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    Familial Mesial Temporal Lobe Epilepsy: Clinical Spectrum and Genetic Evidence for a Polygenic Architecture
    Harris, RV ; Oliver, KL ; Perucca, P ; Striano, P ; Labate, A ; Riva, A ; Grinton, BE ; Reid, J ; Hutton, J ; Todaro, M ; O'Brien, TJ ; Kwan, P ; Sadleir, LG ; Mullen, SA ; Dazzo, E ; Crompton, DE ; Scheffer, IE ; Bahlo, M ; Nobile, C ; Gambardella, A ; Berkovic, SF (WILEY, 2023-11)
    OBJECTIVE: Familial mesial temporal lobe epilepsy (FMTLE) is an important focal epilepsy syndrome; its molecular genetic basis is unknown. Clinical descriptions of FMTLE vary between a mild syndrome with prominent déjà vu to a more severe phenotype with febrile seizures and hippocampal sclerosis. We aimed to refine the phenotype of FMTLE by analyzing a large cohort of patients and asked whether common risk variants for focal epilepsy and/or febrile seizures, measured by polygenic risk scores (PRS), are enriched in individuals with FMTLE. METHODS: We studied 134 families with ≥ 2 first or second-degree relatives with temporal lobe epilepsy, with clear mesial ictal semiology required in at least one individual. PRS were calculated for 227 FMTLE cases, 124 unaffected relatives, and 16,077 population controls. RESULTS: The age of patients with FMTLE onset ranged from 2.5 to 70 years (median = 18, interquartile range = 13-28 years). The most common focal seizure symptom was déjà vu (62% of cases), followed by epigastric rising sensation (34%), and fear or anxiety (22%). The clinical spectrum included rare cases with drug-resistance and/or hippocampal sclerosis. FMTLE cases had a higher mean focal epilepsy PRS than population controls (odds ratio = 1.24, 95% confidence interval = 1.06, 1.46, p = 0.007); in contrast, no enrichment for the febrile seizure PRS was observed. INTERPRETATION: FMTLE is a generally mild drug-responsive syndrome with déjà vu being the commonest symptom. In contrast to dominant monogenic focal epilepsy syndromes, our molecular data support a polygenic basis for FMTLE. Furthermore, the PRS data suggest that sub-genome-wide significant focal epilepsy genome-wide association study single nucleotide polymorphisms are important risk variants for FMTLE. ANN NEUROL 2023;94:825-835.
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    A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
    Grinton, BE ; Robertson, E ; Fearnley, LG ; Scheffer, IE ; Marson, AG ; O'Brien, TJ ; Pickrell, WO ; Rees, M ; Sisodiya, SM ; Balding, DJ ; Bennett, MF ; Bahlo, M ; Berkovic, SF ; Oliver, KL (CELL PRESS, 2022-11-03)
    Genetic epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial epilepsy syndrome characterized by distinctive phenotypic heterogeneity within families. The SCN1B c.363C>G (p.Cys121Trp) variant has been identified in independent, multi-generational families with GEFS+. Although the variant is present in population databases (at very low frequency), there is strong clinical, genetic, and functional evidence to support pathogenicity. Recurrent variants may be due to a founder event in which the variant has been inherited from a common ancestor. Here, we report evidence of a single founder event giving rise to the SCN1B c.363C>G variant in 14 independent families with epilepsy. A common haplotype was observed in all families, and the age of the most recent common ancestor was estimated to be approximately 800 years ago. Analysis of UK Biobank whole-exome-sequencing data identified 74 individuals with the same variant. All individuals carried haplotypes matching the epilepsy-affected families, suggesting all instances of the variant derive from a single mutational event. This unusual finding of a variant causing an autosomal dominant, early-onset disease in an outbred population that has persisted over many generations can be attributed to the relatively mild phenotype in most carriers and incomplete penetrance. Founder events are well established in autosomal recessive and late-onset disorders but are rarely observed in early-onset, autosomal dominant diseases. These findings suggest variants present in the population at low frequencies should be considered potentially pathogenic in mild phenotypes with incomplete penetrance and may be more important contributors to the genetic landscape than previously thought.
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    Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals
    Motelow, JE ; Povysil, G ; Dhindsa, RS ; Stanley, KE ; Allen, AS ; Feng, Y-CA ; Howrigan, DP ; Abbott, LE ; Tashman, K ; Cerrato, F ; Cusick, C ; Singh, T ; Heyne, H ; Byrnes, AE ; Churchhouse, C ; Watts, N ; Solomonson, M ; Lal, D ; Gupta, N ; Neale, BM ; Cavalleri, GL ; Cossette, P ; Cotsapas, C ; De Jonghe, P ; Dixon-Salazar, T ; Guerrini, R ; Hakonarson, H ; Heinzen, EL ; Helbig, I ; Kwan, P ; Marson, AG ; Petrovski, S ; Kamalakaran, S ; Sisodiya, SM ; Stewart, R ; Weckhuysen, S ; Depondt, C ; Dlugos, DJ ; Scheffer, IE ; Striano, P ; Freyer, C ; Krause, R ; May, P ; McKenna, K ; Regan, BM ; Bennett, CA ; Leu, C ; Leech, SL ; O'Brien, TJ ; Todaro, M ; Stamberger, H ; Andrade, DM ; Ali, QZ ; Sadoway, TR ; Krestel, H ; Schaller, A ; Papacostas, SS ; Kousiappa, I ; Tanteles, GA ; Christou, Y ; Sterbova, K ; Vlckova, M ; Sedlackova, L ; Lassuthova, P ; Klein, KM ; Rosenow, F ; Reif, PS ; Knake, S ; Neubauer, BA ; Zimprich, F ; Feucht, M ; Reinthaler, EM ; Kunz, WS ; Zsurka, G ; Surges, R ; Baumgartner, T ; von Wrede, R ; Pendziwiat, M ; Muhle, H ; Rademacher, A ; van Baalen, A ; von Spiczak, S ; Stephani, U ; Afawi, Z ; Korczyn, AD ; Kanaan, M ; Canavati, C ; Kurlemann, G ; Muller-Schluter, K ; Kluger, G ; Haeusler, M ; Blatt, I ; Lemke, JR ; Krey, I ; Weber, YG ; Wolking, S ; Becker, F ; Lauxmann, S ; Bosselmann, C ; Kegele, J ; Hengsbach, C ; Rau, S ; Steinhoff, BJ ; Schulze-Bonhage, A ; Borggraefe, I ; Schankin, CJ ; Schubert-Bast, S ; Schreiber, H ; Mayer, T ; Korinthenberg, R ; Brockmann, K ; Wolff, M ; Dennig, D ; Madeleyn, R ; Kalviainen, R ; Saarela, A ; Timonen, O ; Linnankivi, T ; Lehesjoki, A-E ; Rheims, S ; Lesca, G ; Ryvlin, P ; Maillard, L ; Valton, L ; Derambure, P ; Bartolomei, F ; Hirsch, E ; Michel, V ; Chassoux, F ; Rees, M ; Chung, S-K ; Pickrell, WO ; Powell, R ; Baker, MD ; Fonferko-Shadrach, B ; Lawthom, C ; Anderson, J ; Schneider, N ; Balestrini, S ; Zagaglia, S ; Braatz, V ; Johnson, MR ; Auce, P ; Sills, GJ ; Baum, LW ; Sham, PC ; Cherny, SS ; Lui, CHT ; Delanty, N ; Doherty, CP ; Shukralla, A ; El-Naggar, H ; Widdess-Walsh, P ; Barisi, N ; Canafoglia, L ; Franceschetti, S ; Castellotti, B ; Granata, T ; Ragona, F ; Zara, F ; Iacomino, M ; Riva, A ; Madia, F ; Vari, MS ; Salpietro, V ; Scala, M ; Mancardi, MM ; Nobili, L ; Amadori, E ; Giacomini, T ; Bisulli, F ; Pippucci, T ; Licchetta, L ; Minardi, R ; Tinuper, P ; Muccioli, L ; Mostacci, B ; Gambardella, A ; Labate, A ; Annesi, G ; Manna, L ; Gagliardi, M ; Parrini, E ; Mei, D ; Vetro, A ; Bianchini, C ; Montomoli, M ; Doccini, V ; Barba, C ; Hirose, S ; Ishii, A ; Suzuki, T ; Inoue, Y ; Yamakawa, K ; Beydoun, A ; Nasreddine, W ; Zgheib, NK ; Tumiene, B ; Utkus, A ; Sadleir, LG ; King, C ; Caglayan, SH ; Arslan, M ; Yapici, Z ; Topaloglu, P ; Kara, B ; Yis, U ; Turkdogan, D ; Gundogdu-Eken, A ; Bebek, N ; Tsai, M-H ; Ho, C-J ; Lin, C-H ; Lin, K-L ; Chou, I-J ; Poduri, A ; Shiedley, BR ; Shain, C ; Noebels, JL ; Goldman, A ; Busch, RM ; Jehi, L ; Najm, IM ; Ferguson, L ; Khoury, J ; Glauser, TA ; Clark, PO ; Buono, RJ ; Ferraro, TN ; Sperling, MR ; Lo, W ; Privitera, M ; French, JA ; Schachter, S ; Kuzniecky, R ; Devinsky, O ; Hegde, M ; Greenberg, DA ; Ellis, CA ; Goldberg, E ; Helbig, KL ; Cosico, M ; Vaidiswaran, P ; Fitch, E ; Berkovic, SF ; Lerche, H ; Lowenstein, DH ; Goldstein, DB (CELL PRESS, 2021-06-03)
    Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
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    Climate change and epilepsy: Insights from clinical and basic science studies
    Gulcebi, M ; Bartolini, E ; Lee, O ; Lisgaras, CP ; Onat, F ; Mifsud, J ; Striano, P ; Vezzani, A ; Hildebrand, MS ; Jimenez-Jimenez, D ; Junck, L ; Lewis-Smith, D ; Scheffer, IE ; Thijs, RD ; Zuberi, SM ; Blenkinsop, S ; Fowler, HJ ; Foley, A ; Sisodiya, SM ; Balestrini, S ; Berkovic, S ; Cavalleri, G ; Correa, DJ ; Custodio, HM ; Galovic, M ; Guerrini, R ; Henshall, D ; Howard, O ; Hughes, K ; Katsarou, A ; Koeleman, BPC ; Krause, R ; Lowenstein, D ; Mandelenaki, D ; Marini, C ; O'Brien, TJ ; Pace, A ; De Palma, L ; Perucca, P ; Pitkanen, A ; Quinn, F ; Selmer, KK ; Steward, CA ; Swanborough, N ; Thijs, R ; Tittensor, P ; Trivisano, M ; Weckhuysen, S ; Zara, F (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-03)
    Climate change is with us. As professionals who place value on evidence-based practice, climate change is something we cannot ignore. The current pandemic of the novel coronavirus, SARS-CoV-2, has demonstrated how global crises can arise suddenly and have a significant impact on public health. Global warming, a chronic process punctuated by acute episodes of extreme weather events, is an insidious global health crisis needing at least as much attention. Many neurological diseases are complex chronic conditions influenced at many levels by changes in the environment. This review aimed to collate and evaluate reports from clinical and basic science about the relationship between climate change and epilepsy. The keywords climate change, seasonal variation, temperature, humidity, thermoregulation, biorhythm, gene, circadian rhythm, heat, and weather were used to search the published evidence. A number of climatic variables are associated with increased seizure frequency in people with epilepsy. Climate change-induced increase in seizure precipitants such as fevers, stress, and sleep deprivation (e.g. as a result of more frequent extreme weather events) or vector-borne infections may trigger or exacerbate seizures, lead to deterioration of seizure control, and affect neurological, cerebrovascular, or cardiovascular comorbidities and risk of sudden unexpected death in epilepsy. Risks are likely to be modified by many factors, ranging from individual genetic variation and temperature-dependent channel function, to housing quality and global supply chains. According to the results of the limited number of experimental studies with animal models of seizures or epilepsy, different seizure types appear to have distinct susceptibility to seasonal influences. Increased body temperature, whether in the context of fever or not, has a critical role in seizure threshold and seizure-related brain damage. Links between climate change and epilepsy are likely to be multifactorial, complex, and often indirect, which makes predictions difficult. We need more data on possible climate-driven altered risks for seizures, epilepsy, and epileptogenesis, to identify underlying mechanisms at systems, cellular, and molecular levels for better understanding of the impact of climate change on epilepsy. Further focussed data would help us to develop evidence for mitigation methods to do more to protect people with epilepsy from the effects of climate change.
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    Quantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies
    Abou-Khalil, B ; Afawi, Z ; Allen, AS ; Bautista, JF ; Bellows, ST ; Berkovic, SF ; Bluvstein, J ; Burgess, R ; Cascino, G ; Cossette, P ; Cristofaro, S ; Crompton, DE ; Delanty, N ; Devinsky, O ; Dlugos, D ; Ellis, CA ; Epstein, MP ; Fountain, NB ; Freyer, C ; Geller, EB ; Glauser, T ; Glynn, S ; Goldberg-Stern, H ; Goldstein, DB ; Gravel, M ; Haas, K ; Haut, S ; Heinzen, EL ; Kirsch, HE ; Kivity, S ; Knowlton, R ; Korczyn, AD ; Kossoff, E ; Kuzniecky, R ; Loeb, R ; Lowenstein, DH ; Marson, AG ; McCormack, M ; McKenna, K ; Mefford, HC ; Motika, P ; Mullen, SA ; O'Brien, TJ ; Ottman, R ; Paolicchi, J ; Parent, JM ; Paterson, S ; Petrou, S ; Petrovski, S ; Pickrell, WO ; Poduri, A ; Rees, MI ; Sadleir, LG ; Scheffer, IE ; Shih, J ; Singh, R ; Sirven, J ; Smith, M ; Smith, PEM ; Thio, LL ; Thomas, RH ; Venkat, A ; Vining, E ; Von Allmen, G ; Weisenberg, J ; Widdess-Walsh, P ; Winawer, MR (WILEY, 2019-11)
    OBJECTIVE: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. METHODS: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. RESULTS: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. SIGNIFICANCE: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifying homogeneous sets of individuals that may share underlying disease mechanisms.
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    Epilepsy in families: Age at onset is a familial trait, independent of syndrome
    Ellis, CA ; Churilov, L ; Epstein, MP ; Xie, SX ; Bellows, ST ; Ottman, R ; Berkovic, SF (WILEY, 2019-07)
    OBJECTIVE: We tested 2 hypotheses regarding age at onset within familial epilepsies: (1) family members with epilepsy tend to have similar ages at onset, independent of epilepsy syndrome; and (2) age at onset is younger in successive generations after controlling for sampling bias. METHODS: We analyzed clinical data collected by the Epi4K Consortium (303 multiplex families, 1,120 individuals). To test hypothesis 1, we used both linear mixed models commonly used for heritability analysis and Cox regression models with frailty terms to assess clustering of onset within families after controlling for other predictors. To test hypothesis 2, we used mixed effects models, pairwise analyses, and survival analysis to address sampling-related bias that may mimic anticipation. RESULTS: Regarding hypothesis 1, age at seizure onset was significantly heritable (intraclass correlation coefficient = 0.17, p < 0.001) after adjusting for epilepsy type, sex, site, history of febrile seizure, and age at last observation. This finding remained significant after adjusting for epilepsy syndromes, and was robust across statistical methods in all families and in generalized families. Regarding hypothesis 2, the mean age at onset decreased in successive generations (p < 0.001). After adjusting for age at last observation, this effect was not significant in mixed effects models (p = 0.14), but remained significant in pairwise (p = 0.0003) and survival analyses (p = 0.02). INTERPRETATION: Age at seizure onset is an independent familial trait, and may have genetic determinants distinct from the determinants of particular epilepsy syndromes. Younger onsets in successive generations can be explained in part by sampling bias, but the presence of genetic anticipation cannot be excluded. ANN NEUROL 2019.
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    The severe epilepsy syndromes of infancy: A population-based study
    Howell, KB ; Freeman, JL ; Mackay, MT ; Fahey, MC ; Archer, J ; Berkovic, SF ; Chan, E ; Dabscheck, G ; Eggers, S ; Hayman, M ; Holberton, J ; Hunt, RW ; Jacobs, SE ; Kornberg, AJ ; Leventer, RJ ; Mandelstam, S ; McMahon, JM ; Mefford, HC ; Panetta, J ; Riseley, J ; Rodriguez-Casero, V ; Ryan, MM ; Schneider, AL ; Smith, LJ ; Stark, Z ; Wong, F ; Yiu, EM ; Scheffer, IE ; Harvey, AS (WILEY, 2021-02)
    OBJECTIVE: To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes. METHODS: A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined. RESULTS: Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had "variants" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and "WS-like" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in "WS-like" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, "WS-like," or "unifocal epilepsy" had severe-profound delay, and only two of 64 (3%) were deceased. SIGNIFICANCE: Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or "variant syndrome" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.
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    Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load
    Perucca, P ; Anderson, A ; Jazayeri, D ; Hitchcock, A ; Graham, J ; Todaro, M ; Tomson, T ; Battino, D ; Perucca, E ; Ferri, MM ; Rochtus, A ; Lagae, L ; Canevini, MP ; Zambrelli, E ; Campbell, E ; Koeleman, BPC ; Scheffer, IE ; Berkovic, SF ; Kwan, P ; Sisodiya, SM ; Goldstein, DB ; Petrovski, S ; Craig, J ; Vajda, FJE ; O'Brien, TJ (WILEY, 2020-06)
    OBJECTIVE: The mechanisms by which antiepileptic drugs (AEDs) cause birth defects (BDs) are unknown. Data suggest that AED-induced BDs may result from a genome-wide increase of de novo variants in the embryo, a mechanism that we investigated. METHODS: Whole exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and de novo copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in children exposed prenatally to AEDs (AED-exposed children) versus children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs versus those without BDs, adjusting for confounders. Fisher exact test was used to compare categorical data. RESULTS: Sixty-seven child-parent trios were included: 10 with AED-exposed children with BDs, 46 with AED-exposed unaffected children, and 11 with AED-unexposed unaffected children. The dnSNV/indel burden did not differ between AED-exposed children and AED-unexposed unaffected children (median dnSNV/indel number/child [range] = 3 [0-7] vs 3 [1-5], p = 0.50). Among AED-exposed children, there were no significant differences between those with BDs and those unaffected. Likely deleterious dnSNVs/indels were detected in 9 of 67 (13%) children, none of whom had BDs. The proportion of cases harboring likely deleterious dnSNVs/indels did not differ significantly between AED-unexposed and AED-exposed children. The dnCNV burden was not associated with AED exposure or birth outcome. INTERPRETATION: Our study indicates that prenatal AED exposure does not increase the burden of de novo variants, and that this mechanism is not a major contributor to AED-induced BDs. These results can be incorporated in routine patient counseling. ANN NEUROL 2020;87:897-906.
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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.