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1. Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy

Author

Wolking, S., Moreau, C., Mccormack, M., Krause, R., Krenn, M., Berkovic, S., Cavalleri, G. L., Delanty, N., Depondt, C., Johnson, M. R., Koeleman, B. P. C., Kunz, W. S., Lerche, H., Marson, A. G., O'Brien, T. J., Petrovski, S., Sander, J. W., Sills, G. J., Striano, P., Zara, F., Zimprich, F., Sisodiya, S. M., Girard, S. L., Cossette, P., Avbersek, A., Leu, C., Heggeli, K., Demurtas, R., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Berghuis, B., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Auce, P., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Hutton, J., Muhle, H., Klein, K. M., Moller, R. S., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Craig, J., and Stefansson, H.

Subjects
0301 basic medicine, Male, Candidate gene, Drug Resistant Epilepsy, Neurology [D14] [Human health sciences], Neurosciences. Biological psychiatry. Neuropsychiatry, Drug resistance, Bioinformatics, Polymorphism, Single Nucleotide, Whole Exome Sequencing, Cohort Studies, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Polymorphism, RC346-429, Gene, Exome sequencing, Research Articles, Genetic Association Studies, Neurologie [D14] [Sciences de la santé humaine], business.industry, General Neuroscience, Genetic variants, Genetic Variation, Single Nucleotide, medicine.disease, DEPDC5, Female, 030104 developmental biology, Cohort, Neurology (clinical), Neurology. Diseases of the nervous system, business, 030217 neurology & neurosurgery, RC321-571, Research Article
Abstract

Annals of Clinical and Translational Neurology 8(7), 1376-1387 (2021). doi:10.1002/acn3.51374, Published by Wiley, Chichester [u.a.]

Published
2021

2. Polygenic burden in focal and generalized epilepsies

Author

Leu C., Stevelink R., Smith A. W., Goleva S. B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S. M., Cavalleri G. L., Koeleman B. P. C., Lerche H., Jehi L., Davis L. K., Najm I. M., Palotie A., Daly M. J., Busch R. M., Lal D., Feng Y. -C. A., Howrigan D. P., Abbott L. E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B. M., Berkovic S. F., Goldstein D. B., Lowenstein D. H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E. L., Helbig I., Kwan P., Marson A. G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D. J., Scheffer I. E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B. M., Bellows S. T., Bennett C. A., Johns E. M. C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T. J., Todaro M., Stamberger H., Andrade D. M., Sadoway T. R., Mo K., Krestel H., Gallati S., Papacostas S. S., Kousiappa I., Tanteles G. A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K. M., Rosenow F., Reif P. S., Knake S., Kunz W. S., Zsurka G., Elger C. E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A. D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J. R., Krey I., Weber Y. G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A. F., Steinhoff B. J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C. J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A. -E., Rees M. I., Chung S. -K., Pickrell W. O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M. R., Auce P., Sills G. J., Baum L. W., Sham P. C., Cherny S. S., Lui C. H. T., Barisic N., Delanty N., Doherty C. P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M. S., Mancardi M. M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L. G., King C., Mountier E., Caglayan S. H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B. R., Shain C., Poduri A., Buono R. J., Ferraro T. N., Sperling M. R., Lo W., Privitera M., French J. A., Schachter S., Kuzniecky R. I., Devinsky O., Hegde M., Khankhanian P., Helbig K. L., Ellis C. A., Spalletta G., Piras F., Gili T., Ciullo V., Leu C., Stevelink R., Smith A.W., Goleva S.B., Kanai M., Ferguson L., Campbell C., Kamatani Y., Okada Y., Sisodiya S.M., Cavalleri G.L., Koeleman B.P.C., Lerche H., Jehi L., Davis L.K., Najm I.M., Palotie A., Daly M.J., Busch R.M., Lal D., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Churchhouse C., Gupta N., Neale B.M., Berkovic S.F., Goldstein D.B., Lowenstein D.H., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bellows S.T., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., Van Baalen A., Von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Muccioli L., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Birute T., Ruta M., Algirdas U., Ruta P., Jurgita G., Ruta S., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Sheidley B.R., Shain C., Poduri A., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Commission of the European Communities, Medical Research Council (MRC), Tumienė, Birutė, Mameniškienė, Rūta, Utkus, Algirdas, Praninskienė, Rūta, Grikinienė, Jurgita, Samaitienė-Aleknienė, Rūta, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Helsinki Institute of Life Science HiLIFE, and Department of Medical and Clinical Genetics

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, Epi25 Consortium, Databases, Factual, FEATURES, Genome-wide association study, Epilepsies, 3124 Neurology and psychiatry, Cohort Studies, Epilepsy, 0302 clinical medicine, Cost of Illness, 1ST SEIZURE, HISTORY, genetics, POPULATION, 11 Medical and Health Sciences, education.field_of_study, medicine.diagnostic_test, SCORES, Single Nucleotide, Biobank, 3. Good health, 17 Psychology and Cognitive Sciences, Genetic generalized epilepsy, Epilepsy, Generalized, Female, Partial, Cohort study, Human, medicine.medical_specialty, Population, European Continental Ancestry Group, Clinical Neurology, BIOBANK, Polymorphism, Single Nucleotide, epilepsy, genetic generalized epilepsy, common variant risk, Databases, 03 medical and health sciences, Genetic, Internal medicine, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Polymorphism, GENOME-WIDE ASSOCIATION, Generalized epilepsy, education, SEIZURE RECURRENCE, Factual, METAANALYSIS, Genetic testing, Neurology & Neurosurgery, RISK PREDICTION, Generalized, business.industry, 3112 Neurosciences, Common variant risk, Genetic Variation, Original Articles, medicine.disease, Comorbidity, Cost of Illne, Epilepsies, Partial, Genome-Wide Association Study, 030104 developmental biology, Neurology (clinical), Cohort Studie, business, 030217 neurology & neurosurgery
Abstract

See Hansen and Møller (doi:10.1093/brain/awz318) for a scientific commentary on this article. Using polygenic risk scores from a genome-wide association study in generalized and focal epilepsy, Leu et al. reveal a significantly higher genetic burden for epilepsy in multiple cohorts of people with epilepsy compared to population controls. Quantification of common variant burden may be valuable for epilepsy prognosis and treatment., Rare genetic variants can cause epilepsy, and genetic testing has been widely adopted for severe, paediatric-onset epilepsies. The phenotypic consequences of common genetic risk burden for epilepsies and their potential future clinical applications have not yet been determined. Using polygenic risk scores (PRS) from a European-ancestry genome-wide association study in generalized and focal epilepsy, we quantified common genetic burden in patients with generalized epilepsy (GE-PRS) or focal epilepsy (FE-PRS) from two independent non-Finnish European cohorts (Epi25 Consortium, n = 5705; Cleveland Clinic Epilepsy Center, n = 620; both compared to 20 435 controls). One Finnish-ancestry population isolate (Finnish-ancestry Epi25, n = 449; compared to 1559 controls), two European-ancestry biobanks (UK Biobank, n = 383 656; Vanderbilt biorepository, n = 49 494), and one Japanese-ancestry biobank (BioBank Japan, n = 168 680) were used for additional replications. Across 8386 patients with epilepsy and 622 212 population controls, we found and replicated significantly higher GE-PRS in patients with generalized epilepsy of European-ancestry compared to patients with focal epilepsy (Epi25: P = 1.64×10−15; Cleveland: P = 2.85×10−4; Finnish-ancestry Epi25: P = 1.80×10−4) or population controls (Epi25: P = 2.35×10−70; Cleveland: P = 1.43×10−7; Finnish-ancestry Epi25: P = 3.11×10−4; UK Biobank and Vanderbilt biorepository meta-analysis: P = 7.99×10−4). FE-PRS were significantly higher in patients with focal epilepsy compared to controls in the non-Finnish, non-biobank cohorts (Epi25: P = 5.74×10−19; Cleveland: P = 1.69×10−6). European ancestry-derived PRS did not predict generalized epilepsy or focal epilepsy in Japanese-ancestry individuals. Finally, we observed a significant 4.6-fold and a 4.5-fold enrichment of patients with generalized epilepsy compared to controls in the top 0.5% highest GE-PRS of the two non-Finnish European cohorts (Epi25: P = 2.60×10−15; Cleveland: P = 1.39×10−2). We conclude that common variant risk associated with epilepsy is significantly enriched in multiple cohorts of patients with epilepsy compared to controls—in particular for generalized epilepsy. As sample sizes and PRS accuracy continue to increase with further common variant discovery, PRS could complement established clinical biomarkers and augment genetic testing for patient classification, comorbidity research, and potentially targeted treatment.

Published
2019

3. Antiepileptic Drug Teratogenicity and De Novo Genetic Variation Load

Author

Perucca, P., Anderson, A., Jazayeri, D., Hitchcock, A., Graham, J., Todaro, M., Tomson, T., Battino, D., Perucca, E., Ferri, M. M., Rochtus, A., Lagae, L., Canevini, M. P., Zambrelli, E., Campbell, E., Koeleman, B. P. C., Scheffer, I. E., Berkovic, S. F., Kwan, P., Sisodiya, S. M., Goldstein, D. B., Petrovski, S., Craig, J., Vajda, F. J. E., O'Brien, T. J., Leu, C., Wolking, S., Peter, S., Weber, Y. G., Weckhuysen, S., Moller, R. S., Nikanorova, M., Muhle, H., Avbersek, A., Heggeli, K., Striano, P., Gambardella, A., Langley, S. R., Krenn, M., Klein, K. M., Mccormack, M., Borghei, M., Willis, J., Berghuis, B., Jorgensen, A., Auce, P., Francis, B., Srivastava, P., Sonsma, A. C. M., Sander, Jw., Zimprich, F., Depondt, C., Johnson, M. M., Marson, A. G., Sills, G. J., Kunz, W. S., Cavalleri, G. L., Delanty, N., Zara, F., Krause, R., Lerche, H., Andrade, D., Sen, A., Bazil, C. W., Boland, M., Cavalleri, G., Choi, H., Colombo, S., Costello, D., Devinsky, O., Doherty, C. P., Dugan, P., Frankel, W., Heinzen, E., Johnson, M., Marson, T., Mikati, M., Ottman, R., Pandolfo, M., Radtke, R., Rees, M., Sadoway, T., Valley, N., Walley, N., Wood, N., and Zuberi, S.

Subjects
Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, DNA Copy Number Variations, Polymorphism, Single Nucleotide, Paternal Age, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Pregnancy, Polymorphism (computer science), medicine, Humans, Exome, Copy-number variation, Indel, business.industry, Confounding, Infant, Newborn, Abnormalities, Drug-Induced, Genetic Variation, DNA, medicine.disease, Genetic load, Exact test, Teratogens, 030104 developmental biology, Neurology, Anticonvulsants, Female, Neurology (clinical), Genetic Load, business, 030217 neurology & neurosurgery
Abstract

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 which we investigated. METHODS: Whole-exome sequencing data from child-parent trios were interrogated for de novo single-nucleotide variants/indels (dnSNVs/indels) and copy number variants (dnCNVs). Generalized linear models were applied to assess de novo variant burdens in: children exposed prenatally to AEDs (AED-exposed children) vs children without BDs not exposed prenatally to AEDs (AED-unexposed unaffected children), and AED-exposed children with BDs vs those without BDs, adjusting for confounders. Fisher's exact test was used to compare categorical data. RESULTS: 67 child-parent trios were included: 10 with AED-exposed children with BDs; 46 with AED-exposed unaffected children; 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 9/67 (13%) children, none of whom had BDs. The proportion of cases harbouring 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 counselling. This article is protected by copyright. All rights reserved.

Published
2020

4. De novo variants in neurodevelopmental disorders with epilepsy

Author

Heyne, H. O., Singh, T., Stamberger, H., Abou Jamra, R., Caglayan, H., Craiu, D., De Jonghe, P., Guerrini, R., Helbig, K. L., Koeleman, B. P. C., Kosmicki, J. A., Linnankivi, T., May, P., Muhle, H., Moller, R. S., Neubauer, B. A., Palotie, A., Pendziwiat, M., Striano, P., Tang, S., Wu, S., Afawi, Z., De Kovel, C., Dimova, P., Djemie, T., Endziniene, M., Hoffman-Zacharska, D., Jahn, J., Korff, C., Lehesjoki, A. -E., Marini, C., Muller, S. H., Pal, D., Schwarz, N., Selmer, K., Serratosa, J., Stephani, U., Sterbova, K., Suls, A., Syrbe, S., Talvik, I., Von Spiczak, S., Zara, F., Poduri, A., Weber, Y. G., Weckhuysen, S., Sisodiya, S. M., Daly, M. J., Helbig, I., Lal, D., Lemke, J. R., Children's Hospital, Lastenneurologian yksikkö, Clinicum, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Research Programme for Molecular Neurology, Neuroscience Center, HUS Children and Adolescents, Genomics of Neurological and Neuropsychiatric Disorders, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Korff, Christian, and EuroEPINOMICS RES Consortium

Subjects
Exome/genetics, Male, 0301 basic medicine, ILAE COMMISSION, Joint analysis, Neurodevelopmental Disorders/genetics, Bioinformatics, Epilepsy/genetics, Epilepsy, 0302 clinical medicine, Intellectual disability, SEQUENCE VARIANTS, Missense mutation, Epilepsy is a frequent feature, Exome, TERMINOLOGY, Disease gene, 0303 health sciences, ddc:618, medicine.diagnostic_test, Genetic Predisposition to Disease/genetics, Neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMAN-DISEASE, PREVALENCE, 3. Good health, Genetic Variation/genetics, De novo variants, Female, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Genetic Testing/methods, Disease Association, Biology, CLASSIFICATION, 03 medical and health sciences, Intellectual Disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Limited evidence, 030304 developmental biology, Genetic testing, business.industry, MUTATIONS, AUTISM SPECTRUM DISORDER, Genetic Variation, medicine.disease, Intellectual Disability/genetics, 030104 developmental biology, Neurodevelopmental Disorders, epilepsy, KCNQ2 ENCEPHALOPATHY, Human medicine, 3111 Biomedicine, business, Genetic diagnosis, 030217 neurology & neurosurgery
Abstract

Epilepsy is a frequent feature of neurodevelopmental disorders (NDD) but little is known about genetic differences between NDD with and without epilepsy. We analyzed de novo variants (DNV) in 6753 parent-offspring trios ascertained for different NDD. In the subset of 1942 individuals with NDD with epilepsy, we identified 33 genes with a significant excess of DNV, of which SNAP25 and GABRB2 had previously only limited evidence for disease association. Joint analysis of all individuals with NDD also implicated CACNA1E as a novel disease gene. Comparing NDD with and without epilepsy, we found missense DNV, DNV in specific genes, age of recruitment and severity of intellectual disability to be associated with epilepsy. We further demonstrate to what extent our results impact current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDD with epilepsy.

Published
2018

5. A genome-wide association study of sodium levels and drug metabolism in an epilepsy cohort treated with carbamazepine and oxcarbazepine

Author

Berghuis, B., Stapleton, C., Sonsma, A. C. M., Hulst, J., de Haan, G. -J., Lindhout, D., Demurtas, R., Krause, R., Depondt, C., Kunz, W. S., Zara, F., Striano, P., Craig, J., Auce, P., Marson, A. G., Stefansson, H., O'Brien, T. J., Johnson, M. R., Sills, G. J., Wolking, S., Lerche, H., Sisodiya, S. M., Sander, J. W., Cavalleri, G. L., Koeleman, B. P. C., Mccormack, M., Avbersek, A., Leu, C., Heggeli, K., Willis, J., Speed, D., Sargsyan, N., Chinthapalli, K., Borghei, M., Coppola, A., Gambardella, A., Becker, F., Rau, S., Hengsbach, C., Weber, Y. G., Delanty, N., Campbell, E., Gudmundsson, L. J., Ingason, A., Stefansson, K., Schneider, R., Balling, R., Francis, B., Jorgensen, A., Morris, A., Langley, S., Srivastava, P., Brodie, M., Todaro, M., Petrovski, S., Hutton, J., Zimprich, F., Krenn, M., Muhle, H., Martin Klein, K., Moller, R., Nikanorova, M., Weckhuysen, S., Rener-Primec, Z., Berghuis, Bianca, Stapleton, Caragh, Sonsma, Anja C. M., Hulst, Janic, de Haan, Gerrit-Jan, Lindhout, Dick, Demurtas, Rita, Krause, Roland, Depondt, Chantal, Kunz, Wolfram S., Zara, Federico, Striano, Pasquale, Craig, John, Auce, Paul, Marson, Anthony G., Stefansson, Hreinn, O'Brien, Terence J., Johnson, Michael R., Sills, Graeme J., Wolking, Stefan, Lerche, Holger, Sisodiya, Sanjay M., Sander, Josemir W., Cavalleri, Gianpiero L., Koeleman, Bobby P. C., Mccormack, Mark, Weckhuysen, Sarah, EpiPGX Consortium, Imperial College Healthcare NHS Trust- BRC Funding, and Commission of the European Communities

Subjects
medicine.medical_specialty, hyponatremia, Clinical Neurology, Gastroenterology, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, adverse effects, antiepileptic drugs, EpiPGX Consortium, GWAS, antiepileptic drug, Internal medicine, adverse effect, medicine, Oxcarbazepine, Adverse effect, 030304 developmental biology, 0303 health sciences, business.industry, Généralités, Carbamazepine, medicine.disease, 3. Good health, Neurology, Cohort, Full‐length Original Research, Phenobarbital, Human medicine, Neurology (clinical), Hyponatremia, business, 030217 neurology & neurosurgery, Drug metabolism, medicine.drug
Abstract

Objective: To ascertain the clinical and genetic factors contributing to carbamazepine- and oxcarbazepine-induced hyponatremia (COIH), and to carbamazepine (CBZ) metabolism, in a retrospectively collected, cross-sectional cohort of people with epilepsy. Methods: We collected data on serum sodium levels and antiepileptic drug levels in people with epilepsy attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L. We estimated the CBZ metabolic ratio defined as the log transformation of the ratio of metabolite CBZ-diol to unchanged drug precursor substrate as measured in serum. Results: Clinical and genetic data relating to carbamazepine and oxcarbazepine trials were collected in 1141 patients. We did not observe any genome-wide significant associations with sodium level in a linear trend or hyponatremia as a dichotomous trait. Age, sex, number of comedications, phenytoin use, phenobarbital use, and sodium valproate use were significant predictors of CBZ metabolic ratio. No genome-wide significant associations with CBZ metabolic ratio were found. Significance: Although we did not detect a genetic predictor of hyponatremia or CBZ metabolism in our cohort, our findings suggest that the determinants of CBZ metabolism are multifactorial., SCOPUS: ar.j, info:eu-repo/semantics/published

Published
2019

6. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy

Author

Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH

Subjects
Male, Idiopathic generalized epilepsy, Neuronal, Idiopathic Generalized Epilepsy, 1q21, 1 Microdeletion, Two-hit Hypothesis, Nrxn1, Neuropsychological Tests, Immunoglobulin E, Cell Adhesion Molecules, Neuronal/genetics, Adult, Age of Onset, Anticonvulsant, Exon, 1q21.1 microdeletion, Exons/genetics, Odds Ratio, Nerve Tissue Proteins/genetics, Copy-number variation, Valproic Acid/therapeutic use, Age of Onset, Neural Cell Adhesion Molecules, genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy, Genetics, biology, Triazines, Anticonvulsants/therapeutic use, Electroencephalography, genetics, Family, Female, Fructose, Exons, Middle Aged, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, therapeutic use, Valproic Acid, Neurology, Settore MED/26 - Neurologia, Anticonvulsants, Epilepsy, Generalized, Female, Adult, Case-Control Studies, Cell Adhesion Molecules, Neuronal, DNA Copy Number Variations, Family, Fructose, Gene Deletion, Genotype, Humans, Infant, Microarray Analysis, Nerve Tissue Proteins, Valproic Acid, analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein, therapeutic use, Case-Control Studies, Cell Adhesion Molecule, drug therapy/genetics/psychology, Exon, genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine, Lamotrigine, NRXN1, Topiramate, Epilepsy, Generalized/drug therapy, medicine, Allele, Biology, Gene, Generalized, Point mutation, Calcium-Binding Proteins, Odds ratio, medicine.disease, Triazines/therapeutic use, Settore MED/03 - Genetica Medica, therapeutic use, biology.protein, Fructose/analogs & derivatives, Human medicine, Neurology (clinical), Two-hit hypothesis
Abstract

Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Published
2013

7. Evaluation of Presumably Disease Causing SCN1A Variants in a Cohort of Common Epilepsy Syndromes

Author

Lal, D., Reinthaler, E. M., Dejanovic, B., May, P., Thiele, H., Lehesjoki, A. . E., Schwarz, G., Riesch, E., Ikram, M. A., Van Duijn, C. M., Uitterlinden, A. G., Hofman, A., Steinböck, H., Gruber sedlmayr, U., Neophytou, B., Zara, F., Hahn, A., Gormley, P., Becker, F., Weber, Y. G., Cilio, M. R., Kunz, W. S., Krause, R., Zimprich, F., Lemke, J. R., Nürnberg, P., Sander, T., Lerche, H., Neubauer, B. A., Palotie, A., Ruppert, A. K., Suls, A., Siren, A., Koeleman, B., Haberlandt, E., Ronen, G. M., Caglayan, H., Hjalgrim, H., Muhle, H., Schulz, H., Helbig, I., Altmüller, J., Geldner, J., Schubert, J., Jabbari, K., Everett, K., Feucht, M., Balestri, M., Nothnagel, M., Striano, Pasquale, Møller, R. S., Nabbout, R., Balling, R., Baulac, S., Bianchi, A., La Neve, A., Minetti, Carlo, Giuseppe, C., Neuroscience Center, Research Programs Unit, Anna-Elina Lehesjoki / Principal Investigator, Research Programme for Molecular Neurology, Institute for Molecular Medicine Finland, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, Epidemiology, Neurology, Radiology & Nuclear Medicine, Internal Medicine, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], and Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center]

Subjects
0301 basic medicine, Male, Genetics and Molecular Biology (all), FEBRILE SEIZURES PLUS, Disease, Pathogenesis, Bioinformatics, Pathology and Laboratory Medicine, Biochemistry, Epilepsy, Database and Informatics Methods, 0302 clinical medicine, Risk Factors, Medicine and Health Sciences, Medicine, SCN1A, Myoclonic Seizures, NEURONAL SODIUM-CHANNEL, MUTATION, Multidisciplinary, SEVERE MYOCLONIC EPILEPSY, Research Support, Non-U.S. Gov't, Medicine (all), Syndrome, Clinical Trial, 3. Good health, PREVALENCE, Multicenter Study, Neurology, Cohort, Female, Genetics & genetic processes [F10] [Life sciences], Génétique & processus génétiques [F10] [Sciences du vivant], Sequence Analysis, DRAVET SYNDROME, Research Article, Science, Mutation, Missense, Amino Acid Substitution, Case-Control Studies, Humans, NAV1.1 Voltage-Gated Sodium Channel, Agricultural and Biological Sciences (all), Biochemistry, Genetics and Molecular Biology (all), GENERALIZED EPILEPSY, Sequence Databases, Research and Analysis Methods, ITALIAN PATIENTS, 03 medical and health sciences, Dravet syndrome, Journal Article, Genetics, HEMIPLEGIC MIGRAINE, Tonic-Clonic Seizures, Generalized epilepsy, Molecular Biology Techniques, Sequencing Techniques, Molecular Biology, business.industry, Case-control study, 3112 Neurosciences, Biology and Life Sciences, Human Genetics, Epileptic Seizures, medicine.disease, GENE, Human genetics, 030104 developmental biology, Biological Databases, Epilepsy syndromes, Mutation Databases, Genetics of Disease, 3111 Biomedicine, Missense, business, 030217 neurology & neurosurgery
Abstract

A. Palotie on työryhmän jäsen. Objective The SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic. Methods We screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients. Results and Interpretation We identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p. T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10(-4); OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

Published
2016

8. Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy

Author

Mignot, C., von Stulpnage, C., Nava, C., Ville, D., Sanlaville, D., Lesca, G., Rastetter, A., Gachet, B., Marie, Y., Korenke, G. C., Borggraefe, I., Hoffmann-Zacharska, D., Szczepanik, E., Rudzka-Dybala, M., Uluc, Yis, Caglayan, H., Isapof, A., Marey, I., Panagiotakaki, E., Korff, C., Rossier, E., Riess, A., Beck-Woedl, S., Rauch, A., Zweier, C., Hoyer, J., Reis, A., Mironov, M., Bobylova, M., Mukhin, K., Hernandez-Hernandez, L., Maher, B., Sisodiya, S., Kuhn, M., Glaeser, D., Wechuysen, S., Myers, C. T., Mefford, H. C., Hortnagel, K., Biskup, S., Lemke, J. R., Heron, D., Kluger, G., Depienne, C., Craiu, D., De Jonghe, P., Helbig, I., Guerrini, R., Lehesjoki, A. -E., Marini, C., Muhle, H., Moller, R. S., Neubauer, B., Pal, D., Selmer, K., Stephani, U., Sterbova, K., Striano, P., Talvik, T., von Spiczak, S., Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Paracelsus Medizinische Privatuniversität = Paracelsus Medical University (PMU), Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie Pédiatrique [CHU Lyon], Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique [HCL Groupement Hospitalier Est], Groupement hospitalier Lyon-Est, Université de Lyon, Klinikum Oldenburg [Oldenburg], Zentrum für Kinder- und Jugendmedizin, Dpt of Pediatric Neurology and Developmental Medicine and Epilepsy Center [Munich], University of Munich, Department of Medical Genetics, Institute of Mother and Child, Division of Child Neurology, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Dpt of Molecular Biology and Genetics Istanbul, Boǧaziçi üniversitesi = Boğaziçi University [Istanbul], Service de Neuropédiatrie [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Epilepsie, sommeil et explorations fonctionnelles neuropédiatriques, Hospices Civils de Lyon (HCL)-Hôpital Femme Mère Enfant, Dpt de l'Enfant et de l'Adolescent, Neuropédiatrie [Genève], Hôpitaux Universitaires de Genève (HUG), Institute of Human Genetics [Tuebingen], University of Tuebingen, Institute of Medical Genetics and Applied Genomics [Tübingen], University of Tübingen, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Svt. Luka's Institute of Child Neurology and Epilepsy, Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Genetikum, Neurogenetics Group, Division of Genetic Medicine [Seattle], University of Washington [Seattle], CeGaT GmbH, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Mignot, Cyril, von Stülpnagel, Celina, Korff, Christian, EuroEPINOMICS-RES MAE Working Grp, HAL-UPMC, Gestionnaire, Service de génétique, cytogénétique, embryologie [CHU Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Groupement Hospitalier Lyon-Est (GHE), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Boğaziçi University [Istanbul], CHU Trousseau [APHP], and Universität Heidelberg [Heidelberg] = Heidelberg University

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, Encephalopathy, Myoclonic Jerk, SYNGAP1, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, fluids and secretions, Medizinische Fakultät, Intellectual disability, mental disorders, Genetics, medicine, ddc:610, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Exome, Genetics (clinical), reproductive and urinary physiology, ddc:618, business.industry, medicine.disease, Hypotonia, 3. Good health, 030104 developmental biology, Autism, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Human medicine, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

Mae Euroepinomics-Res Mae; International audience; Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype–phenotype correlations.Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed.Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3′ and 5′ exons. Seizures in patients with mutations in exons 4–5 were more pharmacoresponsive than in patients with mutations in exons 8–15.Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

Published
2016

9. Loss of SYNJ1 dual phosphatase activity leads to early onset refractory seizures and progressive neurological decline

Author

Hardies, K, Cai, Y, Jardel, C, Jansen, Ac, Cao, M, May, P, Djémié, T, Hachon Le Camus, C, Keymolen, K, Deconinck, T, Bhambhani, V, Long, C, Sajan, Sa, Helbig, Kl, Suls, A, Balling, R, Helbig, I, De Jonghe, P, Depienne, C, De Camilli, P, Weckhuysen, S, Afawi, Z, Baulac, S, Barisic, N, Caglayan, H, Craiu, D, De Kovel CG, Lopez, Rg, Guerrini, R, Hjalgrim, H, Lerche, H, Jahn, J, Klein, Km, Koeleman, Bc, Leguern, E, Lemke, J, Marini, C, Muhle, H, Rosenow, F, Serratosa, Jm, Štěrbová, Ks, Møller, Rs, Palotie, A, Striano, P, Weber, Y, Zara, F., Mental Health and Wellbeing research group, Public Health Sciences, Neurogenetics, Clinical sciences, AR Working Grp, and EuroEPINOMICS RES Consortium

Subjects
Male, 0301 basic medicine, Drug Resistant Epilepsy, medicine.medical_specialty, Phosphatase, Nerve Tissue Proteins, Biology, Compound heterozygosity, SYNJ1, Cohort Studies, Consanguinity, 03 medical and health sciences, Epilepsy, Arts and Humanities (miscellaneous), SYNJ1 dual phosphatase activity, Polyphosphoinositide Phosphatase, Internal medicine, early onset epilepsy, medicine, Journal Article, Humans, Missense mutation, Exome, Age of Onset, Child, neurodegenerative disorder, recessive disorder, Medicine (all), Neurology (clinical), Exome sequencing, Synaptic vesicle endocytosis, Genetics, Neurodegenerative Diseases, Heterozygote advantage, Original Articles, Neurodegenerative disorder, medicine.disease, Phosphoric Monoester Hydrolases, Pedigree, Phenotype, 030104 developmental biology, Endocrinology, Child, Preschool, Female, Human medicine
Abstract

SYNJ1 encodes a polyphosphoinositide phosphatase (Synaptojanin 1) with a prominent role in synaptic vesicle dynamics. Hardies et al. report three families (six patients) with autosomal recessive SYNJ1 variants, who display early-onset refractory seizures and progressive neurological decline. The pathogenic variants entail loss of the dual phosphatase activity of Synaptojanin 1.SYNJ1 encodes a polyphosphoinositide phosphatase (Synaptojanin 1) with a prominent role in synaptic vesicle dynamics. Hardies et al. report three families (six patients) with autosomal recessive SYNJ1 variants, who display early-onset refractory seizures and progressive neurological decline. The pathogenic variants entail loss of the dual phosphatase activity of Synaptojanin 1.SYNJ1 encodes a polyphosphoinositide phosphatase, synaptojanin 1, which contains two consecutive phosphatase domains and plays a prominent role in synaptic vesicle dynamics. Autosomal recessive inherited variants in SYNJ1 have previously been associated with two different neurological diseases: a recurrent homozygous missense variant (p.Arg258Gln) that abolishes Sac1 phosphatase activity was identified in three independent families with early onset parkinsonism, whereas a homozygous nonsense variant (p.Arg136*) causing a severe decrease of mRNA transcript was found in a single patient with intractable epilepsy and tau pathology. We performed whole exome or genome sequencing in three independent sib pairs with early onset refractory seizures and progressive neurological decline, and identified novel segregating recessive SYNJ1 defects. A homozygous missense variant resulting in an amino acid substitution (p.Tyr888Cys) was found to impair, but not abolish, the dual phosphatase activity of SYNJ1, whereas three premature stop variants (homozygote p.Trp843* and compound heterozygote p.Gln647Argfs*6/p.Ser1122Thrfs*3) almost completely abolished mRNA transcript production. A genetic follow-up screening in a large cohort of 543 patients with a wide phenotypical range of epilepsies and intellectual disability revealed no additional pathogenic variants, showing that SYNJ1 deficiency is rare and probably linked to a specific phenotype. While variants leading to early onset parkinsonism selectively abolish Sac1 function, our results provide evidence that a critical reduction of the dual phosphatase activity of SYNJ1 underlies a severe disorder with neonatal refractory epilepsy and a neurodegenerative disease course. These findings further expand the clinical spectrum of synaptic dysregulation in patients with severe epilepsy, and emphasize the importance of this biological pathway in seizure pathophysiology.

Published
2016

10. Recessive mutations in SLC13A5 result in a loss of citrate transport and cause neonatal epilepsy, developmental delay and teeth hypoplasia

Author

Hardies, K., De Kovel, C. G. F., Weckhuysen, S., Asselbergh, B., Geuens, T., Deconinck, T., Azmi, A., May, P., Brilstra, E., Becker, F., Barisic, N., Craiu, D., Braun, K. P. J., Lal, D., Thiele, H., Schubert, J., Weber, Y., Van 'T Slot, R., Nurnberg, P., Balling, R., Timmerman, V., Lerche, H., Maudsley, S., Helbig, I., Suls, A., Koeleman, B. P. C., De Jonghe, P., Afawi, Z., Baulac, S., Caglayan, H., Lopez, R. G., Guerrini, R., Hjalgrim, H., Jahn, J., Klein, K. M., Leguern, E., Lemke, J., Marini, C., Muhle, H., Rosenow, F., Serratosa, J., Sterbova, K., Moller, R. S., Striano, P., Zara, F., and EuroEPINOMICS RES Consortium

Subjects
Male, medicine.medical_specialty, Adolescent, anaplerosis, epileptic encephalopathy, NaCT, recessive disorder, SLC13A5, teeth hypoplasia, medicine.medical_treatment, Developmental Disabilities, Mutant, Genes, Recessive, Biology, medicine.disease_cause, Citric Acid, Epilepsy, Internal medicine, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Child, Gene, Anodontia, Genetics, Mutation, Brain Diseases, Symporters, Citrate transport, medicine.disease, Hypoplasia, Pedigree, Endocrinology, HEK293 Cells, Epilepsy syndromes, Female, Neurology (clinical), Human medicine, Ketogenic diet
Abstract

The epileptic encephalopathies are a clinically and aetiologically heterogeneous subgroup of epilepsy syndromes. Most epileptic encephalopathies have a genetic cause and patients are often found to carry a heterozygous de novo mutation in one of the genes associated with the disease entity. Occasionally recessive mutations are identified: a recent publication described a distinct neonatal epileptic encephalopathy (MIM 615905) caused by autosomal recessive mutations in the SLC13A5 gene. Here, we report eight additional patients belonging to four different families with autosomal recessive mutations in SLC13A5. SLC13A5 encodes a high affinity sodium-dependent citrate transporter, which is expressed in the brain. Neurons are considered incapable of de novo synthesis of tricarboxylic acid cycle intermediates; therefore they rely on the uptake of intermediates, such as citrate, to maintain their energy status and neurotransmitter production. The effect of all seven identified mutations (two premature stops and five amino acid substitutions) was studied in vitro, using immunocytochemistry, selective western blot and mass spectrometry. We hereby demonstrate that cells expressing mutant sodium-dependent citrate transporter have a complete loss of citrate uptake due to various cellular loss-of-function mechanisms. In addition, we provide independent proof of the involvement of autosomal recessive SLC13A5 mutations in the development of neonatal epileptic encephalopathies, and highlight teeth hypoplasia as a possible indicator for SLC13A5 screening. All three patients who tried the ketogenic diet responded well to this treatment, and future studies will allow us to ascertain whether this is a recurrent feature in this severe disorder.

Published
2015

11. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes

Author

Schubert, J., Siekierska, A., Langlois, M., May, P., Huneau, C., Becker, F., Muhle, H., Suls, A., Lemke, J. R., de Kovel, C. G. F., Thiele, H., Konrad, K., Kawalia, A., Toliat, M. R., Sander, T., Ruschendorf, F., Caliebe, A., Nagel, I., Kohl, B., Kecskes, A., Jacmin, M., Hardies, K., Weckhuysen, S., Riesch, E., Dorn, T., Brilstra, E. H., Baulac, S., Moller, R. S., Hjalgrim, H., Koeleman, B. P. C., Jurkat-Rott, K., Lehman-Horn, F., Roach, J. C., Glusman, G., Hood, L., Galas, D. J., Martin, B., de Witte, P. A. M., Biskup, S., De Jonghe, P., Helbig, I., Balling, R., Nurnberg, P., Crawford, A. D., Esguerra, C. V., Weber, Y. G., Lerche, H., Euro, Epinomics R. E. S. Consortium, EuroEPINOMICS RES Consortium, [GIN] Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Institute for Systems Biology [Seattle] (ISB), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neurogenetics Group, Institut für Humangenetik, Universität Heidelberg [Heidelberg], Cologne Center for Genomics (CCG), University of Cologne, Department of Molecular and Developmental Genetics (VIB11), Flanders institute of biotechnology, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Medical Genetics Laboratory, Université Grenoble Alpes - UFR Médecine (UGA UFRM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratory of Pharmaceutical Biology, Faculty of Pharmaceutical Sciences Lueven Belgium, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Center for Genomics and Transcriptomics (CEGAT), Antwerp University Hospital [Edegem] (UZA), Children’s Hospital of Philadelphia (CHOP ), Cologne Center for Genomics, University of Cologne, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Heidelberg [Heidelberg] = Heidelberg University, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Genetic Linkage, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Syntaxin 1, medicine.disease_cause, Epilepsy/genetics, Cohort Studies, Epilepsy, 0302 clinical medicine, Syntaxin 1/genetics, Missense mutation, Exome, ComputingMilieux_MISCELLANEOUS, In Situ Hybridization, Fluorescence, Zebrafish, Genetics, 0303 health sciences, Mutation, Comparative Genomic Hybridization, Temperature, PAROXYSMAL KINESIGENIC DYSKINESIA SYNAPTIC VESICLE FUSION DE-NOVO MUTATIONS FEBRILE SEIZURES INFANTILE CONVULSIONS GENERALIZED EPILEPSY PRRT2 MUTATIONS GENERATION DISORDERS ZEBRAFISH, Pedigree, Phenotype, Codon, Nonsense, Female, Molecular Sequence Data, Biology, Polymorphism, Single Nucleotide, Seizures, Febrile, 03 medical and health sciences, SCN1B, medicine, Animals, Humans, Amino Acid Sequence, Seizures, Febrile/genetics, Generalized epilepsy, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, Sequence Analysis, DNA, Paroxysmal dyskinesia, medicine.disease, Epilepsy syndromes, Human medicine, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Gene Deletion
Abstract

Febrile seizures affect 2-4% of all children(1) and have a strong genetic component(2). Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2)(3-5) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B(6), that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees(7,8) identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

Published
2014

12. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1,2q22.3 and 17q21.32

Author

Steffens, M., Leu, C., Ruppert, A., Zara, F., Striano, P., Robbiano, A., Capovilla, G., Tinuper, P., Gambardella, A., Bianchi, A., La neve, A., Crichiutti, G., de kovel, C. G., Trenité, D. K. -N., de haan, G., Lindhout, D., Gaus, V., Schmitz, B., Janz, D., Weber, Y. G., Becker, F., Lerche, H., Steinhoff, B. J., Kleefuß-Lie, A. A., Kunz, W. S., Surges, R., Elger, C. E., Muhle, H., Von spiczak, S., Ostertag, P., Helbig, I., Stephani, U., Møller, R. S., Hjalgrim, H., Dibbens, L. M., Bellows, S., Oliver, K., Mullen, S., Scheffer, I. E., Berkovic, S. F., Everett, K. V., Gardiner, M. R., Marini, Chiara, Guerrini, R., Lehesjoki, A., Siren, A., Guipponi, M., Malafosse, A., Thomas, P., Nabbout, R., Baulac, S., Leguern, E., Guerrero, R., Serratosa, J. M., Reif, P. S., Rosenow, F., Mörzinger, M., Feucht, M., Zimprich, F., Kapser, C., Schankin, C. J., Suls, A., Smets, K., De jonghe, P., Jordanova, A., Caglayan, H., Yapici, Z., Yalcin, D. A., Baykan, B., Bebek, N., Ozbek, U., Gieger, C., Wichmann, H., Balschun, T., Ellinghaus, D., Franke, A., Meesters, C., Becker, T., Wienker, T. F., Hempelmann, A., Schulz, H., Rüschendorf, F., Leber, M., Pauck, S. M., Trucks, H., Toliat, M. R., Nürnberg, P., Avanzini, G., Koeleman, B. P., Sander, T., Weckhuysen, S., Claes, L., Deprez, L., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Lehesjoki, A. -E., von Spiczak, S., Martin Klein, K., Oertel, W. H., Hamer, H. M., Marini, C., Mei, D., Norci, V., Pezzella, M., La Neve, A., Vigliano, P., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Egeo, G., Teresa Giallonardo, M., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., de Haan, G. -J., Giraldez, B. G., Ozbeck, U., Ozdemir, O., Ugur, S., Kocasoy-Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Ozkara, C., Yalcin, O., Turkdogan, D., Dizdarer, G., Agan, K., Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Frederico, Dibbens, Leanne Michelle, Sander, Thomas, EPICURE Consortium, Epicure, Consortium, DEL GIUDICE, Ennio, Steffens, M, Leu, C, Ruppert, Ak, Zara, F, Striano, P, Robbiano, A., Coppola, Antonietta, E. P. I. C. U. R. E. Consortium, E. M. I.Net Consortium, M. Steffen, C. Leu, A. Ruppert, F. Zara, P. Striano, A. Robbiano, G. Capovilla, P. Tinuper, A. Gambardella, A. Bianchi, A. L. Neve, G. Crichiutti, C. G. F, D. K. Trenité, G. d. Haan, D. Lindhout, V. Gau, B. Schmitz, D. Janz, Y. G. Weber, F. Becker, H. Lerche, B. J. Steinhoff, A. A. Kleefuß-Lie, W. S. Kunz, R. Surge, C. E. Elger, H. Muhle, S. v. Spiczak, P. Ostertag, I. Helbig, U. Stephani, R. S. Møller, H. Hjalgrim, L. M. Dibben, S. Bellow, K. Oliver, S. Mullen, I. E. Scheffer, S. F. Berkovic, K. V. Everett, M. R. Gardiner, C. Marini, R. Guerrini, A. Lehesjoki, A. Siren, M. Guipponi, A. Malafosse, P. Thoma, R. Nabbout, S. Baulac, E. Leguern, R. Guerrero, J. M. Serratosa, P. S. Reif, F. Rosenow, M. Mörzinger, M. Feucht, F. Zimprich, C. Kapser, C. J. Schankin, A. Sul, K. Smet, P. D. Jonghe, A. Jordanova, H. Caglayan, Z. Yapici, D. A. Yalcin, B. Baykan, N. Bebek, U. Ozbek, C. Gieger, H. Wichmann, T. Balschun, D. Ellinghau, A. Franke, C. Meester, T. Becker, T. F. Wienker, A. Hempelmann, H. Schulz, F. Rüschendorf, M. Leber, S. M. Pauck, H. Truck, M. R. Toliat, P. Nürnberg, G. Avanzini, B. P. C, and T. Sander

Subjects
Candidate gene, Juvenile, Genome-wide association study, Alleles, Epilepsy, ZEB2 protein, human, VRK2 protein, human, 0302 clinical medicine, genetics [Genetic Predisposition to Disease], genetics, Humans, Myoclonic Epilepsy, genetics [Epilepsy, Generalized], SCN1A protein, human, Genetics (clinical), Genetics, 0303 health sciences, genetics [Epilepsy, Absence], Myoclonic Epilepsy, Juvenile, genetics, Genetic Predisposition to Disease, General Medicine, Protein-Serine-Threonine Kinases, 3. Good health, Chemistry, Absence, genetics, Epilepsy, genetics [Myoclonic Epilepsy, Juvenile], Epilepsy, Generalized, genetics [Receptor, Muscarinic M3], genetics, NAV1.1 Voltage-Gated Sodium Channel, genetics [Homeodomain Proteins], Single-nucleotide polymorphism, genetics [NAV1.1 Voltage-Gated Sodium Channel], Protein Serine-Threonine Kinases, Biology, genetics [Protein-Serine-Threonine Kinases], 03 medical and health sciences, ddc:570, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, genetics, Repressor Protein, Allele, Molecular Biology, Alleles, Zinc Finger E-box Binding Homeobox 2, 030304 developmental biology, Homeodomain Proteins, Receptor, Muscarinic M3, genetics, Protein-Serine-Threonine Kinase, genetics, Receptor, Generalized, genetics, Genome-Wide Association Study, Homeodomain Protein, Heritability, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, Repressor Proteins, genetics [Repressor Proteins], Muscarinic M3, Epilepsy, Absence, Myoclonic epilepsy, Human medicine, Juvenile myoclonic epilepsy, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3\% and account for 20-30\% of all epilepsies. Despite their high heritability of 80\%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.

Published
2012

13. Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: precedent for disorders with complex inheritance

Author

Dibbens, Lm, Mullen, S, Helbig, I, Mefford, Hc, Bayly, Ma, Bellows, S, Leu, C, Trucks, H, Obermeier, T, Wittig, M, Franke, A, Caglayan, H, Yapici, Z, Sander, T, Eichler, Ee, Scheffer, Ie, Mulley, Jc, Berkovic, Sf, De Jonghe, P, Suls, A, Hjalgrim, H, Madsen, Jm, Møller, Rs, Lehesjoki, Ae, Siren, A, Gaus, V, Janz, D, Schmitz, B, Elger, Ce, Hallmann, K, Kleefuß-Lie, Aa, Kunz, Ws, Raabe, A, Muhle, H, Ostertag, P, von Spiczak, S, Stephani, U, Lerche, H, Weber, Yg, Striano, P, Zara, F, Marini, C, Brilstra, Eh, Kastelijn-Nolst, Trenité, Koeleman, D, Bpc, de Kovel, Cgf, Lindhout, D, Swinkels, Mem, Yalcin, O, Baykan, B, Turkdogan, D, Dizdarer, G, Ozkara, C, Lee, Y, Müller-Quernheim, J, Fölster-Holst, R, Hofmann, S, Nebel, A., Schreiber, S, Schürmann, M, Rodriguez, E, Weidinger, S, Baurecht, H, Lie, Ba, Boberg, Km, Karlsen, Th., De Jonghe, Peter, Suls, Arvid, Dibbens, Leanne M, Mullen, Saul, Helbig, Ingo, Mefford, Heather C, Bayly, Marta A, Bellows, Susannah, Leu, Costin, Trucks, Holger, Obermeier, Tanja, Wittig, Michael, Franke, Andre, Caglayan, Hande, Yapici, Zuhal, Sander, Thomas, Eichler, Evan E, Scheffer, Ingrid E, Mulley, John C, and Berkovic, Samuel F

Subjects
Male, Proband, Clinical Sciences, idiopathic generalized epilepsy, European Continental Ancestry Group, Single-nucleotide polymorphism, Pedigree chart, family studies, Biology, White People, Cohort Studies, Idiopathic generalized epilepsy, Epilepsy, single nucleotide polymorphism, genetic inheritance, Genetics, medicine, inheritance, Humans, SNP, Genetic Predisposition to Disease, Molecular Biology, Genetics (clinical), seizures, Chromosomes, Human, Pair 15, Articles, General Medicine, 5q13.3 deletions, medicine.disease, Penetrance, Pedigree, Female, Human medicine, microdeletion, Chromosome Deletion, Comparative genomic hybridization
Abstract

Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determine the relative occurrence of sporadic and familial cases and to examine the likelihood of having seizures for individuals with the microdeletion in familial cases. The 15q13.3 microdeletion was identified in 7 of 539 (1.3%) unrelated cases of IGE using quantitative PCR or SNP arrays and confirmed by array comparative genomic hybridization analysis using probes specific to the 15q13.3 region. The inheritance of this lesion was tracked using family studies. Of the seven microdeletions identified in probands, three were de novo, two were transmitted from an unaffected parent and in two cases the parents were unavailable. Non-penetrance of the microdeletion was identified in 4/7 pedigrees and three pedigrees included other family members with IGE who lacked the 15q13.3 deletion. The odds ratio is 68 (95% confidence interval 29-181), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families. Refereed/Peer-reviewed

Published
2009

14. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author

Joshua E. Motelow, Gundula Povysil, Ryan S. Dhindsa, Kate E. Stanley, Andrew S. Al- len, Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Ka- therine Tashman, Felecia Cerrato, Caroline Cusick, Tarjinder Singh, Henrike Heyne, Andrea E. Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Namrata Gupta, Benjamin M. Neale, Gianpiero L. Cavalleri, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Hakon Hakonarson, Erin L. Heinzen, Ingo Helbig, Patrick Kwan, Anthony G. Marson, Slave ? Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Randy Stewart, Sarah Weckhuysen, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Roland Krause, Patrick May, Kevin McKenna, Brigid M. Regan, Caitlin A. Bennett, Costin Leu, Stephanie L. Leech, Terence J. O'Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Quratulain Zulfiqar Ali, Tara R. Sadoway, Heinz Krestel, Andre ? Schaller, Savvas S. Papacostas, Ioanna Kou- siappa, George A. Tanteles, Yiolanda Christou, Katalin Sterbova ?, Marke ? ta Vlckova ?, Lucie Sedlackova, Petra Lassuthova ?, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Bernd A. Neubauer, Friedrich Zimprich, Martha Feucht, Eva M. Reinthaler, Wolfram S. Kunz, Ga ?bor Zsurka, Rainer Surges, Tobias Baumgart- ner, Randi von Wrede, Manuela Pendziwiat, Hiltrud Muhle, An- nika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Mu ?ller-Schlu ?ter, Gerhard Kluger, Martin Ha ?usler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Stephan Lauxmann, Christian Boßelmann, Josua Kegele, Christian Hengs- bach, Sarah Rau, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, IngoBorggra ?fe, ChristophJ.Schankin, SusanneSchubert-Bast, Herbert Schreiber, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Markus Wolff, Dieter Dennig, Rene Madeleyn, Reetta Ka ?lvia ?inen, Anni Saarela, Oskari Timonen, Tarja Linnankivi, Anna-Elina Lehesjoki, Sylvain Rheims, Gaetan Lesca, Philippe Ryvlin, Louis Maillard, Luc Valton, Philippe Derambure, Fabrice Bartolomei, Edouard Hirsch, Ve ?ronique Michel, Francine Chas- soux, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Mark D. Baker, Beata Fonferko-Shadrach, Charlotte Law- thom, Joseph Anderson, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Norman Delanty, Colin P. Doherty, Arif Shukralla, Hany El-Naggar, Peter Widdess-Walsh, Nina Barisic, Laura 12 The American Journal of Human Genetics 108, 1-18, June 3, 2021 Please cite this article in press as: Epi25 Collaborative, Sub-genic intolerance, ClinVar, the epilepsies: A whole-exome sequencing study of 29, 165 individuals, The American Journal of Human Genetics (2021), https://doi.org/10.1016/j.ajhg.2021.04.009 Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Francesca Ragona, Federico Zara, Michele Iacomino, An- tonella Riva, Francesca Madia, Maria Stella Vari, Vincenzo Salpie- tro, Marcello Scala, Maria Margherita Mancardi, Lino Nobili, Elisa- betta Amadori, Thea Giacomini, Francesca Bisulli, Tommaso Pippucci, Laura Licchetta, Raffaella Minardi, Paolo Tinuper, Lor- enzo Muccioli, Barbara Mostacci, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carmen Barba, Shinichi Hirose, At- sushi Ishii, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Ahmad Beydoun, Wassim Nasreddine, Nathalie Khoueiry Zgheib, Birute Tumiene, Algirdas Utkus, Lynette G. Sadleir, Chontelle King, S. Hande Caglayan, Mutluay Arslan, Zuhal Yap?c?, P?nar To- paloglu, Bulent Kara, Uluc Yis, Dilsad Turkdogan, Asl? Gun- dogdu-Eken, Nerses Bebek, Meng-Han Tsai, Chen-Jui Ho, Chih- Hsiang Lin, Kuang-Lin Lin, I-Jun Chou, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Jeffrey L. Noebels, Alicia Goldman, Robyn M. Busch, Lara Jehi, Imad M. Najm, Lisa Ferguson, Jean Khoury, Tracy A. Glauser, Peggy O. Clark, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jac- queline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, David A. Greenberg, Colin A. Ellis, Ethan Goldberg, Katherine L. Helbig, Mahgenn Cosico, Priya Vaidis- waran, Eryn Fitch, Samuel F. Berkovic, Holger Lerche, Daniel H. Lowenstein, David B. Goldstein., Motelow J.E., Povysil G., Dhindsa R.S., Stanley K.E., Allen A.S., Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Cusick C., Singh T., Heyne H., Byrnes A.E., Churchhouse C., Watts N., Solomonson M., Lal D., Gupta N., Neale B.M., Cavalleri G.L., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Hakonarson H., Heinzen E.L., Helbig I., Kwan P., Marson A.G., Petrovski S., Kamalakaran S., Sisodiya S.M., Stewart R., Weckhuysen S., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., Krause R., May P., McKenna K., Regan B.M., Bennett C.A., Leu C., Leech S.L., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Ali Q.Z., Sadoway T.R., Krestel H., Schaller A., Papacostas S.S., Kousiappa I., Tanteles G.A., Christou Y., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Neubauer B.A., Zimprich F., Feucht M., Reinthaler E.M., Kunz W.S., 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 A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Lauxmann S., Bosselmann C., Kegele J., Hengsbach C., Rau S., Steinhoff B.J., Schulze-Bonhage A., Borggrafe I., Schankin C.J., 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.I., Chung S.-K., Pickrell W.O., Powell R., Baker M.D., Fonferko-Shadrach B., Lawthom C., Anderson J., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Delanty N., Doherty C.P., Shukralla A., El-Naggar H., Widdess-Walsh P., Barisic N., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Ragona F., Zara F., Iacomino M., Riva A., Madia F., Vari M.S., Salpietro V., Scala M., Mancardi M.M., 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., Khoueiry Zgheib N., Tumiene B., Utkus A., Sadleir L.G., King C., Caglayan S.H., 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 B.R., Shain C., Noebels J.L., Goldman A., Busch R.M., Jehi L., Najm I.M., Ferguson L., Khoury J., Glauser T.A., Clark P.O., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Greenberg D.A., Ellis C.A., Goldberg E., Helbig K.L., Cosico M., Vaidiswaran P., Fitch E., Berkovic S.F., Lerche H., Lowenstein D.H., Goldstein D.B., Epi25 Collaborative, Institut de Neurosciences des Systèmes (INS), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, focal epilepsy, Whole Exome Sequencing, Cohort Studies, Epilepsy, 0302 clinical medicine, Genetic Marker, Missense mutation, Exome, whole-exome sequencing, generalized epilepsy, ComputingMilieux_MISCELLANEOUS, Genetics (clinical), Exome sequencing, seizures, Genetics, ClinVar, Phenotype, epileptic encephalopathy, Epi25, intolerance, Case-Control Studie, Human, Genetic Markers, seizure, Disease Association, Biology, Article, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Genetic Testing, Generalized epilepsy, Gene, Louvain, [SCCO.NEUR]Cognitive science/Neuroscience, Correction, Genetic Variation, medicine.disease, epilepsy, Human genetics, 030104 developmental biology, Case-Control Studies, Human medicine, Cohort Studie, Genetic generalized epilepsy, 030217 neurology & neurosurgery
Abstract

Summary 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.

Published
2021

15. KCNT1-related epilepsies and epileptic encephalopathies: phenotypic and mutational spectrum

Author

An-Sofie Schoonjans, Christina Fenger, Joseph Toulouse, Nathalie Villeneuve, Marie-Christine Nougues, Martina Fiannacca, Wen-Hann Tan, Rikke S. Møller, Boudewijn Gunning, Julitta de Bellescize, David Bearden, Federico Zara, Hiltrud Muhle, Gaetan Lesca, Sarah Weckhuysen, Guido Rubboli, Berten Ceulemans, Tobias Baumgartner, Frauke Hornemann, Steffen Syrbe, Leanne M. Dibbens, Hannah Stamberger, Catherine Sarret, Maria Margherita Mancardi, Edouard Hirsch, Salvatore Buono, Chiara Reale, Kern Olofsson, Elena Gardella, Claudia M Bonardi, Hélène Maurey, Henrike O. Heyne, Fabienne Picard, Stéphanie Baulac, Pasquale Striano, Geneviève Demarquay, Fabrice Bartolomei, Antonietta Coppola, Massimiliano Rossi, Vincent des Portes, Hester Y. Kroes, Mark Fitzgerald, Nienke E. Verbeek, David A. Koolen, Caroline Nava, Dorothée Ville, Marjolaine Willems, Cecilia Altuzarra, Bonardi, Claudia M, Heyne, Henrike O, Fiannacca, Martina, Fitzgerald, Mark P, Dibbens, Leanne, Rubboli, Guido, Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), Bonardi, Cm, Heyne, Ho, Fiannacca, M, Fitzgerald, Mp, Gardella, E, Gunning, B, Olofsson, K, Lesca, G, Verbeek, N, Stamberger, H, Striano, P, Zara, F, Mancardi, Mm, Nava, C, Syrbe, S, Buono, S, Baulac, S, Coppola, A, Weckhuysen, S, Schoonjans, A, Ceulemans, B, Sarret, C, Baumgartner, T, Muhle, H, des Portes, V, Toulouse, J, Nougues, Mc, Rossi, M, Demarquay, G, Ville, D, Hirsch, E, Maurey, H, Willems, M, de Bellescize, J, Altuzarra, Cd, Villeneuve, N, Bartolomei, F, Picard, F, Hornemann, F, Koolen, Da, Kroes, Hy, Reale, C, Fenger, Cd, Tan, Wh, Dibbens, L, Bearden, Dr, Møller, R, and Rubboli, G.

Subjects
Male, Potassium Channels, Adolescent, Genotype, KCNT1, Nerve Tissue Proteins, Potassium Channels, Sodium-Activated, Bioinformatics, Temporal lobe, Cohort Studies, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, medicine, epileptic encephalopathies, Missense mutation, Humans, Preschool, Child, 030304 developmental biology, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Seizure types, business.industry, developmental and epileptic encephalopathies, epilepsy of infancy with migrating focal seizures, sleep-related hypermotor epilepsy, Child, Preschool, Female, Infant, Mutation, Phenotype, West Syndrome, medicine.disease, 3. Good health, ddc:616.8, Epileptic spasms, Cohort, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Sodium-Activated, Neurology (clinical), Human medicine, business, 030217 neurology & neurosurgery
Abstract

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies. This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 previously unpublished and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: (i) EIMFS (152 individuals, 33 previously unpublished); (ii) developmental and epileptic encephalopathies other than EIMFS (non-EIMFS developmental and epileptic encephalopathies) (37 individuals, 17 unpublished); (iii) autosomal dominant or sporadic sleep-related hypermotor epilepsy (53 patients, 14 unpublished); and (iv) other phenotypes (six individuals, two unpublished). In our cohort of 66 new cases, the most common phenotypic features were: (i) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; (ii) in non-EIMFS developmental and epileptic encephalopathies, possible onset with West syndrome, occurrence of atypical absences, possible evolution to developmental and epileptic encephalopathies with sleep-related hypermotor epilepsy features; one case of sudden unexplained death in epilepsy; (iii) in autosomal dominant or sporadic sleep-related hypermotor epilepsy, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in ∼50% of the patients, sudden unexplained death in epilepsy in one individual; and (iv) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype–phenotype considerations showed many of the autosomal dominant or sporadic sleep-related hypermotor epilepsy-associated mutations to be clustered around the RCK2 domain in the C terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS developmental and epileptic encephalopathies did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset developmental and epileptic encephalopathies as well as of focal epilepsies, namely autosomal dominant or sporadic sleep-related hypermotor epilepsy.

Published
2020

16. Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals

Author

Yen-Chen Anne Feng, Daniel P. Howrigan, Liam E. Abbott, Katherine Tashman, Felecia Cerrato, Tarjinder Singh, Henrike Heyne, Andrea Byrnes, Claire Churchhouse, Nick Watts, Matthew Solomonson, Dennis Lal, Erin L. Heinzen, Ryan S. Dhindsa, Kate E. Stanley, Gianpiero L. Cavalleri, Hakon Hakonarson, Ingo Helbig, Roland Krause, Patrick May, Sarah Weckhuysen, Slavé Petrovski, Sitharthan Kamalakaran, Sanjay M. Sisodiya, Patrick Cossette, Chris Cotsapas, Peter De Jonghe, Tracy Dixon-Salazar, Renzo Guerrini, Patrick Kwan, Anthony G. Marson, Randy Stewart, Chantal Depondt, Dennis J. Dlugos, Ingrid E. Scheffer, Pasquale Striano, Catharine Freyer, Kevin McKenna, Brigid M. Regan, Susannah T. Bellows, Costin Leu, Caitlin A. Bennett, Esther M.C. Johns, Alexandra Macdonald, Hannah Shilling, Rosemary Burgess, Dorien Weckhuysen, Melanie Bahlo, Terence J. O’Brien, Marian Todaro, Hannah Stamberger, Danielle M. Andrade, Tara R. Sadoway, Kelly Mo, Heinz Krestel, Sabina Gallati, Savvas S. Papacostas, Ioanna Kousiappa, George A. Tanteles, Katalin Štěrbová, Markéta Vlčková, Lucie Sedláčková, Petra Laššuthová, Karl Martin Klein, Felix Rosenow, Philipp S. Reif, Susanne Knake, Wolfram S. Kunz, Gábor Zsurka, Christian E. Elger, Jürgen Bauer, Michael Rademacher, Manuela Pendziwiat, Hiltrud Muhle, Annika Rademacher, Andreas van Baalen, Sarah von Spiczak, Ulrich Stephani, Zaid Afawi, Amos D. Korczyn, Moien Kanaan, Christina Canavati, Gerhard Kurlemann, Karen Müller-Schlüter, Gerhard Kluger, Martin Häusler, Ilan Blatt, Johannes R. Lemke, Ilona Krey, Yvonne G. Weber, Stefan Wolking, Felicitas Becker, Christian Hengsbach, Sarah Rau, Ana F. Maisch, Bernhard J. Steinhoff, Andreas Schulze-Bonhage, Susanne Schubert-Bast, Herbert Schreiber, Ingo Borggräfe, Christoph J. Schankin, Thomas Mayer, Rudolf Korinthenberg, Knut Brockmann, Dieter Dennig, Rene Madeleyn, Reetta Kälviäinen, Pia Auvinen, Anni Saarela, Tarja Linnankivi, Anna-Elina Lehesjoki, Mark I. Rees, Seo-Kyung Chung, William O. Pickrell, Robert Powell, Natascha Schneider, Simona Balestrini, Sara Zagaglia, Vera Braatz, Michael R. Johnson, Pauls Auce, Graeme J. Sills, Larry W. Baum, Pak C. Sham, Stacey S. Cherny, Colin H.T. Lui, Nina Barišić, Norman Delanty, Colin P. Doherty, Arif Shukralla, Mark McCormack, Hany El-Naggar, Laura Canafoglia, Silvana Franceschetti, Barbara Castellotti, Tiziana Granata, Federico Zara, Michele Iacomino, Francesca Madia, Maria Stella Vari, Maria Margherita Mancardi, Vincenzo Salpietro, Francesca Bisulli, Paolo Tinuper, Laura Licchetta, Tommaso Pippucci, Carlotta Stipa, Raffaella Minardi, Antonio Gambardella, Angelo Labate, Grazia Annesi, Lorella Manna, Monica Gagliardi, Elena Parrini, Davide Mei, Annalisa Vetro, Claudia Bianchini, Martino Montomoli, Viola Doccini, Carla Marini, Toshimitsu Suzuki, Yushi Inoue, Kazuhiro Yamakawa, Birute Tumiene, Lynette G. Sadleir, Chontelle King, Emily Mountier, S. Hande Caglayan, Mutluay Arslan, Zuhal Yapıcı, Uluc Yis, Pınar Topaloglu, Bulent Kara, Dilsad Turkdogan, Aslı Gundogdu-Eken, Nerses Bebek, Sibel Uğur-İşeri, Betül Baykan, Barış Salman, Garen Haryanyan, Emrah Yücesan, Yeşim Kesim, Çiğdem Özkara, Annapurna Poduri, Beth R. Shiedley, Catherine Shain, Russell J. Buono, Thomas N. Ferraro, Michael R. Sperling, Warren Lo, Michael Privitera, Jacqueline A. French, Steven Schachter, Ruben I. Kuzniecky, Orrin Devinsky, Manu Hegde, Pouya Khankhanian, Katherine L. Helbig, Colin A. Ellis, Gianfranco Spalletta, Fabrizio Piras, Federica Piras, Tommaso Gili, Valentina Ciullo, Andreas Reif, Andrew McQuillin, Nick Bass, Andrew McIntosh, Douglas Blackwood, Mandy Johnstone, Aarno Palotie, Michele T. Pato, Carlos N. Pato, Evelyn J. Bromet, Celia Barreto Carvalho, Eric D. Achtyes, Maria Helena Azevedo, Roman Kotov, Douglas S. Lehrer, Dolores Malaspina, Stephen R. Marder, Helena Medeiros, Christopher P. Morley, Diana O. Perkins, Janet L. Sobell, Peter F. Buckley, Fabio Macciardi, Mark H. Rapaport, James A. Knowles, Ayman H. Fanous, Steven A. McCarroll, Namrata Gupta, Stacey B. Gabriel, Mark J. Daly, Eric S. Lander, Daniel H. Lowenstein, David B. Goldstein, Holger Lerche, Samuel F. Berkovic, Benjamin M. Neale, Wellcome Trust, Department of Health, Institute of Neurology, UCL, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, Medical Research Council (MRC), Feng Y.-C.A., Howrigan D.P., Abbott L.E., Tashman K., Cerrato F., Singh T., Heyne H., Byrnes A., Churchhouse C., Watts N., Solomonson M., Lal D., Heinzen E.L., Dhindsa R.S., Stanley K.E., Cavalleri G.L., Hakonarson H., Helbig I., Krause R., May P., Weckhuysen S., Petrovski S., Kamalakaran S., Sisodiya S.M., Cossette P., Cotsapas C., De Jonghe P., Dixon-Salazar T., Guerrini R., Kwan P., Marson A.G., Stewart R., Depondt C., Dlugos D.J., Scheffer I.E., Striano P., Freyer C., McKenna K., Regan B.M., Bellows S.T., Leu C., Bennett C.A., Johns E.M.C., Macdonald A., Shilling H., Burgess R., Weckhuysen D., Bahlo M., O'Brien T.J., Todaro M., Stamberger H., Andrade D.M., Sadoway T.R., Mo K., Krestel H., Gallati S., Papacostas S.S., Kousiappa I., Tanteles G.A., Sterbova K., Vlckova M., Sedlackova L., Lassuthova P., Klein K.M., Rosenow F., Reif P.S., Knake S., Kunz W.S., Zsurka G., Elger C.E., Bauer J., Rademacher M., Pendziwiat M., Muhle H., Rademacher A., van Baalen A., von Spiczak S., Stephani U., Afawi Z., Korczyn A.D., Kanaan M., Canavati C., Kurlemann G., Muller-Schluter K., Kluger G., Hausler M., Blatt I., Lemke J.R., Krey I., Weber Y.G., Wolking S., Becker F., Hengsbach C., Rau S., Maisch A.F., Steinhoff B.J., Schulze-Bonhage A., Schubert-Bast S., Schreiber H., Borggrafe I., Schankin C.J., Mayer T., Korinthenberg R., Brockmann K., Dennig D., Madeleyn R., Kalviainen R., Auvinen P., Saarela A., Linnankivi T., Lehesjoki A.-E., Rees M.I., Chung S.-K., Pickrell W.O., Powell R., Schneider N., Balestrini S., Zagaglia S., Braatz V., Johnson M.R., Auce P., Sills G.J., Baum L.W., Sham P.C., Cherny S.S., Lui C.H.T., Barisic N., Delanty N., Doherty C.P., Shukralla A., McCormack M., El-Naggar H., Canafoglia L., Franceschetti S., Castellotti B., Granata T., Zara F., Iacomino M., Madia F., Vari M.S., Mancardi M.M., Salpietro V., Bisulli F., Tinuper P., Licchetta L., Pippucci T., Stipa C., Minardi R., Gambardella A., Labate A., Annesi G., Manna L., Gagliardi M., Parrini E., Mei D., Vetro A., Bianchini C., Montomoli M., Doccini V., Marini C., Suzuki T., Inoue Y., Yamakawa K., Tumiene B., Sadleir L.G., King C., Mountier E., Caglayan S.H., Arslan M., Yapici Z., Yis U., Topaloglu P., Kara B., Turkdogan D., Gundogdu-Eken A., Bebek N., Ugur-Iseri S., Baykan B., Salman B., Haryanyan G., Yucesan E., Kesim Y., Ozkara C., Poduri A., Shiedley B.R., Shain C., Buono R.J., Ferraro T.N., Sperling M.R., Lo W., Privitera M., French J.A., Schachter S., Kuzniecky R.I., Devinsky O., Hegde M., Khankhanian P., Helbig K.L., Ellis C.A., Spalletta G., Piras F., Gili T., Ciullo V., Reif A., McQuillin A., Bass N., McIntosh A., Blackwood D., Johnstone M., Palotie A., Pato M.T., Pato C.N., Bromet E.J., Carvalho C.B., Achtyes E.D., Azevedo M.H., Kotov R., Lehrer D.S., Malaspina D., Marder S.R., Medeiros H., Morley C.P., Perkins D.O., Sobell J.L., Buckley P.F., Macciardi F., Rapaport M.H., Knowles J.A., Fanous A.H., McCarroll S.A., Gupta N., Gabriel S.B., Daly M.J., Lander E.S., Lowenstein D.H., Goldstein D.B., Lerche H., Berkovic S.F., Neale B.M., Epi25 Collaborative, YÜCESAN, EMRAH, Institute for Molecular Medicine Finland, Children's Hospital, HUS Children and Adolescents, Department of Medical and Clinical Genetics, University Management, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, and Genomics of Neurological and Neuropsychiatric Disorders

Subjects
s.berkovic@unimelb.edu.au [Epi25 Collaborative. Electronic address], 0301 basic medicine, GAMMA-2-SUBUNIT, burden analysi, DNA Mutational Analysis, PROTEIN, Neurodegenerative, VARIANTS, SUSCEPTIBILITY, Medical and Health Sciences, Epilepsy, 0302 clinical medicine, 2.1 Biological and endogenous factors, EPIDEMIOLOGY, Missense mutation, Exome, Aetiology, Genetics (clinical), Exome sequencing, 11 Medical and Health Sciences, seizures, GABRG2, Genetics, Genetics & Heredity, 0303 health sciences, biology, COMMON EPILEPSIES, 1184 Genetics, developmental biology, physiology, sequencing, Biological Sciences, Epi25 Collaborative, Phenotype, GENOME, epileptic encephalopathy, burden analysis, Neurological, Biotechnology, Genetic Markers, seizure, EEF1A2, Burden analysis, epilepsy, exome, Article, 03 medical and health sciences, Clinical Research, Exome Sequencing, Genetic variation, medicine, Humans, Genetic Predisposition to Disease, Gene, EPILEPTIC SEIZURES, METAANALYSIS, 030304 developmental biology, Human Genome, Neurosciences, Genetic Variation, 06 Biological Sciences, medicine.disease, Brain Disorders, 030104 developmental biology, Genetic marker, DE-NOVO MUTATIONS, Case-Control Studies, biology.protein, 3111 Biomedicine, Human medicine, 030217 neurology & neurosurgery
Abstract

Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,364 controls of European ancestry. We focused on three phenotypic groups; the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.

Published
2019

17. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author

Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.

Subjects
0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Published
2018

18. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Author

Eva M. Reinthaler, Dennis Lal, Sebastien Lebon, Michael S. Hildebrand, Hans-Henrik M. Dahl, Brigid M. Regan, Martha Feucht, Hannelore Steinböck, Birgit Neophytou, Gabriel M. Ronen, Laurian Roche, Ursula Gruber-Sedlmayr, Julia Geldner, Edda Haberlandt, Per Hoffmann, Stefan Herms, Christian Gieger, Melanie Waldenberger, Andre Franke, Michael Wittig, Susanne Schoch, Albert J. Becker, Andreas Hahn, Katrin Männik, Mohammad R. Toliat, Georg Winterer, Holger Lerche, Peter Nürnberg, Heather Mefford, Ingrid E. Scheffer, Samuel F. Berkovic, Jacques S. Beckmann, Thomas Sander, Sebastien Jacquemont, Alexandre Reymond, Fritz Zimprich, Bernd A. Neubauer, Bernd Neubauer, Martina Mörzinger, Arvid Suls, Sarah Weckhuysen, Lieve Claes, Liesbet Deprez, Katrien Smets, Tine Van Dyck, Tine Deconinck, Peter De Jonghe, Rikke S Møller, Laura L. Klitten, Helle Hjalgrim, Kiel Campus, Ingo Helbig, Hiltrud Muhle, Philipp Ostertag, Sarah von Spiczak, Ulrich Stephani, Holger Trucks, Christian E. Elger, Ailing A. Kleefuß-Lie, Wolfram S. Kunz, Rainer Surges, Verena Gaus, Dieter Janz, Bettina Schmitz, Felix Rosenow, Karl Martin Klein, Philipp S. Reif, Wolfgang H. Oertel, Hajo M. Hamer, Felicitas Becker, Yvonne Weber, Bobby P.C. Koeleman, Carolien de Kovel, Dick Lindhout, Agnès Ameil, Joris Andrieux, Sonia Bouquillon, Odile Boute, Jeanne de Flandre, Jean Marie Cuisset, Jean-Christophe Cuvellier, Roger Salengro, Albert David, Bert de Vries, Marie-Ange Delrue, Martine Doco-Fenzy, Bridget A. Fernandez, Delphine Heron, Boris Keren, Robert Lebel, Bruno Leheup, Suzanne Lewis, Maria Antonietta Mencarelli, Cyril Mignot, Jean-Claude Minet, Alexandre Moerman, Fanny Morice-Picard, Mafalda Mucciolo, Katrin Ounap, Laurent Pasquier, Florence Petit, Francesca Ragona, Evica Rajcan-Separovic, Alessandra Renieri, Claudine Rieubland, Damien Sanlaville, Elisabeth Sarrazin, Yiping Shen, Mieke van Haelst, Anneke Vulto-van Silfhout, 16p11.2 European Consortium, EPICURE Consortium, EuroEPINOMICS Consortium, Reinthaler, EM., Zimprich, F., Feucht, M., Steinböck, H., Neophytou, B., Geldner, J., Gruber-Sedlmayr, U., Haberlandt, E., Ronen, GM., Roche, L., Lal, D., Nürnberg, P., Sander, T., Lerche, H., Neubauer, B., Mörzinger, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Møller, RS., Klitten, LL., Hjalgrim, H., Campus, K., Helbig, I., Muhle, H., Ostertag, P., von Spiczak, S., Stephani, U., Trucks, H., Elger, CE., Kleefuß-Lie, AA., Kunz, WS., Surges, R., Gaus, V., Janz, D., Schmitz, B., Rosenow, F., Klein, KM., Reif, PS., Oertel, WH., Hamer, HM., Becker, F., Weber, Y., Koeleman, BP., de Kovel, C., Lindhout, D., Ameil, A., Andrieux, J., Bouquillon, S., Boute, O., Cordier, MP., Cuisset, JM., Cuvellier, JC., David, A., de Vries, B., Delrue, MA., Doco-Fenzy, M., Fernandez, BA., Heron, D., Keren, B., Lebel, R., Leheup, B., Lewis, S., Mencarelli, MA., Mignot, C., Minet, JC., Moerman, A., Morice-Picard, F., Mucciolo, M., Ounap, K., Pasquier, L., Petit, F., Ragona, F., Rajcan-Separovic, E., Renieri, A., Rieubland, C., Sanlaville, D., Sarrazin, E., Shen, Y., van Haelst, M., Vulto-van Silfhout, A., and Other departments

Subjects
Male, DNA Copy Number Variations, Chromosomes, Human, Pair 22, 610 Medicine & health, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Temporal lobe, Epilepsy, Gene duplication, Chromosome Duplication, Genetics, medicine, Humans, Copy-number variation, Child, Molecular Biology, Genetics (clinical), Chromosomes, Human, Pair 15, Infant, General Medicine, Odds ratio, medicine.disease, Epilepsy, Rolandic, Rolandic epilepsy, Exact test, Chromosomes, Human, Pair 1, Child, Preschool, Female, Chromosomes, Human, Pair 16
Abstract

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Published
2014

19. RARS1 ‐related hypomyelinating leukodystrophy: Expanding the spectrum

Author

Chiara Aiello, Isabella Moroni, Mary Kay Koenig, Bryce A. Mendelsohn, Geneviève Bernard, Nicole I. Wolf, Enrico Bertini, Sarah von Spiczak, Gajja S. Salomons, Davide Tonduti, Adeline L. Vanderver, Desirée E.C. Smith, Ingo Helbig, Nicola Brunetti-Pierri, Shanice Beerepoot, Ettore Salsano, Jozef Hertecant, Marjo S van der Knaap, Jullie Rhee, Hiltrud Muhle, John H. Livingston, Gerarda Cappuccio, Laura Russell, Jamie L. Fraser, Lisa Emrick, Katherine L. Helbig, Franco Taroni, Marisa I. Mendes, Omar Ismayl, Lydia Green, Daniela Di Bella, Stefania Magri, Mendes, M. I., Green, L. M. C., Bertini, E., Tonduti, D., Aiello, C., Smith, D., Salsano, E., Beerepoot, S., Hertecant, J., von Spiczak, S., Livingston, J. H., Emrick, L., Fraser, J., Russell, L., Bernard, G., Magri, S., Di Bella, D., Taroni, F., Koenig, M. K., Moroni, I., Cappuccio, G., Brunetti-Pierri, N., Rhee, J., Mendelsohn, B. A., Helbig, I., Helbig, K., Muhle, H., Ismayl, O., Vanderver, A. L., Salomons, G. S., van der Knaap, M. S., Wolf, N. I., Laboratory Genetic Metabolic Diseases, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Medicine, AGEM - Endocrinology, metabolism and nutrition, AGEM - Inborn errors of metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Pediatric surgery, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Reproduction & Development (AR&D), and Functional Genomics

Subjects
Adult, 0301 basic medicine, Pathology, medicine.medical_specialty, Adolescent, Neurosciences. Biological psychiatry. Neuropsychiatry, Nystagmus, Severity of Illness Index, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Atrophy, SDG 3 - Good Health and Well-being, Demyelinating disease, medicine, Humans, Missense mutation, Spasticity, Age of Onset, RC346-429, Child, Genetic Association Studies, Research Articles, business.industry, General Neuroscience, Leukodystrophy, Genetic disorder, Infant, Arginine-tRNA Ligase, medicine.disease, Magnetic Resonance Imaging, Hereditary Central Nervous System Demyelinating Diseases, Cross-Sectional Studies, 030104 developmental biology, Child, Preschool, Neurology. Diseases of the nervous system, Neurology (clinical), Age of onset, medicine.symptom, business, 030217 neurology & neurosurgery, RC321-571, Research Article
Abstract

OBJECTIVE: Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships.METHODS: We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot.RESULTS: Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform.INTERPRETATION: Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early-onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination.

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