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6. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author

Koko, M, Motelow, JE, Stanley, KE, Bobbili, DR, Dhindsa, RS, May, P, Alldredge, BK, Allen, AS, Altmüller, J, Amrom, D, Andermann, E, Auce, P, Avbersek, A, Baulac, S, Bautista, JF, Becker, F, Bellows, Susannah, Berghuis, B, Berkovic, SF, Bluvstein, J, Boro, A, Bridgers, J, Burgess, R, Caglayan, H, Cascino, GD, Cavalleri, GL, Chung, SK, Cieuta-Walti, C, Cloutier, V, Consalvo, D, Cossette, P, Crumrine, P, Delanty, N, Depondt, C, Desbiens, R, Devinsky, O, Dlugos, D, Epstein, MP, Everett, K, Fiol, M, Fountain, NB, Francis, B, French, J, Freyer, C, Friedman, D, Gambardella, A, Geller, EB, Girard, S, Glauser, T, Glynn, S, Goldstein, DB, Gravel, M, Haas, K, Haut, SR, Heinzen, EL, Helbig, I, Hildebrand, MS, Johnson, MR, Jorgensen, A, Joshi, S, Kanner, A, Kirsch, HE, Klein, KM, Knowlton, RC, Koeleman, BPC, Kossoff, EH, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Langley, SR, LeGuern, E, Lehesjoki, AE, Lerche, H, Leu, C, Lortie, A, Lowenstein, DH, Marson, AG, Mebane, C, Mefford, HC, Meloche, C, Moreau, C, Motika, PV, Muhle, H, Møller, RS, Nabbout, R, Nguyen, DK, Nikanorova, M, Novotny, EJ, Nürnberg, P, Ottman, R, O’Brien, TJ, Paolicchi, JM, Parent, JM, Park, K, Peter, S, Petrou, S, Petrovski, S, Pickrell, WO, Poduri, A, Koko, M, Motelow, JE, Stanley, KE, Bobbili, DR, Dhindsa, RS, May, P, Alldredge, BK, Allen, AS, Altmüller, J, Amrom, D, Andermann, E, Auce, P, Avbersek, A, Baulac, S, Bautista, JF, Becker, F, Bellows, Susannah, Berghuis, B, Berkovic, SF, Bluvstein, J, Boro, A, Bridgers, J, Burgess, R, Caglayan, H, Cascino, GD, Cavalleri, GL, Chung, SK, Cieuta-Walti, C, Cloutier, V, Consalvo, D, Cossette, P, Crumrine, P, Delanty, N, Depondt, C, Desbiens, R, Devinsky, O, Dlugos, D, Epstein, MP, Everett, K, Fiol, M, Fountain, NB, Francis, B, French, J, Freyer, C, Friedman, D, Gambardella, A, Geller, EB, Girard, S, Glauser, T, Glynn, S, Goldstein, DB, Gravel, M, Haas, K, Haut, SR, Heinzen, EL, Helbig, I, Hildebrand, MS, Johnson, MR, Jorgensen, A, Joshi, S, Kanner, A, Kirsch, HE, Klein, KM, Knowlton, RC, Koeleman, BPC, Kossoff, EH, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Langley, SR, LeGuern, E, Lehesjoki, AE, Lerche, H, Leu, C, Lortie, A, Lowenstein, DH, Marson, AG, Mebane, C, Mefford, HC, Meloche, C, Moreau, C, Motika, PV, Muhle, H, Møller, RS, Nabbout, R, Nguyen, DK, Nikanorova, M, Novotny, EJ, Nürnberg, P, Ottman, R, O’Brien, TJ, Paolicchi, JM, Parent, JM, Park, K, Peter, S, Petrou, S, Petrovski, S, Pickrell, WO, and Poduri, A

Published
2022

7. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author

Koko, M., Motelow, J. E., Stanley, K. E., Bobbili, D. R., Dhindsa, R. S., May, P., Alldredge, B. K., Allen, A. S., Altmuller, J., Amrom, D., Andermann, E., Auce, P., Avbersek, A., Baulac, S., Bautista, J. F., Becker, F., Bellows, S. T., Berghuis, B., Berkovic, S. F., Bluvstein, J., Boro, A., Bridgers, J., Burgess, R., Caglayan, H., Cascino, G. D., Cavalleri, G. L., Chung, S. -K., Cieuta-Walti, C., Cloutier, V., Consalvo, D., Cossette, P., Crumrine, P., Delanty, N., Depondt, C., Desbiens, R., Devinsky, O., Dlugos, D., Epstein, M. P., Everett, K., Fiol, M., Fountain, N. B., Francis, B., French, J., Freyer, C., Friedman, D., Gambardella, A., Geller, E. B., Girard, S., Glauser, T., Glynn, S., Goldstein, D. B., Gravel, M., Haas, K., Haut, S. R., Heinzen, E. L., Helbig, I., Hildebrand, M. S., Johnson, M. R., Jorgensen, A., Joshi, S., Kanner, A., Kirsch, H. E., Klein, K. M., Knowlton, R. C., Koeleman, B. P. C., Kossoff, E. H., Krause, R., Krenn, M., Kunz, W. S., Kuzniecky, R., Langley, S. R., Leguern, E., Lehesjoki, A. -E., Lerche, H., Leu, C., Lortie, A., Lowenstein, D. H., Marson, A. G., Mebane, C., Mefford, H. C., Meloche, C., Moreau, C., Motika, P. V., Muhle, H., Moller, R. S., Nabbout, R., Nguyen, D. K., Nikanorova, M., Novotny, E. J., Nurnberg, P., Ottman, R., O'Brien, T. J., Paolicchi, J. M., Parent, J. M., Park, K., Peter, S., Petrou, S., Petrovski, S., Pickrell, W. O., Poduri, A., Radtke, R. A., Rees, M. I., Regan, B. M., Ren, Z., Sadleir, L. G., Sander, J. W., Sander, T., Scheffer, I. E., Schubert, J., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Shinnar, S., Sills, G. J., Singh, R. K., Siren, A., Sirven, J., Sisodiya, S. M., Smith, M. C., Sonsma, A. C. M., Striano, P., Sullivan, J., Thio, L. L., Thomas, R. H., Venkat, A., Vining, E. P. G., Von Allmen, G. K., Wang, Q., Weber, Y. G., Weckhuysen, S., Weisenberg, J. L., Widdess-Walsh, P., Winawer, M. R., Wolking, S., Zara, F., Zimprich, F., Canadian Epilepsy Network, Epi4K Consortium, Epilepsy Phenome/Genome Project, EpiPGX Consortium, EuroEPINOMICS-CoGIE Consortium, Department of Medical and Clinical Genetics, Medicum, Fonds National de la Recherche - FnR [sponsor], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Peter, Sarah, Petrou, Steven, Petrovski, Slavé, Pickrell, William O., Poduri, Annapurna, Radtke, Rodney A., Rees, Mark I., Regan, Brigid M., Ren, Zhong, Sadleir, Lynette G., Alldredge, Brian K., Sander, Josemir W., Sander, Thomas, Scheffer, Ingrid E., Schubert, Julian, Shellhaas, Renée A., Sherr, Elliott H., Shih, Jerry J., Shinnar, Shlomo, Sills, Graeme J., Singh, Rani K., Allen, Andrew S., Siren, Auli, Sirven, Joseph, Sisodiya, Sanjay M., Smith, Michael C., Sonsma, Anja C. M., Striano, Pasquale, Sullivan, Joseph, Thio, Liu Lin, Thomas, Rhys H., Venkat, Anu, Altmüller, Janine, Vining, Eileen P. G., Von Allmen, Gretchen K., Wang, Quanli, Weber, Yvonne G., Weckhuysen, Sarah, Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Wolking, Stefan, Zara, Federico, Amrom, Dina, Zimprich, Fritz, Andermann, Eva, Auce, Pauls, Avbersek, Andreja, Baulac, Stéphanie, Bautista, Jocelyn F., Becker, Felicitas, Bellows, Susannah T., Berghuis, Bianca, Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Bridgers, Joshua, Burgess, Rosemary, Caglayan, Hande, Cascino, Gregory D., Cavalleri, Gianpiero L., Chung, Seo-Kyung, Cieuta-Walti, Cécile, Cloutier, Véronique, Consalvo, Damian, Cossette, Patrick, Crumrine, Patricia, Delanty, Norman, Depondt, Chantal, Desbiens, Richard, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Everett, Kate, Fiol, Miguel, Fountain, Nathan B., Francis, Ben, French, Jacqueline, Freyer, Catharine, Friedman, Daniel, Gambardella, Antonio, Geller, Eric B., Girard, Simon, Glauser, Tracy, Glynn, Simon, Goldstein, David B., Gravel, Micheline, Haas, Kevin, Haut, Sheryl R., Heinzen, Erin L., Helbig, Ingo, Hildebrand, Michael S., Johnson, Michael R., Jorgensen, Andrea, Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Klein, Karl M., Knowlton, Robert C., Koeleman, Bobby P. C., Kossoff, Eric H., Krause, Roland, Krenn, Martin, Kunz, Wolfram S., Kuzniecky, Ruben, Langley, Sarah R., LeGuern, Eric, Lehesjoki, Anna-Elina, Lerche, Holger, Leu, Costin, Lortie, Anne, Lowenstein, Daniel H., Marson, Anthony G., Mebane, Caroline, Mefford, Heather C., Meloche, Caroline, Moreau, Claudia, Motika, Paul V., Muhle, Hiltrud, Møller, Rikke S., Nabbout, Rima, Nguyen, Dang K., Nikanorova, Marina, Novotny, Edward J., Nürnberg, Peter, Ottman, Ruth, O'Brien, Terence J., Paolicchi, Juliann M., Parent, Jack M., and Park, Kristen

Subjects
GABA receptors, Neurology [D14] [Human health sciences], Clinical Sciences, GABA(A) receptors, GABRG2, familial epilepsy, Article, Clinical Research, Receptors, Exome Sequencing, Genetics, 2.1 Biological and endogenous factors, Humans, GGE, Genetic Predisposition to Disease, sporadic epilepsy, EpiPGX Consortium, Aetiology, gamma-Aminobutyric Acid, GABAA receptors, Epi4K Consortium, Epilepsy, Neurology & Neurosurgery, Neurologie [D14] [Sciences de la santé humaine], Generalized, GABA-A, Prevention, Human Genome, Neurosciences, 1184 Genetics, developmental biology, physiology, 3112 Neurosciences, Receptors, GABA-A, EuroEPINOMICS-CoGIE Consortium, Neurology, Case-Control Studies, Epilepsy, Generalized, Canadian Epilepsy Network, Neurology (clinical), Genetics & genetic processes [F10] [Life sciences], 3111 Biomedicine, Human medicine, Génétique & processus génétiques [F10] [Sciences du vivant], Epilepsy Phenome/Genome Project
Abstract

ObjectiveWe aimed to identify genes associated with genetic generalized epilepsy (GGE) by combining large cohorts enriched with individuals with a positive family history. Secondarily, we set out to compare the association of genes independently with familial and sporadic GGE.MethodsWe performed a case-control whole exome sequencing study in unrelated individuals of European descent diagnosed with GGE (previously recruited and sequenced through multiple international collaborations) and ancestry-matched controls. The association of ultra-rare variants (URVs; in 18834 protein-coding genes) with epilepsy was examined in 1928 individuals with GGE (vs. 8578 controls), then separately in 945 individuals with familial GGE (vs. 8626 controls), and finally in 1005 individuals with sporadic GGE (vs. 8621 controls). We additionally examined the association of URVs with familial and sporadic GGE in two gene sets important for inhibitory signaling (19genes encoding γ-aminobutyric acid type A [GABAA ] receptors, 113genes representing the GABAergic pathway).ResultsGABRG2 was associated with GGE (p=1.8×10-5 ), approaching study-wide significance in familial GGE (p=3.0×10-6 ), whereas no gene approached a significant association with sporadic GGE. Deleterious URVs in the most intolerant subgenic regions in genes encoding GABAA receptors were associated with familial GGE (odds ratio [OR]=3.9, 95% confidence interval [CI]=1.9-7.8, false discovery rate [FDR]-adjusted p=.0024), whereas their association with sporadic GGE had marginally lower odds (OR=3.1, 95% CI=1.3-6.7, FDR-adjusted p=.022). URVs in GABAergic pathway genes were associated with familial GGE (OR=1.8, 95% CI=1.3-2.5, FDR-adjusted p=.0024) but not with sporadic GGE (OR=1.3, 95% CI=.9-1.9, FDR-adjusted p=.19).SignificanceURVs in GABRG2 are likely an important risk factor for familial GGE. The association of gene sets of GABAergic signaling with familial GGE is more prominent than with sporadic GGE.

Published
2022
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9. Quantitative Proteomics in Drosophila with Holidic Stable-Isotope Labeling of Amino Acids in Fruit Flies (SILAF)

Author

Schober, F., Atanassov, I., Freyer, C., and Wredenberg, A.

Abstract

Protein-focused research has been challenging in Drosophila melanogaster due to few specific antibodies for Western blotting and the lack of effective labeling methods for quantitative proteomics. Herein, we describe the preparation of a holidic medium that allows stable-isotope labeling of amino acids in fruit flies (SILAF). Furthermore, in this chapter, we provide a protocol for mitochondrial enrichments from Drosophila larvae and flies together with a procedure to generate high-quality peptides for further analysis by mass spectrometry. Samples obtained following this protocol can be used for various functional studies such as comprehensive proteome profiling or quantitative analysis of posttranslational modifications upon enrichment. SILAF is based on standard fly routines in a basic wet lab environment and provides a flexible and cost-effective tool for quantitative protein expression analysis.

Published
2021

10. Diverse genetic causes of polymicrogyria with epilepsy

Author

Allen, AS, Aggarwal, V, Berkovic, SF, Cossette, P, Delanty, N, Dlugos, D, Eichler, EE, Epstein, MP, Freyer, C, Goldstein, DB, Guerrini, R, Glauser, T, Heinzen, EL, Johnson, MR, Kuzniecky, R, Lowenstein, DH, Marson, AG, Mefford, HC, O'Brien, TJ, Ottman, R, Poduri, A, Petrou, S, Petrovski, S, Ruzzo, EK, Scheffer, IE, Sherr, EH, Abou-Khalil, B, Amrom, D, Andermann, E, Andermann, F, Bluvstein, J, Boro, A, Cascino, G, Consalvo, D, Crumrine, P, Devinsky, O, Fountain, N, Friedman, D, Geller, E, Glynn, S, Haas, K, Haut, S, Joshi, S, Kirsch, H, Knowlton, R, Kossoff, E, Motika, PV, Paolicchi, JM, Parent, JM, Shellhaas, RA, Shih, JJ, Shinnar, S, Singh, RK, Sperling, M, Smith, MC, Sullivan, J, Vining, EPG, Von Allmen, GK, Widdess-Walsh, P, Winawer, MR, Bautista, J, Fiol, M, Hayward, J, Helmers, S, Park, K, Sirven, J, Thio, LL, Venkat, A, Weisenberg, J, Kuperman, R, McGuire, S, Novotny, E, Sadleir, L, Allen, AS, Aggarwal, V, Berkovic, SF, Cossette, P, Delanty, N, Dlugos, D, Eichler, EE, Epstein, MP, Freyer, C, Goldstein, DB, Guerrini, R, Glauser, T, Heinzen, EL, Johnson, MR, Kuzniecky, R, Lowenstein, DH, Marson, AG, Mefford, HC, O'Brien, TJ, Ottman, R, Poduri, A, Petrou, S, Petrovski, S, Ruzzo, EK, Scheffer, IE, Sherr, EH, Abou-Khalil, B, Amrom, D, Andermann, E, Andermann, F, Bluvstein, J, Boro, A, Cascino, G, Consalvo, D, Crumrine, P, Devinsky, O, Fountain, N, Friedman, D, Geller, E, Glynn, S, Haas, K, Haut, S, Joshi, S, Kirsch, H, Knowlton, R, Kossoff, E, Motika, PV, Paolicchi, JM, Parent, JM, Shellhaas, RA, Shih, JJ, Shinnar, S, Singh, RK, Sperling, M, Smith, MC, Sullivan, J, Vining, EPG, Von Allmen, GK, Widdess-Walsh, P, Winawer, MR, Bautista, J, Fiol, M, Hayward, J, Helmers, S, Park, K, Sirven, J, Thio, LL, Venkat, A, Weisenberg, J, Kuperman, R, McGuire, S, Novotny, E, and Sadleir, L

Abstract

OBJECTIVE: We sought to identify novel genes and to establish the contribution of known genes in a large cohort of patients with nonsyndromic sporadic polymicrogyria and epilepsy. METHODS: We enrolled participants with polymicrogyria and their parents through the Epilepsy Phenome/Genome Project. We performed phenotyping and whole exome sequencing (WES), trio analysis, and gene-level collapsing analysis to identify de novo or inherited variants, including germline or mosaic (postzygotic) single nucleotide variants, small insertion-deletion (indel) variants, and copy number variants present in leukocyte-derived DNA. RESULTS: Across the cohort of 86 individuals with polymicrogyria and epilepsy, we identified seven with pathogenic or likely pathogenic variants in PIK3R2, including four germline and three mosaic variants. PIK3R2 was the only gene harboring more than expected de novo variants across the entire cohort, and likewise the only gene that passed the genome-wide threshold of significance in the gene-level rare variant collapsing analysis. Consistent with previous reports, the PIK3R2 phenotype consisted of bilateral polymicrogyria concentrated in the perisylvian region with macrocephaly. Beyond PIK3R2, we also identified one case each with likely causal de novo variants in CCND2 and DYNC1H1 and biallelic variants in WDR62, all genes previously associated with polymicrogyria. Candidate genetic explanations in this cohort included single nucleotide de novo variants in other epilepsy-associated and neurodevelopmental disease-associated genes (SCN2A in two individuals, GRIA3, CACNA1C) and a 597-kb deletion at 15q25, a neurodevelopmental disease susceptibility locus. SIGNIFICANCE: This study confirms germline and postzygotically acquired de novo variants in PIK3R2 as an important cause of bilateral perisylvian polymicrogyria, notably with macrocephaly. In total, trio-based WES identified a genetic diagnosis in 12% and a candidate diagnosis in 6% of our polymicrogyria

Published
2021

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

Author

Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, Goldstein, DB, Motelow, JE, Povysil, G, Dhindsa, RS, Stanley, KE, Allen, AS, Feng, Y-CA, Howrigan, DP, Abbott, LE, Tashman, K, Cerrato, F, Cusick, C, Singh, T, Heyne, H, Byrnes, AE, Churchhouse, C, Watts, N, Solomonson, M, Lal, D, Gupta, N, Neale, BM, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Bennett, CA, Leu, C, Leech, SL, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Ali, QZ, Sadoway, TR, Krestel, H, Schaller, A, Papacostas, SS, Kousiappa, I, Tanteles, GA, Christou, Y, Sterbova, K, Vlckova, M, Sedlackova, L, Lassuthova, P, Klein, KM, Rosenow, F, Reif, PS, Knake, S, Neubauer, BA, Zimprich, F, Feucht, M, Reinthaler, EM, Kunz, WS, Zsurka, G, Surges, R, Baumgartner, T, von Wrede, R, Pendziwiat, M, Muhle, H, Rademacher, A, van Baalen, A, von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Muller-Schluter, K, Kluger, G, Haeusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Lauxmann, S, Bosselmann, C, Kegele, J, Hengsbach, C, Rau, S, Steinhoff, BJ, Schulze-Bonhage, A, Borggraefe, I, Schankin, CJ, Schubert-Bast, S, Schreiber, H, Mayer, T, Korinthenberg, R, Brockmann, K, Wolff, M, Dennig, D, Madeleyn, R, Kalviainen, R, Saarela, A, Timonen, O, Linnankivi, T, Lehesjoki, A-E, Rheims, S, Lesca, G, Ryvlin, P, Maillard, L, Valton, L, Derambure, P, Bartolomei, F, Hirsch, E, Michel, V, Chassoux, F, Rees, M, Chung, S-K, Pickrell, WO, Powell, R, Baker, MD, Fonferko-Shadrach, B, Lawthom, C, Anderson, J, Schneider, N, Balestrini, S, Zagaglia, S, Braatz, V, Johnson, MR, Auce, P, Sills, GJ, Baum, LW, Sham, PC, Cherny, SS, Lui, CHT, Delanty, N, Doherty, CP, Shukralla, A, El-Naggar, H, Widdess-Walsh, P, Barisi, N, Canafoglia, L, Franceschetti, S, Castellotti, B, Granata, T, Ragona, F, Zara, F, Iacomino, M, Riva, A, Madia, F, Vari, MS, Salpietro, V, Scala, M, Mancardi, MM, Nobili, L, Amadori, E, Giacomini, T, Bisulli, F, Pippucci, T, Licchetta, L, Minardi, R, Tinuper, P, Muccioli, L, Mostacci, B, Gambardella, A, Labate, A, Annesi, G, Manna, L, Gagliardi, M, Parrini, E, Mei, D, Vetro, A, Bianchini, C, Montomoli, M, Doccini, V, Barba, C, Hirose, S, Ishii, A, Suzuki, T, Inoue, Y, Yamakawa, K, Beydoun, A, Nasreddine, W, Zgheib, NK, Tumiene, B, Utkus, A, Sadleir, LG, King, C, Caglayan, SH, Arslan, M, Yapici, Z, Topaloglu, P, Kara, B, Yis, U, Turkdogan, D, Gundogdu-Eken, A, Bebek, N, Tsai, M-H, Ho, C-J, Lin, C-H, Lin, K-L, Chou, I-J, Poduri, A, Shiedley, BR, Shain, C, Noebels, JL, Goldman, A, Busch, RM, Jehi, L, Najm, IM, Ferguson, L, Khoury, J, Glauser, TA, Clark, PO, Buono, RJ, Ferraro, TN, Sperling, MR, Lo, W, Privitera, M, French, JA, Schachter, S, Kuzniecky, R, Devinsky, O, Hegde, M, Greenberg, DA, Ellis, CA, Goldberg, E, Helbig, KL, Cosico, M, Vaidiswaran, P, Fitch, E, Berkovic, SF, Lerche, H, Lowenstein, DH, and Goldstein, DB

Abstract

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

12. 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
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14. Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects

Author

Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, Becker, F, Niestroj, LM, Perez-Palma, E, Howrigan, DP, Zhou, Y, Cheng, F, Saarentaus, E, Nürnberg, P, Stevelink, R, Daly, MJ, Palotie, A, Lal, D, Feng, YCA, Abbott, LE, Tashman, K, Cerrato, F, Churchhouse, C, Gupta, N, Neale, BM, Berkovic, SF, Lerche, H, Goldstein, DB, Lowenstein, DH, Cavalleri, GL, Cossette, P, Cotsapas, C, De Jonghe, P, Dixon-Salazar, T, Guerrini, R, Hakonarson, H, Heinzen, EL, Helbig, I, Kwan, P, Marson, AG, Petrovski, S, Kamalakaran, S, Sisodiya, SM, Stewart, R, Weckhuysen, S, Depondt, C, Dlugos, DJ, Scheffer, IE, Striano, P, Freyer, C, Krause, R, May, P, McKenna, K, Regan, BM, Leu, C, Bennett, CA, Bellows, Susannah, Johns, EMC, MacDonald, A, Shilling, H, Burgess, R, Weckhuysen, D, Bahlo, M, O'Brien, TJ, Todaro, M, Stamberger, H, Andrade, DM, Sadoway, TR, Mo, K, Krestel, H, Gallati, S, Papacostas, SS, Kousiappa, I, Tanteles, GA, Šterbová, K, Vlcková, M, Sedlácková, L, Laššuthová, P, Martin, K, Rosenow, F, Reif, PS, Knake, S, Kunz, WS, Zsurka, G, Elger, CE, Bauer, J, Rademacher, M, Pendziwiat, M, Muhle, H, Rademacher, A, Van Baalen, A, Von Spiczak, S, Stephani, U, Afawi, Z, Korczyn, AD, Kanaan, M, Canavati, C, Kurlemann, G, Müller-Schlüter, K, Kluger, G, Häusler, M, Blatt, I, Lemke, JR, Krey, I, Weber, YG, Wolking, S, and Becker, F

Abstract

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The character

Published
2020

18. Quantitative analysis of phenotypic elements augments traditional electroclinical classification of common familial epilepsies

Author

Abou-Khalil, B, Afawi, Z, Allen, AS, Bautista, JF, Bellows, ST, Berkovic, SF, Bluvstein, J, Burgess, R, Cascino, G, Cossette, P, Cristofaro, S, Crompton, DE, Delanty, N, Devinsky, O, Dlugos, D, Ellis, CA, Epstein, MP, Fountain, NB, Freyer, C, Geller, EB, Glauser, T, Glynn, S, Goldberg-Stern, H, Goldstein, DB, Gravel, M, Haas, K, Haut, S, Heinzen, EL, Kirsch, HE, Kivity, S, Knowlton, R, Korczyn, AD, Kossoff, E, Kuzniecky, R, Loeb, R, Lowenstein, DH, Marson, AG, McCormack, M, McKenna, K, Mefford, HC, Motika, P, Mullen, SA, O'Brien, TJ, Ottman, R, Paolicchi, J, Parent, JM, Paterson, S, Petrou, S, Petrovski, S, Pickrell, WO, Poduri, A, Rees, MI, Sadleir, LG, Scheffer, IE, Shih, J, Singh, R, Sirven, J, Smith, M, Smith, PEM, Thio, LL, Thomas, RH, Venkat, A, Vining, E, Von Allmen, G, Weisenberg, J, Widdess-Walsh, P, Winawer, MR, Abou-Khalil, B, Afawi, Z, Allen, AS, Bautista, JF, Bellows, ST, Berkovic, SF, Bluvstein, J, Burgess, R, Cascino, G, Cossette, P, Cristofaro, S, Crompton, DE, Delanty, N, Devinsky, O, Dlugos, D, Ellis, CA, Epstein, MP, Fountain, NB, Freyer, C, Geller, EB, Glauser, T, Glynn, S, Goldberg-Stern, H, Goldstein, DB, Gravel, M, Haas, K, Haut, S, Heinzen, EL, Kirsch, HE, Kivity, S, Knowlton, R, Korczyn, AD, Kossoff, E, Kuzniecky, R, Loeb, R, Lowenstein, DH, Marson, AG, McCormack, M, McKenna, K, Mefford, HC, Motika, P, Mullen, SA, O'Brien, TJ, Ottman, R, Paolicchi, J, Parent, JM, Paterson, S, Petrou, S, Petrovski, S, Pickrell, WO, Poduri, A, Rees, MI, Sadleir, LG, Scheffer, IE, Shih, J, Singh, R, Sirven, J, Smith, M, Smith, PEM, Thio, LL, Thomas, RH, Venkat, A, Vining, E, Von Allmen, G, Weisenberg, J, Widdess-Walsh, P, and Winawer, MR

Abstract

OBJECTIVE: Classification of epilepsy into types and subtypes is important for both clinical care and research into underlying disease mechanisms. A quantitative, data-driven approach may augment traditional electroclinical classification and shed new light on existing classification frameworks. METHODS: We used latent class analysis, a statistical method that assigns subjects into groups called latent classes based on phenotypic elements, to classify individuals with common familial epilepsies from the Epi4K Multiplex Families study. Phenotypic elements included seizure types, seizure symptoms, and other elements of the medical history. We compared class assignments to traditional electroclinical classifications and assessed familial aggregation of latent classes. RESULTS: A total of 1120 subjects with epilepsy were assigned to five latent classes. Classes 1 and 2 contained subjects with generalized epilepsy, largely reflecting the distinction between absence epilepsies and younger onset (class 1) versus myoclonic epilepsies and older onset (class 2). Classes 3 and 4 contained subjects with focal epilepsies, and in contrast to classes 1 and 2, these did not adhere as closely to clinically defined focal epilepsy subtypes. Class 5 contained nearly all subjects with febrile seizures plus or unknown epilepsy type, as well as a few subjects with generalized epilepsy and a few with focal epilepsy. Family concordance of latent classes was similar to or greater than concordance of clinically defined epilepsy types. SIGNIFICANCE: Quantitative classification of epilepsy has the potential to augment traditional electroclinical classification by (1) combining some syndromes into a single class, (2) splitting some syndromes into different classes, (3) helping to classify subjects who could not be classified clinically, and (4) defining the boundaries of clinically defined classifications. This approach can guide future research, including molecular genetic studies, by identifyi

Published
2019

22. Intelligenz

Author

Hering, Eduard M, Freyer, C T, and BioStor

Published
1856

23. Heterozygous HNRNPU variants cause early onset epilepsy and severe intellectual disability

Author

Bramswig, N.C., Ludecke, H.J., Hamdan, F.F., Altmuller, J., Beleggia, F., Elcioglu, N.H., Freyer, C., Gerkes, E.H., Demirkol, Y.K., Knupp, K.G., Kuechler, A., Li, Y., Lowenstein, D.H., Michaud, J.L., Park, K., Stegmann, A.P., Veenstra-Knol, H.E., Wieland, T., Wollnik, B., Engels, H., Strom, T.M., Kleefstra, T., Wieczorek, D., Bramswig, N.C., Ludecke, H.J., Hamdan, F.F., Altmuller, J., Beleggia, F., Elcioglu, N.H., Freyer, C., Gerkes, E.H., Demirkol, Y.K., Knupp, K.G., Kuechler, A., Li, Y., Lowenstein, D.H., Michaud, J.L., Park, K., Stegmann, A.P., Veenstra-Knol, H.E., Wieland, T., Wollnik, B., Engels, H., Strom, T.M., Kleefstra, T., and Wieczorek, D.

Abstract

Contains fulltext : 174755.pdf (publisher's version ) (Closed access), Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.

Published
2017

24. EUS guided drainage of the biliary tree is effective and safe for both benign and malignant indications: A multicentre study.

Author

Saxena P., Kaffes A., Keegan M., Choo L., Croagh D., Freyer C., Saxena P., Kaffes A., Keegan M., Choo L., Croagh D., and Freyer C.

Abstract

Background and aims: In the majority of benign and malignant causes of biliary obstruction, drainage can be achieved via endoscopic retrograde cholangiography (ERC). However, in cases of failed ERC, the management algorithm usually encompasses percutaneous transhepatic cholangiography (PTC) or surgical bypass. The latter two are associated with significant morbidity. Therefore, a minimally invasive approach is preferable. The evolution of therapeutic EUS has permitted development of novel drainage techniques without the need for external drainage catheters or major surgery. The aim of this study is to evaluate outcomes of EUS-drainage procedures in benign and malignant causes of biliary obstruction. Method(s): This is a multicentre, retrospective review of all patients undergoing EUS-guided intervention to achieve drainage of the biliary tree. Patient demographics, procedural technical data, pre- and post- procedure bilirubin and adverse events were recorded. Technical success was defined as placement of stent in intended location. Clinical success was defined as >50% decline in bilirubin 2 weeks post procedure. Result(s): Between October 2013 and May 2016, a total of 14 patients, (mean age 63 +/- 19 years, 8/14 male) underwent EUS-biliary drainage procedures at 3 tertiary academic centres. Majority (72%) were for malignant obstruction (pancreatic cancer, n = 6, cholangiocarcinoma, n = 2, colorectal cancer metastasis, n = 2) and 28% (4/14) were for benign disease (benign biliary stricture, n = 2, cholangitis, n = 1, cholecystitis, n = 1). Reasons for failed ERC included obscured ampulla (n = 4), gastric outlet obstruction (n = 3), failed deep wire cannulation (n = 5), 1 ampulla within diverticulum and 1 patient unfit for laparoscopic cholecystectomy. EUS-guided drainage was performed via extrahepatic access in 64% (9/14) of cases. Seven choledochoduodenostomies, 4 hepatogastrostomies, 1 rendezvous, 1 antegrade stent and 1 gallbladder drainage were performed. Tract d

Published
2016

25. Nucleic Acids Res

Author

Hagstrxf6m E, Freyer C, Battersby BJ, Stewart JB, and Larsson N.-G.

Published
2014

29. Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26

Author

Kishita, Y., Pajak, A., Bolar, N.A., Marobbio, C.M., Maffezzini, C., Miniero, D.V., Monne, M., Kohda, M., Stranneheim, H., Murayama, K., Naess, K., Lesko, N., Bruhn, H., Mourier, A., Wibom, R., Nennesmo, I., Jespers, A., Govaert, P., Ohtake, A., Laer, L. Van, Loeys, B.L., Freyer, C., Palmieri, F., Wredenberg, A., Okazaki, Y., Wedell, A., Kishita, Y., Pajak, A., Bolar, N.A., Marobbio, C.M., Maffezzini, C., Miniero, D.V., Monne, M., Kohda, M., Stranneheim, H., Murayama, K., Naess, K., Lesko, N., Bruhn, H., Mourier, A., Wibom, R., Nennesmo, I., Jespers, A., Govaert, P., Ohtake, A., Laer, L. Van, Loeys, B.L., Freyer, C., Palmieri, F., Wredenberg, A., Okazaki, Y., and Wedell, A.

Abstract

Contains fulltext : 152388.pdf (Publisher’s version ) (Open Access), S-adenosylmethionine (SAM) is the predominant methyl group donor and has a large spectrum of target substrates. As such, it is essential for nearly all biological methylation reactions. SAM is synthesized by methionine adenosyltransferase from methionine and ATP in the cytoplasm and subsequently distributed throughout the different cellular compartments, including mitochondria, where methylation is mostly required for nucleic-acid modifications and respiratory-chain function. We report a syndrome in three families affected by reduced intra-mitochondrial methylation caused by recessive mutations in the gene encoding the only known mitochondrial SAM transporter, SLC25A26. Clinical findings ranged from neonatal mortality resulting from respiratory insufficiency and hydrops to childhood acute episodes of cardiopulmonary failure and slowly progressive muscle weakness. We show that SLC25A26 mutations cause various mitochondrial defects, including those affecting RNA stability, protein modification, mitochondrial translation, and the biosynthesis of CoQ10 and lipoic acid.

Published
2015

30. PLoS Genetics

Author

Wredenberg, A, Lagouge, M, Bratic, A, Metodiev, M.D, Spxe5hr, H, Mourier, A, Freyer, C, Ruzzenente, B, Tain, L, Grxf6nke, S, Baggio, F, Kukat, C, Kremmer, E, Wibom, R, Polosa, L.P, Habermann, B, Partridge, L, Park, C.B, and Larsson, N.-G.

Published
2013

31. Nat Genet

Author

Freyer C, Cree LM, Mourier A, Stewart JB, Koolmeister C, Milenkovic D, Wai T, Floros VI, Hagstrxf6m E, Chatzidaki EE, Wiesner RJ, Samuels DC, Larsson N.-G, and Chinnery PF

Published
2012

32. Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway

Author

Acuna Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M.H., Conner, P., Grigelioniene, G., Nilsson, D., Nordenskjold, M., Wedell, A., Freyer, C., Wredenberg, A., Wieczorek, D., Gillessen-Kaesbach, G., Kayserili, H., Elcioglu, N., Ghaderi-Sohi, S., Goodarzi, P., Setayesh, H., Vorst, M. van de, Steehouwer, M., Pfundt, R.P., Krabichler, B., Curry, C., MacKenzie, M.G., Boycott, K.M., Gilissen, C., Janecke, A.R., Hoischen, A., Zenker, M., Acuna Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M.H., Conner, P., Grigelioniene, G., Nilsson, D., Nordenskjold, M., Wedell, A., Freyer, C., Wredenberg, A., Wieczorek, D., Gillessen-Kaesbach, G., Kayserili, H., Elcioglu, N., Ghaderi-Sohi, S., Goodarzi, P., Setayesh, H., Vorst, M. van de, Steehouwer, M., Pfundt, R.P., Krabichler, B., Curry, C., MacKenzie, M.G., Boycott, K.M., Gilissen, C., Janecke, A.R., Hoischen, A., and Zenker, M.

Abstract

Contains fulltext : 136372.pdf (Publisher’s version ) (Closed access), Neu-Laxova syndrome (NLS) is a rare autosomal-recessive disorder characterized by a recognizable pattern of severe malformations leading to prenatal or early postnatal lethality. Homozygous mutations in PHGDH, a gene involved in the first and limiting step in L-serine biosynthesis, were recently identified as the cause of the disease in three families. By studying a cohort of 12 unrelated families affected by NLS, we provide evidence that NLS is genetically heterogeneous and can be caused by mutations in all three genes encoding enzymes of the L-serine biosynthesis pathway. Consistent with recently reported findings, we could identify PHGDH missense mutations in three unrelated families of our cohort. Furthermore, we mapped an overlapping homozygous chromosome 9 region containing PSAT1 in four consanguineous families. This gene encodes phosphoserine aminotransferase, the enzyme for the second step in L-serine biosynthesis. We identified six families with three different missense and frameshift PSAT1 mutations fully segregating with the disease. In another family, we discovered a homozygous frameshift mutation in PSPH, the gene encoding phosphoserine phosphatase, which catalyzes the last step of L-serine biosynthesis. Interestingly, all three identified genes have been previously implicated in serine-deficiency disorders, characterized by variable neurological manifestations. Our findings expand our understanding of NLS as a disorder of the L-serine biosynthesis pathway and suggest that NLS represents the severe end of serine-deficiency disorders, demonstrating that certain complex syndromes characterized by early lethality could indeed be the extreme end of the phenotypic spectrum of already known disorders.

Published
2014

33. FOXP3 over-expression inhibits melanoma tumorigenesis via effects on proliferation and apoptosis

Author

Tan, B, Anaka, M, Deb, S, Freyer, C, Ebert, LM, Chueh, AC, Al-Obaidi, S, Behren, A, Jayachandran, A, Cebon, J, Chen, W, Mariadason, JM, Tan, B, Anaka, M, Deb, S, Freyer, C, Ebert, LM, Chueh, AC, Al-Obaidi, S, Behren, A, Jayachandran, A, Cebon, J, Chen, W, and Mariadason, JM

Abstract

The Forkhead box P3 (FOXP3) transcription factor is the key driver of regulatory T cell (Treg cells) differentiation and immunosuppressive function. In addition, FOXP3 has been reported to be expressed in many tumors, including melanoma. However, its role in tumorigenesis is conflicting, with both tumor suppressive and tumor promoting functions described. The aim of the current study was to characterize the expression and function of FOXP3 in melanoma. FOXP3 expression was detected by immunohistochemistry (IHC) in 12% (18/146) of stage III and IV melanomas. However expression was confined to fewer than 1% of cells in these tumors. Stable over-expression of FOXP3 in the SK-MEL-28 melanoma cell line reduced cell proliferation and clonogenicity in vitro, and reduced xenograft growth in vivo. FOXP3 over-expression also increased pigmentation and the rate of apoptosis of SK-MEL-28 cells. Based on its infrequent expression in human melanoma, and its growth inhibitory and pro-apoptotic effect in over-expressing melanoma cells, we conclude that FOXP3 is not likely to be a key tumor suppressor or promoter in melanoma.

Published
2014

38. Controlled Metal Build Up (CMB): Schneller Aufbau und automatische Reparatur von Werkzeugen

Author

Klocke, F., Freyer, C., and Publica

Subjects
Rapid Tooling, Werkzeug- und Formenbau, Laserauftragschweißen, Metallprototyp, Rapid Prototyping, HSC, CMB, controlled metal build up
Abstract

Das Controlled Metal Build Up (CMB) wurde am Fraunhofer IPT entwickelt mit der Zielsetzung, die Vorteile des generativen Ansatzes der bekannten Rapid Prototyping/Rapid Tooling Technologien mit einer bis dato nicht erreichbaren hohen Festigkeit und Genauigkeit zu verbinden. Im Rahmen der bisherigen Arbeiten zeigte sich dabei, dass die Eigenschaften der mittels CMB hergestellten Werkzeuge einen Einsatz auch im Serienwerkzeugbau und hier insbesondere auch zur automatischen Reparatur und Modifikation von Werkzeugen in Aussicht stellen. Dieser Artikel resultiert aus Arbeiten zu diesem Forschungsgebiet im Rahmen eines Teilprojekts im DZ FoKus zur Konzeption einer »automatischen Änderungs- und Reparaturzelle CMB«. Er beschreibt die Ausgangssituation und Idee, den grundsätzlichen Aufbau sowie Beispiele zur Machbarkeit.

Published
2001

39. Schneller Aufbau hochfester Werkzeuge mittels Controlled Metal Build Up (CMB)

Author

Klocke, F., Freyer, C., and Publica

Subjects
Rapid Tooling, Werkzeug- und Formenbau, Laserauftragschweißen, Metallprototyp, Rapid Prototyping, HSC, CMB, controlled metal build up
Abstract

Der vorliegende Artikel beschreibt das am Fraunhofer IPT in Aachen entwickelte Controlled Metal Build Up (CMB) und dessen Einsatzmöglichkeiten. Das CMB ermöglicht durch den schichtweisen Aufbau in einer Kombination von Laserauftragschweißen und Fräsen den schnellen Aufbau oder die Reparatur von Werkzeugen aus Stahl. Beide Bearbeitungsschritte sind dabei in einer Maschine integriert. Das Verfahren wird von der Fa. Albrecht Röders GmbH in Soltau kommerzialisiert und ist bereits erfolgreich in der industriellen Praxis im Einsatz, wenngleich in einigen Bereichen nach wie vor noch Forschungsbedarf besteht. Die im Text erwähnten Beispiele sind auf der Euromold 2000 in Frankfurt zu sehen und entstammen einem mit EU-Fördermitteln unterstützten Gemeinschaftsforschungsprojekt mit mittelständischen Unternehmen.

Published
2001

40. Fast manufacturing, modification and repair of molds using controlled metal build up (CMB)

Author

Klocke, F., Freyer, C., and Publica

Subjects
high speed milling, laser deposition welding, die maker, Rapid Tooling, metal prototype, mold maker, Rapid Prototyping, CMB, controlled metal build up
Abstract

The Controlled Metal Build Up (CMB) technology developed at Fraunhofer IPT enables a fast production of steel molds using a combination of laser deposition welding and high speed cutting integrated into one machine. Additionally, also repair or modification of serial molds becomes possible with this approach, as both the welding and the cutting are techniques known from serial mold making. This article describes idea and approach of CMB as well as some results of the current work.

Published
2001

41. Investment casting shells in 1 day using Selective Laser Sintering (SLS)

Author

Klocke, F., Wirtz, H., Freyer, C., and Publica

Subjects
metal prototype, ceramic, investment casting, SLS, Rapid Prototyping, selective laser sintering
Abstract

The Fraunhofer Institute of Production Technology has been successful in using Selective Laser Sintering to build ceramic shells directly from zirconium silicate. Shells for complex metal parts may be built in less than a day, accelerating the process of creating metal prototypes dramatically. No thermoplastic binders are used and there is no need for additional sintering; the shells are readily usable once they have been laser sintered and cleaned of excess powder. Parts that are hard to produce the traditional way have been cast using this new technology, demonstrating the enormous potential in putting down on product development time.

Published
2000

42. Selective Laser Sintering of Zirconium Silicate Shells for Investment Casting

Author

Klocke, F., Wirtz, H., Freyer, C., and Publica

Subjects
metal prototype, ceramic, investment casting, SLS, Rapid Prototyping, selective laser sintering
Abstract

Selective Laser Sintering (SLS) of zirconium silicate as a ceramic material used for investment casting shells and cores is an attractive alternative to the conventional, time-consuming way of producing these shells from a wax master. As opposed to about 10 days with the conventional method, the preparation of the data, the laser sintering of the shell and the casting is done in about two days using the new approach. This paper will present current process results concerning laser sintering of shells made from zirconium silicate and explain the related potentials and benefits.

Published
2000

43. Direkte Herstellung von Feingussformschalen durch selektives Lasersintern

Author

Klocke, F., Freyer, C., and Publica

Subjects
Metallprototyp, SLS, Rapid Prototyping, selective laser sintering, Keramik, Feinguß
Abstract

Die direkte Fertigung keramischer Feingussformschalen durch selektives Lasersintern ermöglicht die Einsparung des zeitaufwendigen Besandungs- und Beschlickerprozesses bei der Herstellung metallischer Prototypen. Dadurch können Prototypen wesentlich schneller als bisher erzeugt werden.

Published
2000

44. Direct manufacturing of ceramic investment casting shells using SLS

Author

Klocke, F., Freyer, C., and Publica

Subjects
metal prototype, ceramic, investment casting, SLS, Rapid Prototyping, selective laser sintering
Abstract

lt is becoming increasingly important in the field of product development, to minimise both the manufacturing time and the closeness to net shape of the parts produced. Whilst numerous approaches have already been successfully implemented and market for plastic parts, Rapid Prototyping for metallic parts, has stubbornly remained an area fraught with difficulties. Although several variations of the powderbased techniques such as Selective Laser Sintering (SLS) and Laser Generation have been commercialised, the metal parts produced cannot, as a rule, be described as near net-shape. This disadvantage can be avoided by switching to casting techniques which use moulds manufactured in rapid prototyping operations - either indirectly via a master model produced using rapid prototyping techniques or directly made from croning sand, for example.

Published
2000

45. Direct manufacturing of investment shells

Author

Klocke, F., Wirtz, H., Freyer, C., and Publica

Subjects
metal prototype, ceramic, investment casting, SLS, Rapid Prototyping, selective laser sintering
Abstract

Rapid prototyping has been used to create master models for investment casting for several years, accelerating the process of making a complicated lost wax model. However the time-saving potential is not fully exploited, since the investment casting shell is made the traditional way, most of the time consuming about two weeks before either prototype can be cast.

Published
1999

46. Schnell zu metallischen Prototypen: Direkte Herstellung von Feingußformschalen mit dem Selektiven Lasersintern

Author

Klocke, F., Wirtz, H., Freyer, C., and Publica

Subjects
Metallprototyp, SLS, Al203-Keramik, Rapid Prototyping, selective laser sintering, Keramik, Feinguß
Abstract

Die direkte Herstellung keramischer Feingussformschalen mit dem Selektiven Lasersintern erschließt dem Gießer und Anwender neue Möglichkeiten des Zeitgewinns bei der Herstellung metallischer Prototypen im Feinguss. Durch die Einsparung des zeitaufwendigen Besandungs- und Beschlickerprozesses können Prototypen mit dem Feinguss wesentlich schneller als bisher erzeugt werden. Beschrieben wird das Prinzip und die Anwendung des am Fraunhofer-Institut für Produktionstechnologie IPT in Aachen entwickelten Verfahrens.

Published
1999

47. Direct manufacturing of ceramic investment casting shells using selective laser sintering

Author

Klocke, F., Freyer, C., and Publica

Subjects
metal prototype, ceramic, investment casting, SLS, Rapid Prototyping, selective laser sintering
Abstract

lt is becoming increasingly important in the field of product development, to minimise both the manufacturing time and the closeness to net shape of the parts produced. Whilst numerous approaches have already been successfully implemented and market for plastic parts, Rapid Prototyping for metallic parts, has stubbornly remained an area fraught with difficulties. Although several variations of the powderbased techniques like "Selective Laser Sintering (SLS)" and "Laser Generation" have been commercialised, as a rule, be described as "near net-shape".

Published
1999

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