silva, BM ; da Silva, AM ; de Graan, PNE ; Koeleman, BPC ; Becker, A ; Schoch, S ; von Lehe, M ; Reif, PS ; Rosenow, F ; Becker, F ; Weber, Y ; Lerche, H ; Roessler, K ; Buchfelder, M ; Hamer, HM ; Kobow, K ; Coras, R ; Blumcke, I ; Scheffer, IE ; Berkovic, SF ; Weale, ME ; Delanty, N ; Depondt, C ; Cavalleri, GL ; Kunz, WS ; Sisodiya, SM (OXFORD UNIV PRESS, 2013-10)
    Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.