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1. Brain mosaicism of hedgehog signalling and other cilia genes in hypothalamic hamartoma

Author

Green, TE, Fujita, A, Ghaderi, N, Heinzen, EL, Matsumoto, N, Klein, KM, Berkovic, SF, Hildebrand, MS, Green, TE, Fujita, A, Ghaderi, N, Heinzen, EL, Matsumoto, N, Klein, KM, Berkovic, SF, and Hildebrand, MS

Abstract

Hypothalamic hamartoma (HH) is a rare benign developmental brain lesion commonly associated with a well characterized epilepsy phenotype. Most individuals with HH are non-syndromic without additional developmental anomalies nor a family history of disease. Nonetheless, HH is a feature of Pallister-Hall (PHS) and Oro-Facial-Digital Type VI (OFD VI) syndromes, both characterized by additional developmental anomalies. Initial genetic of analysis HH began with syndromic HH, where germline inherited or de novo variants in GLI3, encoding a central transcription factor in the sonic hedgehog (Shh) signalling pathway, were identified in most individuals with PHS. Following these discoveries in syndromic HH, the hypothesis that post-zygotic mosaicism in related genes may underly non-syndromic HH was tested. We discuss the identified mosaic variants within individuals with non-syndromic HH, review the analytical methodologies and diagnostic yields, and explore understanding of the functional role of the implicated genes with respect to Shh signalling, and cilia development and function. We also outline future challenges in studying non-syndromic HH and suggest potential novel strategies to interrogate brain mosaicism in HH.

Published
2023

2. GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Author

Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, Ali, QZ, Stevelink, R, Campbell, C, Chen, S, Abou-Khalil, B, Adesoji, OM, Afawi, Z, Amadori, E, Anderson, A, Anderson, J, Andrade, DM, Annesi, G, Auce, P, Avbersek, A, Bahlo, M, Baker, MD, Balagura, G, Balestrini, S, Barba, C, Barboza, K, Bartolomei, F, Bast, T, Baum, L, Baumgartner, T, Baykan, B, Bebek, N, Becker, AJ, Becker, F, Bennett, CA, Berghuis, B, Berkovic, SF, Beydoun, A, Bianchini, C, Bisulli, F, Blatt, I, Bobbili, DR, Borggraefe, I, Bosselmann, C, Braatz, V, Bradfield, JP, Brockmann, K, Brody, LC, Buono, RJ, Busch, RM, Caglayan, H, Campbell, E, Canafoglia, L, Canavati, C, Cascino, GD, Castellotti, B, Catarino, CB, Cavalleri, GL, Cerrato, F, Chassoux, F, Cherny, SS, Cheung, C-L, Chinthapalli, K, Chou, I-J, Chung, S-K, Churchhouse, C, Clark, PO, Cole, AJ, Compston, A, Coppola, A, Cosico, M, Cossette, P, Craig, JJ, Cusick, C, Daly, MJ, Davis, LK, de Haan, G-J, Delanty, N, Depondt, C, Derambure, P, Devinsky, O, Di Vito, L, Dlugos, DJ, Doccini, V, Doherty, CP, El-Naggar, H, Elger, CE, Ellis, CA, Eriksson, JG, Faucon, A, Feng, Y-CA, Ferguson, L, Ferraro, TN, Ferri, L, Feucht, M, Fitzgerald, M, Fonferko-Shadrach, B, Fortunato, F, Franceschetti, S, Franke, A, French, JA, Freri, E, Gagliardi, M, Gambardella, A, Geller, EB, Giangregorio, T, Gjerstad, L, Glauser, T, Goldberg, E, Goldman, A, Granata, T, Greenberg, DA, Guerrini, R, Gupta, N, Haas, KF, Hakonarson, H, Hallmann, K, Hassanin, E, Hegde, M, Heinzen, EL, Helbig, I, Hengsbach, C, Heyne, HO, Hirose, S, Hirsch, E, Hjalgrim, H, Howrigan, DP, Hucks, D, Hung, P-C, Iacomino, M, Imbach, LL, Inoue, Y, Ishii, A, Jamnadas-Khoda, J, Jehi, L, Johnson, MR, Kalviainen, R, Kamatani, Y, Kanaan, M, Kanai, M, Kantanen, A-M, Kara, B, Kariuki, SM, Kasperaviciute, D, Trenite, DK-N, Kato, M, Kegele, J, Kesim, Y, Khoueiry-Zgheib, N, King, C, Kirsch, HE, Klein, KM, Kluger, G, Knake, S, Knowlton, RC, Koeleman, BPC, Korczyn, AD, Koupparis, A, Kousiappa, I, Krause, R, Krenn, M, Krestel, H, Krey, I, Kunz, WS, Kurki, MI, Kurlemann, G, Kuzniecky, R, Kwan, P, Labate, A, Lacey, A, Lal, D, Landoulsi, Z, Lau, Y-L, Lauxmann, S, Leech, SL, Lehesjoki, A-E, Lemke, JR, Lerche, H, Lesca, G, Leu, C, Lewin, N, Lewis-Smith, D, Li, GH-Y, Li, QS, Licchetta, L, Lin, K-L, Lindhout, D, Linnankivi, T, Lopes-Cendes, I, Lowenstein, DH, Lui, CHT, Madia, F, Magnusson, S, Marson, AG, May, P, McGraw, CM, Mei, D, Mills, JL, Minardi, R, Mirza, N, Moller, RS, Molloy, AM, Montomoli, M, Mostacci, B, Muccioli, L, Muhle, H, Mueller-Schlueter, K, Najm, IM, Nasreddine, W, Neale, BM, Neubauer, B, Newton, CRJC, Noethen, MM, Nothnagel, M, Nuernberg, P, O'Brien, TJ, Okada, Y, Olafsson, E, Oliver, KL, Ozkara, C, Palotie, A, Pangilinan, F, Papacostas, SS, Parrini, E, Pato, CN, Pato, MT, Pendziwiat, M, Petrovski, S, Pickrell, WO, Pinsky, R, Pippucci, T, Poduri, A, Pondrelli, F, Powell, RHW, Privitera, M, Rademacher, A, Radtke, R, Ragona, F, Rau, S, Rees, MI, Regan, BM, Reif, PS, Rhelms, S, Riva, A, Rosenow, F, Ryvlin, P, Saarela, A, Sadleir, LG, Sander, JW, Sander, T, Scala, M, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Schubert-Bast, S, Schulze-Bonhage, A, Scudieri, P, Sham, P, Sheidley, BR, Shih, JJ, Sills, GJ, Sisodiya, SM, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Stefansson, H, Stefansson, K, Steinhoff, BJ, Stephani, U, Stewart, WC, Stipa, C, Striano, P, Stroink, H, Strzelczyk, A, Surges, R, Suzuki, T, Tan, KM, Taneja, RS, Tanteles, GA, Tauboll, E, Thio, LL, Thomas, GN, Thomas, RH, Timonen, O, Tinuper, P, Todaro, M, Topaloglu, P, Tozzi, R, Tsai, M-H, Tumiene, B, Turkdogan, D, Unnsteinsdottir, U, Utkus, A, Vaidiswaran, P, Valton, L, van Baalen, A, Vetro, A, Vining, EPG, Visscher, F, von Brauchitsch, S, von Wrede, R, Wagner, RG, Weber, YG, Weckhuysen, S, Weisenberg, J, Weller, M, Widdess-Walsh, P, Wolff, M, Wolking, S, Wu, D, Yamakawa, K, Yang, W, Yapici, Z, Yucesan, E, Zagaglia, S, Zahnert, F, Zara, F, Zhou, W, Zimprich, F, Zsurka, G, and Ali, QZ

Abstract

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.

Published
2023

3. Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy

Author

Perucca, P, Stanley, K, Harris, N, McIntosh, AM, Asadi-Pooya, AA, Mikati, MA, Andrade, DM, Dugan, P, Depondt, C, Choi, H, Heinzen, EL, Cavalleri, GL, Buono, RJ, Devinsky, O, Sperling, MR, Berkovic, SF, Delanty, N, Goldstein, DB, O'Brien, TJ, Perucca, P, Stanley, K, Harris, N, McIntosh, AM, Asadi-Pooya, AA, Mikati, MA, Andrade, DM, Dugan, P, Depondt, C, Choi, H, Heinzen, EL, Cavalleri, GL, Buono, RJ, Devinsky, O, Sperling, MR, Berkovic, SF, Delanty, N, Goldstein, DB, and O'Brien, TJ

Abstract

OBJECTIVE: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. METHODS: We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. RESULTS: Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. INTERPRETATION: Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.

Published
2023

4. Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy

Author

Khoshkhoo, S, Wang, Y, Chahine, Y, Erson-Omay, EZ, Robert, SM, Kiziltug, E, Damisah, EC, Nelson-Williams, C, Zhu, G, Kong, W, Huang, AY, Stronge, E, Phillips, HW, Chhouk, BH, Bizzotto, S, Chen, MH, Adikari, TN, Ye, Z, Witkowski, T, Lai, D, Lee, N, Lokan, J, Scheffer, IE, Berkovic, SF, Haider, S, Hildebrand, MS, Yang, E, Gunel, M, Lifton, RP, Richardson, RM, Bluemcke, I, Alexandrescu, S, Huttner, A, Heinzen, EL, Zhu, J, Poduri, A, DeLanerolle, N, Spencer, DD, Lee, EA, Walsh, CA, Kahle, KT, Khoshkhoo, S, Wang, Y, Chahine, Y, Erson-Omay, EZ, Robert, SM, Kiziltug, E, Damisah, EC, Nelson-Williams, C, Zhu, G, Kong, W, Huang, AY, Stronge, E, Phillips, HW, Chhouk, BH, Bizzotto, S, Chen, MH, Adikari, TN, Ye, Z, Witkowski, T, Lai, D, Lee, N, Lokan, J, Scheffer, IE, Berkovic, SF, Haider, S, Hildebrand, MS, Yang, E, Gunel, M, Lifton, RP, Richardson, RM, Bluemcke, I, Alexandrescu, S, Huttner, A, Heinzen, EL, Zhu, J, Poduri, A, DeLanerolle, N, Spencer, DD, Lee, EA, Walsh, CA, and Kahle, KT

Abstract

IMPORTANCE: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. OBJECTIVE: To test the association between pathogenic somatic variants in the hippocampus and MTLE. DESIGN, SETTING, AND PARTICIPANTS: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. EXPOSURES: Drug-resistant MTLE. MAIN OUTCOMES AND MEASURES: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. RESULTS: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] v

Published
2023

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. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam

Author

Campbell, C, McCormack, M, Patel, S, Stapleton, C, Bobbili, D, Krause, R, Depondt, C, Sills, GJ, Koeleman, BP, Striano, P, Zara, F, Sander, JW, Lerche, H, Kunz, WS, Stefansson, K, Stefansson, H, Doherty, CP, Heinzen, EL, Scheffer, IE, Goldstein, DB, O'Brien, T, Cotter, D, Berkovic, SF, Sisodiya, SM, Delanty, N, Cavalleri, GL, Campbell, C, McCormack, M, Patel, S, Stapleton, C, Bobbili, D, Krause, R, Depondt, C, Sills, GJ, Koeleman, BP, Striano, P, Zara, F, Sander, JW, Lerche, H, Kunz, WS, Stefansson, K, Stefansson, H, Doherty, CP, Heinzen, EL, Scheffer, IE, Goldstein, DB, O'Brien, T, Cotter, D, Berkovic, SF, Sisodiya, SM, Delanty, N, and Cavalleri, GL

Abstract

OBJECTIVE: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV. METHODS: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122). RESULTS: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls. SIGNIFICANCE: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs.

Published
2022

8. Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions

Author

Green, TE, Motelow, JE, Bennett, MF, Ye, Z, Bennett, CA, Griffin, NG, Damiano, JA, Leventer, RJ, Freeman, JL, Harvey, AS, Lockhart, PJ, Sadleir, LG, Boys, A, Scheffer, IE, Major, H, Darbro, BW, Bahlo, M, Goldstein, DB, Kerrigan, JF, Heinzen, EL, Berkovic, SF, Hildebrand, MS, Green, TE, Motelow, JE, Bennett, MF, Ye, Z, Bennett, CA, Griffin, NG, Damiano, JA, Leventer, RJ, Freeman, JL, Harvey, AS, Lockhart, PJ, Sadleir, LG, Boys, A, Scheffer, IE, Major, H, Darbro, BW, Bahlo, M, Goldstein, DB, Kerrigan, JF, Heinzen, EL, Berkovic, SF, and Hildebrand, MS

Abstract

Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy.

Published
2022

9. Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery

Author

Oliver, KL, Ellis, CA, Scheffer, IE, Ganesan, S, Leu, C, Sadleir, LG, Heinzen, EL, Mefford, HC, Bass, AJ, Curtis, SW, Harris, R, Whiteman, DC, Helbig, I, Ottman, R, Epstein, MP, Bahlo, M, Berkovic, SF, Oliver, KL, Ellis, CA, Scheffer, IE, Ganesan, S, Leu, C, Sadleir, LG, Heinzen, EL, Mefford, HC, Bass, AJ, Curtis, SW, Harris, R, Whiteman, DC, Helbig, I, Ottman, R, Epstein, MP, Bahlo, M, and Berkovic, SF

Abstract

BACKGROUND: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies. METHODS: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1,818 from 1,181 families), their unaffected relatives (n = 771), sporadic patients (n = 1,182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalised epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry. FINDINGS: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, padj = 5×10-9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (padj = 5×10-11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases. INTERPRETATION: The aggregate effects of common genetic variants, measured as polygenic risk scores, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known gene

Published
2022

10. CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity

Author

Ernst, ME, Baugh, EH, Thomas, A, Bier, L, Lippa, N, Stong, N, Mulhern, MS, Kushary, S, Akman, CI, Heinzen, EL, Yeh, R, Bi, W, Hanchard, NA, Burrage, LC, Leduc, MS, Chong, JSC, Bend, R, Lyons, MJ, Lee, JA, Suwannarat, P, Brilstra, E, Simon, M, Koopmans, M, van Binsbergen, E, Groepper, D, Fleischer, J, Nava, C, Keren, B, Mignot, C, Mathieu, S, Mancini, GMS, Madan-Khetarpal, S, Infante, EM, Bluvstein, J, Seeley, A, Bachman, K, Klee, EW, Schultz-Rogers, LE, Hasadsri, L, Barnett, S, Ellingson, MS, Ferber, MJ, Narayanan, V, Ramsey, K, Rauch, A, Joset, P, Steindl, K, Sheehan, T, Poduri, A, Vasquez, A, Ruivenkamp, C, White, SM, Pais, L, Monaghan, KG, Goldstein, DB, Sands, TT, Aggarwal, V, Ernst, ME, Baugh, EH, Thomas, A, Bier, L, Lippa, N, Stong, N, Mulhern, MS, Kushary, S, Akman, CI, Heinzen, EL, Yeh, R, Bi, W, Hanchard, NA, Burrage, LC, Leduc, MS, Chong, JSC, Bend, R, Lyons, MJ, Lee, JA, Suwannarat, P, Brilstra, E, Simon, M, Koopmans, M, van Binsbergen, E, Groepper, D, Fleischer, J, Nava, C, Keren, B, Mignot, C, Mathieu, S, Mancini, GMS, Madan-Khetarpal, S, Infante, EM, Bluvstein, J, Seeley, A, Bachman, K, Klee, EW, Schultz-Rogers, LE, Hasadsri, L, Barnett, S, Ellingson, MS, Ferber, MJ, Narayanan, V, Ramsey, K, Rauch, A, Joset, P, Steindl, K, Sheehan, T, Poduri, A, Vasquez, A, Ruivenkamp, C, White, SM, Pais, L, Monaghan, KG, Goldstein, DB, Sands, TT, and Aggarwal, V

Abstract

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Published
2021

11. 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

12. 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

13. 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

14. Autism and developmental disability caused by KCNQ3 gain-of-function variants

Author

Sands, TT, Miceli, F, Lesca, G, Beck, AE, Sadleir, LG, Arrington, DK, Schonewolf-Greulich, B, Moutton, S, Lauritano, A, Nappi, P, Soldovieri, MV, Scheffer, IE, Mefford, HC, Stong, N, Heinzen, EL, Goldstein, DB, Perez, AG, Kossoff, EH, Stocco, A, Sullivan, JA, Shashi, V, Gerard, B, Francannet, C, Bisgaard, A-M, Tumer, Z, Willems, M, Rivier, F, Vitobello, A, Thakkar, K, Rajan, DS, Barkovich, AJ, Weckhuysen, S, Cooper, EC, Taglialatela, M, Cilio, MR, Sands, TT, Miceli, F, Lesca, G, Beck, AE, Sadleir, LG, Arrington, DK, Schonewolf-Greulich, B, Moutton, S, Lauritano, A, Nappi, P, Soldovieri, MV, Scheffer, IE, Mefford, HC, Stong, N, Heinzen, EL, Goldstein, DB, Perez, AG, Kossoff, EH, Stocco, A, Sullivan, JA, Shashi, V, Gerard, B, Francannet, C, Bisgaard, A-M, Tumer, Z, Willems, M, Rivier, F, Vitobello, A, Thakkar, K, Rajan, DS, Barkovich, AJ, Weckhuysen, S, Cooper, EC, Taglialatela, M, and Cilio, MR

Abstract

OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.

Published
2019

15. 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

16. The Epilepsy Genetics Initiative: Systematic reanalysis of diagnostic exomes increases yield

Author

Berkovic, SF, Goldstein, DB, Heinzen, EL, Laughlin, BL, Lowenstein, DH, Lubbers, L, Stewart, R, Whittemore, V, Angione, K, Bazil, CW, Bier, L, Bluvstein, J, Brimble, E, Campbell, C, Cavalleri, G, Chambers, C, Choi, H, Cilio, MR, Ciliberto, M, Cornes, S, Delanty, N, Demarest, S, Devinsky, O, Dlugos, D, Dubbs, H, Dugan, P, Ernst, ME, Gibbons, M, Goodkin, HP, Helbig, I, Jansen, L, Johnson, K, Joshi, C, Lippa, NC, Marsh, E, Martinez, A, Millichap, J, Mulhern, MS, Numis, A, Park, K, Pippucci, T, Poduri, A, Porter, B, Regan, B, Sands, TT, Scheffer, IE, Schreiber, JM, Sheidley, B, Singhal, N, Smith, L, Sullivan, J, Taylor, A, Tolete, P, Afgani, TM, Aggarwal, V, Burgess, R, Dixon-Salazar, T, Hemati, P, Milder, J, Petrovski, S, Revah-Politi, A, Stong, N, Berkovic, SF, Goldstein, DB, Heinzen, EL, Laughlin, BL, Lowenstein, DH, Lubbers, L, Stewart, R, Whittemore, V, Angione, K, Bazil, CW, Bier, L, Bluvstein, J, Brimble, E, Campbell, C, Cavalleri, G, Chambers, C, Choi, H, Cilio, MR, Ciliberto, M, Cornes, S, Delanty, N, Demarest, S, Devinsky, O, Dlugos, D, Dubbs, H, Dugan, P, Ernst, ME, Gibbons, M, Goodkin, HP, Helbig, I, Jansen, L, Johnson, K, Joshi, C, Lippa, NC, Marsh, E, Martinez, A, Millichap, J, Mulhern, MS, Numis, A, Park, K, Pippucci, T, Poduri, A, Porter, B, Regan, B, Sands, TT, Scheffer, IE, Schreiber, JM, Sheidley, B, Singhal, N, Smith, L, Sullivan, J, Taylor, A, Tolete, P, Afgani, TM, Aggarwal, V, Burgess, R, Dixon-Salazar, T, Hemati, P, Milder, J, Petrovski, S, Revah-Politi, A, and Stong, N

Abstract

OBJECTIVE: The Epilepsy Genetics Initiative (EGI) was formed in 2014 to create a centrally managed database of clinically generated exome sequence data. EGI performs systematic research-based reanalysis to identify new molecular diagnoses that were not possible at the time of initial sequencing and to aid in novel gene discovery. Herein we report on the efficacy of this approach 3 years after inception. METHODS: One hundred sixty-six individuals with epilepsy who underwent diagnostic whole exome sequencing (WES) were enrolled, including 139 who had not received a genetic diagnosis. Sequence data were transferred to the EGI and periodically reevaluated on a research basis. RESULTS: Eight new diagnoses were made as a result of updated annotations or the discovery of novel epilepsy genes after the initial diagnostic analysis was performed. In five additional cases, we provided new evidence to support or contradict the likelihood of variant pathogenicity reported by the laboratory. One novel epilepsy gene was discovered through dual interrogation of research and clinically generated WES. SIGNIFICANCE: EGI's diagnosis rate of 5.8% represents a considerable increase in diagnostic yield and demonstrates the value of periodic reinterrogation of whole exome data. The initiative's contributions to gene discovery underscore the importance of data sharing and the value of collaborative enterprises.

Published
2019

17. Refining the phenotype associated with GNB1 mutations: Clinical data on 18 newly identified patients and review of the literature

Author

Hemati, P, Revah-Politi, A, Bassan, H, Petrovski, S, Bilancia, CG, Ramsey, K, Griffin, NG, Bier, L, Cho, MT, Rosello, M, Lynch, SA, Colombo, S, Weber, A, Haug, M, Heinzen, EL, Sands, TT, Narayanan, V, Primiano, M, Aggarwal, VS, Millan, F, Sattler-Holtrop, SG, Caro-Llopis, A, Pillar, N, Baker, J, Freedman, R, Kroes, HY, Sacharow, S, Stong, N, Lapunzina, P, Schneider, MC, Mendelsohn, NJ, Singleton, A, Ramey, VL, Wou, K, Kuzminsky, A, Monfort, S, Weiss, M, Doyle, S, Iglesias, A, Martinez, F, Mckenzie, F, Orellana, C, van Gassen, KLI, Palomares, M, Bazak, L, Lee, A, Bircher, A, Basel-Vanagaite, L, Hafstrom, M, Houge, G, Goldstein, DB, Anyane-Yeboa, K, C4RCD Res Grp, and DDD Study

Subjects
mastocytosis, developmental disabilities, hypotonia, GNB1, seizures, whole exome sequencing
Abstract

De novo germline mutations in GNB1 have been associated with a neurodevelopmental phenotype. To date, 28 patients with variants classified as pathogenic have been reported. We add 18 patients with de novo mutations to this cohort, including a patient with mosaicism for a GNB1 mutation who presented with a milder phenotype. Consistent with previous reports, developmental delay in these patients was moderate to severe, and more than half of the patients were non-ambulatory and nonverbal. The most observed substitution affects the p.Ile80 residue encoded in exon 6, with 28% of patients carrying a variant at this residue. Dystonia and growth delay were observed more frequently in patients carrying variants in this residue, suggesting a potential genotype-phenotype correlation. In the new cohort of 18 patients, 50% of males had genitourinary anomalies and 61% of patients had gastrointestinal anomalies, suggesting a possible association of these findings with variants in GNB1. In addition, cutaneous mastocytosis, reported once before in a patient with a GNB1 variant, was observed in three additional patients, providing further evidence for an association to GNB1. We will review clinical and molecular data of these new cases and all previously reported cases to further define the phenotype and establish possible genotype-phenotype correlations.

Published
2018

18. De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy

Author

Berkovic, SF, Dixon-Salazar, T, Goldstein, DB, Heinzen, EL, Laughlin, BL, Lowenstein, DH, Lubbers, L, Milder, J, Stewart, R, Whittemore, V, Angione, K, Bazil, CW, Bier, L, Bluvstein, J, Brimble, E, Campbell, C, Chambers, C, Choi, H, Cilio, MR, Ciliberto, M, Cornes, S, Delanty, N, Demarest, S, Devinsky, O, Dlugos, D, Dubbs, H, Dugan, P, Ernst, ME, Gallentine, W, Gibbons, M, Goodkin, H, Grinton, B, Helbig, I, Jansen, L, Johnson, K, Joshi, C, Lippa, NC, Makati, MA, Marsh, E, Martinez, A, Millichap, J, Moskovich, Y, Mulhern, MS, Numis, A, Park, K, Poduri, A, Porter, B, Sands, TT, Scheffer, IE, Sheidley, B, Singhal, N, Smith, L, Sullivan, J, Riviello, JJ, Taylor, A, Tolete, P, Berkovic, SF, Dixon-Salazar, T, Goldstein, DB, Heinzen, EL, Laughlin, BL, Lowenstein, DH, Lubbers, L, Milder, J, Stewart, R, Whittemore, V, Angione, K, Bazil, CW, Bier, L, Bluvstein, J, Brimble, E, Campbell, C, Chambers, C, Choi, H, Cilio, MR, Ciliberto, M, Cornes, S, Delanty, N, Demarest, S, Devinsky, O, Dlugos, D, Dubbs, H, Dugan, P, Ernst, ME, Gallentine, W, Gibbons, M, Goodkin, H, Grinton, B, Helbig, I, Jansen, L, Johnson, K, Joshi, C, Lippa, NC, Makati, MA, Marsh, E, Martinez, A, Millichap, J, Moskovich, Y, Mulhern, MS, Numis, A, Park, K, Poduri, A, Porter, B, Sands, TT, Scheffer, IE, Sheidley, B, Singhal, N, Smith, L, Sullivan, J, Riviello, JJ, Taylor, A, and Tolete, P

Abstract

PurposeAs part of the Epilepsy Genetics Initiative, we re-evaluated clinically generated exome sequence data from 54 epilepsy patients and their unaffected parents to identify molecular diagnoses not provided in the initial diagnostic interpretation.MethodsWe compiled and analyzed exome sequence data from 54 genetically undiagnosed trios using a validated analysis pipeline. We evaluated the significance of the genetic findings by reanalyzing sequence data generated at Ambry Genetics, and from a number of additional case and control cohorts.ResultsIn 54 previously undiagnosed trios, we identified two de novo missense variants in SCN8A in the highly expressed alternative exon 5 A-an exon only recently added to the Consensus Coding Sequence database. One additional undiagnosed epilepsy patient harboring a de novo variant in exon 5 A was found in the Ambry Genetics cohort. Missense variants in SCN8A exon 5 A are extremely rare in the population, further supporting the pathogenicity of the de novo alterations identified.ConclusionThese results expand the range of SCN8A variants in epileptic encephalopathy patients and illustrate the necessity of ongoing reanalysis of negative exome sequences, as advances in the knowledge of disease genes and their annotations will permit new diagnoses to be made.

Published
2018

19. Genetic literacy series: Primer part 2-Paradigm shifts in epilepsy genetics

Author

Helbig, I, Heinzen, EL, Mefford, HC, Helbig, I, Heinzen, EL, and Mefford, HC

Abstract

This is the second of a 2-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we covered types of genetic variation, inheritance patterns, and their relationship to disease. In Part 2, we apply these basic principles to the case of a young boy with epileptic encephalopathy and ask 3 important questions: (1) Is the gene in question an established genetic etiology for epilepsy? (2) Is the variant in this particular gene pathogenic by established variant interpretation criteria? (3) Is the variant considered causative in the clinical context? These questions are considered and then answered for the clinical case in question.

Published
2018

20. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

Author

Abou-Khalil, B, Auce, P, Avbersek, A, Bahlo, M, Balding, DJ, Bast, T, Baum, L, Becker, AJ, Becker, F, Berghuis, B, Berkovic, SF, Boysen, KE, Bradfield, JP, Brody, LC, Buono, RJ, Campbell, E, Cascino, GD, Catarino, CB, Cavalleri, GL, Cherny, SS, Chinthapalli, K, Coffey, AJ, Compston, A, Coppola, A, Cossette, P, Craig, JJ, de Haan, G-J, De Jonghe, P, de Kovel, CGF, Delanty, N, Depondt, C, Devinsky, O, Dlugos, DJ, Doherty, CP, Elger, CE, Eriksson, JG, Ferraro, TN, Feucht, M, Francis, B, Franke, A, French, JA, Freytag, S, Gaus, V, Geller, EB, Gieger, C, Glauser, T, Glynn, S, Goldstein, DB, Gui, H, Guo, Y, Haas, KF, Hakonarson, H, Hallmann, K, Haut, S, Heinzen, EL, Helbig, I, Hengsbach, C, Hjalgrim, H, Iacomino, M, Ingason, A, Jamnadas-Khoda, J, Johnson, MR, Kalviainen, R, Kantanen, A-M, Kasperaviciute, D, Trenite, DK-N, Kirsch, HE, Knowlton, RC, Koeleman, BPC, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Kwan, P, Lal, D, Lau, Y-L, Lehesjoki, A-E, Lerche, H, Leu, C, Lieb, W, Lindhout, D, Lo, WD, Lopes-Cendes, I, Lowenstein, DH, Malovini, A, Marson, AG, Mayer, T, McCormack, M, Mills, JL, Mirza, N, Moerzinger, M, Moller, RS, Molloy, AM, Muhle, H, Newton, M, Ng, P-W, Noethen, MM, Nuernberg, P, O'Brien, TJ, Oliver, KL, Palotie, A, Pangilinan, F, Peter, S, Petrovski, S, Poduri, A, Privitera, M, Radtke, R, Rau, S, Reif, PS, Reinthaler, EM, Rosenow, F, Sander, JW, Sander, T, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Sham, PC, Shih, JJ, Sills, GJ, Sisodiya, SM, Slattery, L, Smith, A, Smith, DF, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Steinhoff, BJ, Stephani, U, Stevelink, R, Strauch, K, Striano, P, Stroink, H, Surges, R, Tan, KM, Thio, LL, Thomas, GN, Todaro, M, Tozzi, R, Vari, MS, Vining, EPG, Visscher, F, von Spiczak, S, Walley, NM, Weber, YG, Wei, Z, Weisenberg, J, Whelan, CD, Widdess-Walsh, P, Wolff, M, Wolking, S, Yang, W, Zara, F, Zimprich, F, Abou-Khalil, B, Auce, P, Avbersek, A, Bahlo, M, Balding, DJ, Bast, T, Baum, L, Becker, AJ, Becker, F, Berghuis, B, Berkovic, SF, Boysen, KE, Bradfield, JP, Brody, LC, Buono, RJ, Campbell, E, Cascino, GD, Catarino, CB, Cavalleri, GL, Cherny, SS, Chinthapalli, K, Coffey, AJ, Compston, A, Coppola, A, Cossette, P, Craig, JJ, de Haan, G-J, De Jonghe, P, de Kovel, CGF, Delanty, N, Depondt, C, Devinsky, O, Dlugos, DJ, Doherty, CP, Elger, CE, Eriksson, JG, Ferraro, TN, Feucht, M, Francis, B, Franke, A, French, JA, Freytag, S, Gaus, V, Geller, EB, Gieger, C, Glauser, T, Glynn, S, Goldstein, DB, Gui, H, Guo, Y, Haas, KF, Hakonarson, H, Hallmann, K, Haut, S, Heinzen, EL, Helbig, I, Hengsbach, C, Hjalgrim, H, Iacomino, M, Ingason, A, Jamnadas-Khoda, J, Johnson, MR, Kalviainen, R, Kantanen, A-M, Kasperaviciute, D, Trenite, DK-N, Kirsch, HE, Knowlton, RC, Koeleman, BPC, Krause, R, Krenn, M, Kunz, WS, Kuzniecky, R, Kwan, P, Lal, D, Lau, Y-L, Lehesjoki, A-E, Lerche, H, Leu, C, Lieb, W, Lindhout, D, Lo, WD, Lopes-Cendes, I, Lowenstein, DH, Malovini, A, Marson, AG, Mayer, T, McCormack, M, Mills, JL, Mirza, N, Moerzinger, M, Moller, RS, Molloy, AM, Muhle, H, Newton, M, Ng, P-W, Noethen, MM, Nuernberg, P, O'Brien, TJ, Oliver, KL, Palotie, A, Pangilinan, F, Peter, S, Petrovski, S, Poduri, A, Privitera, M, Radtke, R, Rau, S, Reif, PS, Reinthaler, EM, Rosenow, F, Sander, JW, Sander, T, Scattergood, T, Schachter, SC, Schankin, CJ, Scheffer, IE, Schmitz, B, Schoch, S, Sham, PC, Shih, JJ, Sills, GJ, Sisodiya, SM, Slattery, L, Smith, A, Smith, DF, Smith, MC, Smith, PE, Sonsma, ACM, Speed, D, Sperling, MR, Steinhoff, BJ, Stephani, U, Stevelink, R, Strauch, K, Striano, P, Stroink, H, Surges, R, Tan, KM, Thio, LL, Thomas, GN, Todaro, M, Tozzi, R, Vari, MS, Vining, EPG, Visscher, F, von Spiczak, S, Walley, NM, Weber, YG, Wei, Z, Weisenberg, J, Whelan, CD, Widdess-Walsh, P, Wolff, M, Wolking, S, Yang, W, Zara, F, and Zimprich, F

Abstract

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.

Published
2018

21. De novo and inherited private variants in MAP1B in periventricular nodular heterotopia

Author

Hallmayer, J, Heinzen, EL, O'Neill, AC, Zhu, X, Allen, AS, Bahlo, M, Chelly, J, Chen, MH, Dobyns, WB, Freytag, S, Guerrini, R, Leventer, RJ, Poduri, A, Robertson, SP, Walsh, CA, Zhang, M, Hallmayer, J, Heinzen, EL, O'Neill, AC, Zhu, X, Allen, AS, Bahlo, M, Chelly, J, Chen, MH, Dobyns, WB, Freytag, S, Guerrini, R, Leventer, RJ, Poduri, A, Robertson, SP, Walsh, CA, and Zhang, M

Abstract

Periventricular nodular heterotopia (PVNH) is a malformation of cortical development commonly associated with epilepsy. We exome sequenced 202 individuals with sporadic PVNH to identify novel genetic risk loci. We first performed a trio-based analysis and identified 219 de novo variants. Although no novel genes were implicated in this initial analysis, PVNH cases were found overall to have a significant excess of nonsynonymous de novo variants in intolerant genes (p = 3.27x10-7), suggesting a role for rare new alleles in genes yet to be associated with the condition. Using a gene-level collapsing analysis comparing cases and controls, we identified a genome-wide significant signal driven by four ultra-rare loss-of-function heterozygous variants in MAP1B, including one de novo variant. In at least one instance, the MAP1B variant was inherited from a parent with previously undiagnosed PVNH. The PVNH was frontally predominant and associated with perisylvian polymicrogyria. These results implicate MAP1B in PVNH. More broadly, our findings suggest that detrimental mutations likely arising in immediately preceding generations with incomplete penetrance may also be responsible for some apparently sporadic diseases.

Published
2018

22. A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations

Author

Cooper, GM, Zhu, X, Padmanabhan, R, Copeland, B, Bridgers, J, Ren, Z, Kamalakaran, S, O'Driscoll-Collins, A, Berkovic, SF, Scheffer, IE, Poduri, A, Mei, D, Guerrini, R, Lowenstein, DH, Allen, AS, Heinzen, EL, Goldstein, DB, Cooper, GM, Zhu, X, Padmanabhan, R, Copeland, B, Bridgers, J, Ren, Z, Kamalakaran, S, O'Driscoll-Collins, A, Berkovic, SF, Scheffer, IE, Poduri, A, Mei, D, Guerrini, R, Lowenstein, DH, Allen, AS, Heinzen, EL, and Goldstein, DB

Abstract

Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p<2.68×10-6). In addition, six of the 10 most significantly associated genes are known EE genes, and the majority of the known EE genes (17 out of 25) originally implicated in trio sequencing are nominally significant (p<0.05), a proportion significantly higher than the expected (Fisher's exact p = 2.33×10-17). Our results indicate that a case-control collapsing analysis can identify several of the EE genes originally implicated in trio sequencing studies, and clearly show that additional genes would be implicated with larger sample sizes. The case-control analysis not only makes discovery easier and more economical in early onset disorders, particularly when large cohorts are available, but also supports the use of this approach to identify genes in diseases that present later in life when parents are not readily available.

Published
2017

23. Annotating pathogenic non-coding variants in genic regions

Author

Gelfman, S, Wang, Q, McSweeney, KM, Ren, Z, La Carpia, F, Halvorsen, M, Schoch, K, Ratzon, F, Heinzen, EL, Boland, MJ, Petrovski, S, Goldstein, DB, Gelfman, S, Wang, Q, McSweeney, KM, Ren, Z, La Carpia, F, Halvorsen, M, Schoch, K, Ratzon, F, Heinzen, EL, Boland, MJ, Petrovski, S, and Goldstein, DB

Abstract

Identifying the underlying causes of disease requires accurate interpretation of genetic variants. Current methods ineffectively capture pathogenic non-coding variants in genic regions, resulting in overlooking synonymous and intronic variants when searching for disease risk. Here we present the Transcript-inferred Pathogenicity (TraP) score, which uses sequence context alterations to reliably identify non-coding variation that causes disease. High TraP scores single out extremely rare variants with lower minor allele frequencies than missense variants. TraP accurately distinguishes known pathogenic and benign variants in synonymous (AUC = 0.88) and intronic (AUC = 0.83) public datasets, dismissing benign variants with exceptionally high specificity. TraP analysis of 843 exomes from epilepsy family trios identifies synonymous variants in known epilepsy genes, thus pinpointing risk factors of disease from non-coding sequence data. TraP outperforms leading methods in identifying non-coding variants that are pathogenic and is therefore a valuable tool for use in gene discovery and the interpretation of personal genomes.While non-coding synonymous and intronic variants are often not under strong selective constraint, they can be pathogenic through affecting splicing or transcription. Here, the authors develop a score that uses sequence context alterations to predict pathogenicity of synonymous and non-coding genetic variants, and provide a web server of pre-computed scores.

Published
2017

24. A roadmap for precision medicine in the epilepsies (vol 14, pg 1219, 2014)

Author

Berkovic, F, Scheffer, IE, Petrou, S, Delanty, N, Dixon-Salazar, TJ, Dlugos, DJ, Helbig, I, Frankel, WN, Goldstein, DB, Heinzen, EL, Lowenstein, DH, Mefford, HC, Parent, JM, Poduri, A, Traynelis, SF, Berkovic, F, Scheffer, IE, Petrou, S, Delanty, N, Dixon-Salazar, TJ, Dlugos, DJ, Helbig, I, Frankel, WN, Goldstein, DB, Heinzen, EL, Lowenstein, DH, Mefford, HC, Parent, JM, Poduri, A, and Traynelis, SF

Abstract

Technological advances have paved the way for accelerated genomic discovery and are bringing precision medicine clearly into view. Epilepsy research in particular is well suited to serve as a model for the development and deployment of targeted therapeutics in precision medicine because of the rapidly expanding genetic knowledge base in epilepsy, the availability of good in-vitro and in-vivo model systems to efficiently study the biological consequences of genetic mutations, the ability to turn these models into effective drug-screening platforms, and the establishment of collaborative research groups. Moving forward, it is crucial that these collaborations are strengthened, particularly through integrated research platforms, to provide robust analyses both for accurate personal genome analysis and gene and drug discovery. Similarly, the implementation of clinical trial networks will allow the expansion of patient sample populations with genetically defined epilepsy so that drug discovery can be translated into clinical practice.

Published
2016

25. Primer Part 1-The building blocks of epilepsy genetics

Author

Helbig, I, Heinzen, EL, Mefford, HC, Helbig, I, Heinzen, EL, and Mefford, HC

Abstract

This is the first of a two-part primer on the genetics of the epilepsies within the Genetic Literacy Series of the Genetics Commission of the International League Against Epilepsy. In Part 1, we cover the foundations of epilepsy genetics including genetic epidemiology and the range of genetic variants that can affect the risk for developing epilepsy. We discuss various epidemiologic study designs that have been applied to the genetics of the epilepsies including population studies, which provide compelling evidence for a strong genetic contribution in many epilepsies. We discuss genetic risk factors varying in size, frequency, inheritance pattern, effect size, and phenotypic specificity, and provide examples of how genetic risk factors within the various categories increase the risk for epilepsy. We end by highlighting trends in epilepsy genetics including the increasing use of massive parallel sequencing technologies.

Published
2016

26. Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients

Author

Panagiotakaki, E, De Grandis, E, Stagnaro, M, Heinzen, EL, Fons, C, Sisodiya, S, de Vries, B, Goubau, C, Weckhuysen, S, Kemlink, D, Scheffer, I, Lesca, G, Rabilloud, M, Klich, A, Ramirez-Camacho, A, Ulate-Campos, A, Campistol, J, Giannotta, M, Moutard, M-L, Doummar, D, Hubsch-Bonneaud, C, Jaffer, F, Cross, H, Gurrieri, F, Tiziano, D, Nevsimalova, S, Nicole, S, Neville, B, van den Maagdenberg, AMJM, Mikati, M, Goldstein, DB, Vavassori, R, Arzimanoglou, A, Panagiotakaki, E, De Grandis, E, Stagnaro, M, Heinzen, EL, Fons, C, Sisodiya, S, de Vries, B, Goubau, C, Weckhuysen, S, Kemlink, D, Scheffer, I, Lesca, G, Rabilloud, M, Klich, A, Ramirez-Camacho, A, Ulate-Campos, A, Campistol, J, Giannotta, M, Moutard, M-L, Doummar, D, Hubsch-Bonneaud, C, Jaffer, F, Cross, H, Gurrieri, F, Tiziano, D, Nevsimalova, S, Nicole, S, Neville, B, van den Maagdenberg, AMJM, Mikati, M, Goldstein, DB, Vavassori, R, and Arzimanoglou, A

Abstract

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clust

Published
2015

27. Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis

Author

Dhindsa, RS, Bradrick, SS, Yao, X, Heinzen, EL, Petrovski, S, Krueger, BJ, Johnson, MR, Frankel, WN, Petrou, S, Boumil, RM, Goldstein, DB, Dhindsa, RS, Bradrick, SS, Yao, X, Heinzen, EL, Petrovski, S, Krueger, BJ, Johnson, MR, Frankel, WN, Petrou, S, Boumil, RM, and Goldstein, DB

Abstract

OBJECTIVE: To elucidate the functional consequences of epileptic encephalopathy-causing de novo mutations in DNM1 (A177P, K206N, G359A), which encodes a large mechanochemical GTPase essential for neuronal synaptic vesicle endocytosis. METHODS: HeLa and COS-7 cells transfected with wild-type and mutant DNM1 constructs were used for transferrin assays, high-content imaging, colocalization studies, Western blotting, and electron microscopy (EM). EM was also conducted on the brain sections of mice harboring a middle-domain Dnm1 mutation (Dnm1 (Ftfl)). RESULTS: We demonstrate that the expression of each mutant protein decreased endocytosis activity in a dominant-negative manner. One of the G-domain mutations, K206N, decreased protein levels. The G359A mutation, which occurs in the middle domain, disrupted higher-order DNM1 oligomerization. EM of mutant DNM1-transfected HeLa cells and of the Dnm1 (Ftfl) mouse brain revealed vesicle defects, indicating that the mutations likely interfere with DNM1's vesicle scission activity. CONCLUSION: Together, these data suggest that the dysfunction of vesicle scission during synaptic vesicle endocytosis can lead to serious early-onset epilepsies.

Published
2015

28. Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy

Author

Abou-Khalil, B, Alldredge, BK, Allen, AS, Andermann, E, Andermann, F, Amrom, D, Bautista, JF, Berkovic, SF, Boro, A, Cascino, G, Coe, BP, Consalvo, D, Cook, J, Cossette, P, Crumrine, P, Delanty, N, Devinsky, O, Dlugos, D, Eichler, EE, Epstein, MP, Fiol, M, Fountain, NB, French, J, Friedman, D, Geller, EB, Glauser, T, Glynn, S, Goldstein, DB, Haut, SR, Hayward, J, Heinzen, EL, Helmers, SL, Johnson, MR, Joshi, S, Kanner, A, Kirsch, HE, Knowlton, RC, Kossoff, EH, Krumm, N, Kuperman, R, Kuzniecky, R, Lowenstein, DH, Marson, AG, McGuire, SM, Mefford, HC, Motika, PV, Nelson, B, Nieh, SE, Novotny, EJ, O'Brien, TJ, Ottman, R, Paolicchi, JM, Parent, J, Park, K, Petrou, S, Petrovski, S, Poduri, A, Raja, A, Ruzzo, EK, Scheffer, IE, Shellhaas, RA, Sherr, E, Shih, JJ, Singh, R, Sirven, J, Smith, MC, Sullivan, J, Liu, LT, Venkat, A, Vining, EPG, Von Allmen, GK, Weisenberg, JL, Widdess-Walsh, P, Winawer, MR, Abou-Khalil, B, Alldredge, BK, Allen, AS, Andermann, E, Andermann, F, Amrom, D, Bautista, JF, Berkovic, SF, Boro, A, Cascino, G, Coe, BP, Consalvo, D, Cook, J, Cossette, P, Crumrine, P, Delanty, N, Devinsky, O, Dlugos, D, Eichler, EE, Epstein, MP, Fiol, M, Fountain, NB, French, J, Friedman, D, Geller, EB, Glauser, T, Glynn, S, Goldstein, DB, Haut, SR, Hayward, J, Heinzen, EL, Helmers, SL, Johnson, MR, Joshi, S, Kanner, A, Kirsch, HE, Knowlton, RC, Kossoff, EH, Krumm, N, Kuperman, R, Kuzniecky, R, Lowenstein, DH, Marson, AG, McGuire, SM, Mefford, HC, Motika, PV, Nelson, B, Nieh, SE, Novotny, EJ, O'Brien, TJ, Ottman, R, Paolicchi, JM, Parent, J, Park, K, Petrou, S, Petrovski, S, Poduri, A, Raja, A, Ruzzo, EK, Scheffer, IE, Shellhaas, RA, Sherr, E, Shih, JJ, Singh, R, Sirven, J, Smith, MC, Sullivan, J, Liu, LT, Venkat, A, Vining, EPG, Von Allmen, GK, Weisenberg, JL, Widdess-Walsh, P, and Winawer, MR

Abstract

Infantile spasms (IS) and Lennox-Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early onset, intractable seizures, and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome-predicted CNVs by array-based methods is still required due to false-positive rates of prediction algorithms. Our exome-based results are consistent with recent array-based studies in similar cohorts and highlight novel candidate genes for IS and LGS.

Published
2015

29. Clinical profile of patients with ATP1A3 mutations in Alternating Hemiplegia of Childhood-a study of 155 patients.

Author

Gurrieri, Fiorella, Panagiotakaki, E, De Grandis, E, Stagnaro, M, Heinzen, El, Fons, C, Sisodiya, S, Tiziano, Francesco Danilo, Nicole, Nevsimalova, S, Neville, B, Van Den Maagdenberg, Am, Mikati, M, Goldstein, D., Gurrieri, Fiorella (ORCID:0000-0002-6775-5972), Tiziano, Francesco Danilo (ORCID:0000-0002-5545-6158), Gurrieri, Fiorella, Panagiotakaki, E, De Grandis, E, Stagnaro, M, Heinzen, El, Fons, C, Sisodiya, S, Tiziano, Francesco Danilo, Nicole, Nevsimalova, S, Neville, B, Van Den Maagdenberg, Am, Mikati, M, Goldstein, D., Gurrieri, Fiorella (ORCID:0000-0002-6775-5972), and Tiziano, Francesco Danilo (ORCID:0000-0002-5545-6158)

Abstract

BACKGROUND: Mutations in the gene ATP1A3 have recently been identified to be prevalent in patients with alternating hemiplegia of childhood (AHC2). Based on a large series of patients with AHC, we set out to identify the spectrum of different mutations within the ATP1A3 gene and further establish any correlation with phenotype. METHODS: Clinical data from an international cohort of 155 AHC patients (84 females, 71 males; between 3 months and 52 years) were gathered using a specifically formulated questionnaire and analysed relative to the mutational ATP1A3 gene data for each patient. RESULTS: In total, 34 different ATP1A3 mutations were detected in 85 % (132/155) patients, seven of which were novel. In general, mutations were found to cluster into five different regions. The most frequent mutations included: p.Asp801Asn (43 %; 57/132), p.Glu815Lys (16 %; 22/132), and p.Gly947Arg (11 %; 15/132). Of these, p.Glu815Lys was associated with a severe phenotype, with more severe intellectual and motor disability. p.Asp801Asn appeared to confer a milder phenotypic expression, and p.Gly947Arg appeared to correlate with the most favourable prognosis, compared to the other two frequent mutations. Overall, the comparison of the clinical profiles suggested a gradient of severity between the three major mutations with differences in intellectual (p = 0.029) and motor (p = 0.039) disabilities being statistically significant. For patients with epilepsy, age at onset of seizures was earlier for patients with either p.Glu815Lys or p.Gly947Arg mutation, compared to those with p.Asp801Asn mutation (p < 0.001). With regards to the five mutation clusters, some clusters appeared to correlate with certain clinical phenotypes. No statistically significant clinical correlations were found between patients with and without ATP1A3 mutations. CONCLUSIONS: Our results, demonstrate a highly variable clinical phenotype in patients with AHC2 that correlates with certain mutations and possibly clust

Published
2015

30. Exome sequencing of 20,979 individuals with epilepsy reveals shared and distinct ultra-rare genetic risk across disorder subtypes.

Author

Chen S, Abou-Khalil BW, Afawi Z, Ali QZ, Amadori E, Anderson A, Anderson J, Andrade DM, Annesi G, Arslan M, Auce P, Bahlo M, Baker MD, Balagura G, Balestrini S, Banks E, Barba C, Barboza K, Bartolomei F, Bass N, Baum LW, Baumgartner TH, Baykan B, Bebek N, Becker F, Bennett CA, Beydoun A, Bianchini C, Bisulli F, Blackwood D, Blatt I, Borggräfe I, Bosselmann C, Braatz V, Brand H, Brockmann K, Buono RJ, Busch RM, Caglayan SH, Canafoglia L, Canavati C, Castellotti B, Cavalleri GL, Cerrato F, Chassoux F, Cherian C, Cherny SS, Cheung CL, Chou IJ, Chung SK, Churchhouse C, Ciullo V, Clark PO, Cole AJ, Cosico M, Cossette P, Cotsapas C, Cusick C, Daly MJ, Davis LK, Jonghe P, Delanty N, Dennig D, Depondt C, Derambure P, Devinsky O, Di Vito L, Dickerson F, Dlugos DJ, Doccini V, Doherty CP, El-Naggar H, Ellis CA, Epstein L, Evans M, Faucon A, Feng YA, Ferguson L, Ferraro TN, Da Silva IF, Ferri L, Feucht M, Fields MC, Fitzgerald M, Fonferko-Shadrach B, Fortunato F, Franceschetti S, French JA, Freri E, Fu JM, Gabriel S, Gagliardi M, Gambardella A, Gauthier L, Giangregorio T, Gili T, Glauser TA, Goldberg E, Goldman A, Goldstein DB, Granata T, Grant R, Greenberg DA, Guerrini R, Gundogdu-Eken A, Gupta N, Haas K, Hakonarson H, Haryanyan G, Häusler M, Hegde M, Heinzen EL, Helbig I, Hengsbach C, Heyne H, Hirose S, Hirsch E, Ho CJ, Hoeper O, Howrigan DP, Hucks D, Hung PC, Iacomino M, Inoue Y, Inuzuka LM, Ishii A, Jehi L, Johnson MR, Johnstone M, Kälviäinen R, Kanaan M, Kara B, Kariuki SM, Kegele J, Kesim Y, Khoueiry-Zgheib N, Khoury J, King C, Klein KM, Kluger G, Knake S, Kok F, Korczyn AD, Korinthenberg R, Koupparis A, Kousiappa I, Krause R, Krenn M, Krestel H, Krey I, Kunz WS, Kurlemann G, Kuzniecky RI, Kwan P, La Vega-Talbott M, Labate A, Lacey A, Lal D, Laššuthová P, Lauxmann S, Lawthom C, Leech SL, Lehesjoki AE, Lemke JR, Lerche H, Lesca G, Leu C, Lewin N, Lewis-Smith D, Li GH, Liao C, Licchetta L, Lin CH, Lin KL, Linnankivi T, Lo W, Lowenstein DH, Lowther C, Lubbers L, Lui CHT, Macedo-Souza LI, Madeleyn R, Madia F, Magri S, Maillard L, Marcuse L, Marques P, Marson AG, Matthews AG, May P, Mayer T, McArdle W, McCarroll SM, McGoldrick P, McGraw CM, McIntosh A, McQuillan A, Meador KJ, Mei D, Michel V, Millichap JJ, Minardi R, Montomoli M, Mostacci B, Muccioli L, Muhle H, Müller-Schlüter K, Najm IM, Nasreddine W, Neaves S, Neubauer BA, Newton CRJC, Noebels JL, Northstone K, Novod S, O'Brien TJ, Owusu-Agyei S, Özkara Ç, Palotie A, Papacostas SS, Parrini E, Pato C, Pato M, Pendziwiat M, Pennell PB, Petrovski S, Pickrell WO, Pinsky R, Pinto D, Pippucci T, Piras F, Piras F, Poduri A, Pondrelli F, Posthuma D, Powell RHW, Privitera M, Rademacher A, Ragona F, Ramirez-Hamouz B, Rau S, Raynes HR, Rees MI, Regan BM, Reif A, Reinthaler E, Rheims S, Ring SM, Riva A, Rojas E, Rosenow F, Ryvlin P, Saarela A, Sadleir LG, Salman B, Salmon A, Salpietro V, Sammarra I, Scala M, Schachter S, Schaller A, Schankin CJ, Scheffer IE, Schneider N, Schubert-Bast S, Schulze-Bonhage A, Scudieri P, Sedláčková L, Shain C, Sham PC, Shiedley BR, Siena SA, Sills GJ, Sisodiya SM, Smoller JW, Solomonson M, Spalletta G, Sparks KR, Sperling MR, Stamberger H, Steinhoff BJ, Stephani U, Štěrbová K, Stewart WC, Stipa C, Striano P, Strzelczyk A, Surges R, Suzuki T, Talarico M, Talkowski ME, Taneja RS, Tanteles GA, Timonen O, Timpson NJ, Tinuper P, Todaro M, Topaloglu P, Tsai MH, Tumiene B, Turkdogan D, Uğur-İşeri S, Utkus A, Vaidiswaran P, Valton L, van Baalen A, Vari MS, Vetro A, Vlčková M, von Brauchitsch S, von Spiczak S, Wagner RG, Watts N, Weber YG, Weckhuysen S, Widdess-Walsh P, Wiebe S, Wolf SM, Wolff M, Wolking S, Wong I, von Wrede R, Wu D, Yamakawa K, Yapıcı Z, Yis U, Yolken R, Yücesan E, Zagaglia S, Zahnert F, Zara F, Zimprich F, Zizovic M, Zsurka G, Neale BM, and Berkovic SF

Abstract

Identifying genetic risk factors for highly heterogeneous disorders like epilepsy remains challenging. Here, we present the largest whole-exome sequencing study of epilepsy to date, with >54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate seven individual genes, three gene sets, and four copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies, generalized and focal epilepsies, while most other gene discoveries are subtype-specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single nucleotide/short indel-, copy number-, and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies., Competing Interests: Competing Interests B.M.N is a member of the scientific advisory board at Deep Genomics and Neumora. No other authors have competing interests to declare

Published
2024
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32. Loss of Slc35a2 alters development of the mouse cerebral cortex.

Author

Elziny S, Sran S, Yoon H, Corrigan RR, Page J, Ringland A, Lanier A, Lapidus S, Foreman J, Heinzen EL, Iffland P, Crino PB, and Bedrosian TA

Subjects
Animals, Mice, Mice, Knockout, Neurons metabolism, Oligodendroglia metabolism, Female, Epilepsy genetics, Epilepsy pathology, Cell Movement, Cerebral Cortex metabolism, Monosaccharide Transport Proteins genetics, Monosaccharide Transport Proteins deficiency
Abstract

Brain somatic variants in SLC35A2, an intracellular UDP-galactose transporter, are commonly identified mutations associated with drug-resistant neocortical epilepsy and developmental brain malformations, including focal cortical dysplasia type I and mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). However, the causal effects of altered SLC35A2 function on cortical development remain untested. We hypothesized that focal Slc35a2 knockout (KO) or knockdown (KD) in the developing mouse cortex would disrupt cortical development and change network excitability. Through two independent studies, we used in utero electroporation (IUE) to introduce CRISPR/Cas9/targeted guide RNAs or short-hairpin RNAs into the embryonic mouse brain at day 14.5-15.5 to achieve Slc35a2 KO or KD, respectively, from neural precursor cells. Slc35a2 KO or KD caused disrupted radial migration of electroporated neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter. Slc35a2 KO in neurons did not induce changes in oligodendrocyte number, importantly suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects of Slc35a2 mutations. Adult KO mice were implanted with EEG electrodes for 72-hour continuous recording. Spontaneous seizures were not observed in focal Slc35a2 KO mice, but there was reduced seizure threshold following pentylenetetrazol injection. Here we demonstrate that focal Slc35a2 KO or KD in vivo disrupts corticogenesis through altered neuronal migration and that KO leads to reduced seizure threshold. Together these results demonstrate a direct causal role for SLC35A2 in cortical development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2024
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33. Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis.

Author

Carton RJ, Doyle MG, Kearney H, Steward CA, Lench NJ, Rogers A, Heinzen EL, McDonald S, Fay J, Lacey A, Beausang A, Cryan J, Brett F, El-Naggar H, Widdess-Walsh P, Costello D, Kilbride R, Doherty CP, Sweeney KJ, O'Brien DF, Henshall DC, Delanty N, Cavalleri GL, and Benson KA

Subjects
Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Young Adult, Filamins genetics, Genetic Variation, Malformations of Cortical Development genetics, Malformations of Cortical Development complications, Malformations of Cortical Development pathology, Drug Resistant Epilepsy genetics, Drug Resistant Epilepsy etiology, Drug Resistant Epilepsy pathology, Epilepsy, Temporal Lobe genetics, Epilepsy, Temporal Lobe pathology, Hippocampal Sclerosis genetics, Hippocampal Sclerosis pathology
Abstract

Objective: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy., Methods: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585× and 1360×, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing., Results: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development., Significance: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2024
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34. Exome sequencing of ATP1A3-negative cases of alternating hemiplegia of childhood reveals SCN2A as a novel causative gene.

Author

Panagiotakaki E, Tiziano FD, Mikati MA, Vijfhuizen LS, Nicole S, Lesca G, Abiusi E, Novelli A, Di Pietro L, Harder AVE, Walley NM, De Grandis E, Poulat AL, Portes VD, Lépine A, Nassogne MC, Arzimanoglou A, Vavassori R, Koenderink J, Thompson CH, George AL Jr, Gurrieri F, van den Maagdenberg AMJM, and Heinzen EL

Subjects
Humans, Exome Sequencing, Mutation, Sodium-Potassium-Exchanging ATPase genetics, GTP-Binding Proteins genetics, Tumor Suppressor Proteins genetics, NAV1.2 Voltage-Gated Sodium Channel genetics, Hemiplegia diagnosis, Hemiplegia genetics, Mutation, Missense
Abstract

Alternating hemiplegia of childhood (AHC) is a rare neurodevelopment disorder that is typically characterized by debilitating episodic attacks of hemiplegia, seizures, and intellectual disability. Over 85% of individuals with AHC have a de novo missense variant in ATP1A3 encoding the catalytic α3 subunit of neuronal Na +/ K + ATPases. The remainder of the patients are genetically unexplained. Here, we used next-generation sequencing to search for the genetic cause of 26 ATP1A3-negative index patients with a clinical presentation of AHC or an AHC-like phenotype. Three patients had affected siblings. Using targeted sequencing of exonic, intronic, and flanking regions of ATP1A3 in 22 of the 26 index patients, we found no ultra-rare variants. Using exome sequencing, we identified the likely genetic diagnosis in 9 probands (35%) in five genes, including RHOBTB2 (n = 3), ATP1A2 (n = 3), ANK3 (n = 1), SCN2A (n = 1), and CHD2 (n = 1). In follow-up investigations, two additional ATP1A3-negative individuals were found to have rare missense SCN2A variants, including one de novo likely pathogenic variant and one likely pathogenic variant for which inheritance could not be determined. Functional evaluation of the variants identified in SCN2A and ATP1A2 supports the pathogenicity of the identified variants. Our data show that genetic variants in various neurodevelopmental genes, including SCN2A, lead to AHC or AHC-like presentation. Still, the majority of ATP1A3-negative AHC or AHC-like patients remain unexplained, suggesting that other mutational mechanisms may account for the phenotype or that cases may be explained by oligo- or polygenic risk factors., (© 2023. The Author(s), under exclusive licence to European Society of Human Genetics.)

Published
2024
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35. LUSTR: a new customizable tool for calling genome-wide germline and somatic short tandem repeat variants.

Author

Lu J, Toro C, Adams DR, Moreno CAM, Lee WP, Leung YY, Harms MB, Vardarajan B, and Heinzen EL

Subjects
Humans, Germ Cells, High-Throughput Nucleotide Sequencing, Genome, Human, Microsatellite Repeats genetics
Abstract

Background: Short tandem repeats (STRs) are widely distributed across the human genome and are associated with numerous neurological disorders. However, the extent that STRs contribute to disease is likely under-estimated because of the challenges calling these variants in short read next generation sequencing data. Several computational tools have been developed for STR variant calling, but none fully address all of the complexities associated with this variant class., Results: Here we introduce LUSTR which is designed to address some of the challenges associated with STR variant calling by enabling more flexibility in defining STR loci, allowing for customizable modules to tailor analyses, and expanding the capability to call somatic and multiallelic STR variants. LUSTR is a user-friendly and easily customizable tool for targeted or unbiased genome-wide STR variant screening that can use either predefined or novel genome builds. Using both simulated and real data sets, we demonstrated that LUSTR accurately infers germline and somatic STR expansions in individuals with and without diseases., Conclusions: LUSTR offers a powerful and user-friendly approach that allows for the identification of STR variants and can facilitate more comprehensive studies evaluating the role of pathogenic STR variants across human diseases., (© 2024. The Author(s).)

Published
2024
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36. RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.

Author

Dharmadhikari AV, Abad MA, Khan S, Maroofian R, Sands TT, Ullah F, Samejima I, Wear MA, Moore KE, Kondakova E, Mitina N, Schaub T, Lee GK, Umandap CH, Berger SM, Iglesias AD, Popp B, Jamra RA, Gabriel H, Rentas S, Rippert AL, Izumi K, Conlin LK, Koboldt DC, Mosher TM, Hickey SE, Albert DVF, Norwood H, Lewanda AF, Dai H, Liu P, Mitani T, Marafi D, Pehlivan D, Posey JE, Lippa N, Vena N, Heinzen EL, Goldstein DB, Mignot C, de Sainte Agathe JM, Al-Sannaa NA, Zamani M, Sadeghian S, Azizimalamiri R, Seifia T, Zaki MS, Abdel-Salam GMH, Abdel-Hamid M, Alabdi L, Alkuraya FS, Dawoud H, Lofty A, Bauer P, Zifarelli G, Afzal E, Zafar F, Efthymiou S, Gossett D, Towne MC, Yeneabat R, Wontakal SN, Aggarwal VS, Rosenfeld JA, Tarabykin V, Ohta S, Lupski JR, Houlden H, Earnshaw WC, Davis EE, Jeyaprakash AA, and Liao J

Abstract

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, we identified 24 individuals with neurodevelopmental delays from 18 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants showed reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicated that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 revealed that most disease-associated missense variants mapped to the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants had reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS ( SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

Published
2024
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37. Loss of Slc35a2 alters development of the mouse cerebral cortex.

Author

Elziny S, Sran S, Yoon H, Corrigan RR, Page J, Ringland A, Lanier A, Lapidus S, Foreman J, Heinzen EL, Iffland P, Crino PB, and Bedrosian TA

Abstract

Brain somatic variants in SLC35A2 are associated with clinically drug-resistant epilepsy and developmental brain malformations, including mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). SLC35A2 encodes a uridine diphosphate galactose translocator that is essential for protein glycosylation; however, the neurodevelopmental mechanisms by which SLC35A2 disruption leads to clinical and histopathological features remain unspecified. We hypothesized that focal knockout (KO) or knockdown (KD) of Slc35a2 in the developing mouse cortex would disrupt cerebral cortical development through altered neuronal migration and cause changes in network excitability. We used in utero electroporation (IUE) to introduce CRISPR/Cas9 and targeted guide RNAs or short-hairpin RNAs to achieve Slc35a2 KO or KD, respectively, during early corticogenesis. Following Slc35a2 KO or KD, we observed disrupted radial migration of transfected neurons evidenced by heterotopic cells located in lower cortical layers and in the sub-cortical white matter. Slc35a2 KO in neurons did not induce changes in oligodendrocyte number, suggesting that the oligodendroglial hyperplasia observed in MOGHE originates from distinct cell autonomous effects. Spontaneous seizures were not observed, but intracranial EEG recordings after focal KO showed a reduced seizure threshold following pentylenetetrazol injection. These results demonstrate that Slc35a2 KO or KD in vivo disrupts corticogenesis through altered neuronal migration., Competing Interests: Competing Interest Statement The authors have no competing interests to declare.

Published
2023
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38. Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy.

Author

Miller KE, Rivaldi AC, Shinagawa N, Sran S, Navarro JB, Westfall JJ, Miller AR, Roberts RD, Akkari Y, Supinger R, Hester ME, Marhabaie M, Gade M, Lu J, Rodziyevska O, Bhattacharjee MB, Von Allmen GK, Yang E, Lidov HGW, Harini C, Shah MN, Leonard J, Pindrik J, Shaikhouni A, Goldman JE, Pierson CR, Thomas DL, Boué DR, Ostendorf AP, Mardis ER, Poduri A, Koboldt DC, Heinzen EL, and Bedrosian TA

Subjects
Humans, Mouth Mucosa, Mutation, Brain, Mosaicism, Epilepsies, Partial genetics
Abstract

Somatic mosaicism is a known cause of neurological disorders, including developmental brain malformations and epilepsy. Brain mosaicism is traditionally attributed to post-zygotic genetic alterations arising in fetal development. Here we describe post-zygotic rescue of meiotic errors as an alternate origin of brain mosaicism in patients with focal epilepsy who have mosaic chromosome 1q copy number gains. Genomic analysis showed evidence of an extra parentally derived chromosome 1q allele in the resected brain tissue from five of six patients. This copy number gain is observed only in patient brain tissue, but not in blood or buccal cells, and is strongly enriched in astrocytes. Astrocytes carrying chromosome 1q gains exhibit distinct gene expression signatures and hyaline inclusions, supporting a novel genetic association for astrocytic inclusions in epilepsy. Further, these data demonstrate an alternate mechanism of brain chromosomal mosaicism, with parentally derived copy number gain isolated to brain, reflecting rescue in other tissues during development., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Published
2023
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39. Prophecy or empiricism? Clinical value of predicting versus determining genetic variant functions.

Author

Brunklaus A, George AL Jr, Lal D, Heinzen EL, and Goldman AM

Subjects
Humans, Empiricism, Genetic Testing, Genetic Variation genetics, Epilepsy diagnosis, Epilepsy genetics
Abstract

The recent explosion of epilepsy genetic testing has created challenges for interpretation of gene variants. Assessments of the functional consequences of genetic variants either by predictive or experimental strategies can contribute to estimating pathogenicity, but there is no consensus on which approach is best. The Special Interest Group on Epilepsy Genetics hosted a session during the Annual American Epilepsy Society Meeting in December 2022 to discuss this topic. The session featured a debate of the relative advantages and limitations of predicting (prophecy) versus experimentally determining (empiricism) variant function using ion channel gene variants as examples. This commentary summarizes these discussions., (© 2023 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2023
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40. Brain mosaicism of hedgehog signalling and other cilia genes in hypothalamic hamartoma.

Author

Green TE, Fujita A, Ghaderi N, Heinzen EL, Matsumoto N, Klein KM, Berkovic SF, and Hildebrand MS

Subjects
Cilia metabolism, Brain metabolism, Hedgehog Proteins genetics, Mosaicism
Abstract

Hypothalamic hamartoma (HH) is a rare benign developmental brain lesion commonly associated with a well characterized epilepsy phenotype. Most individuals with HH are non-syndromic without additional developmental anomalies nor a family history of disease. Nonetheless, HH is a feature of Pallister-Hall (PHS) and Oro-Facial-Digital Type VI (OFD VI) syndromes, both characterized by additional developmental anomalies. Initial genetic of analysis HH began with syndromic HH, where germline inherited or de novo variants in GLI3, encoding a central transcription factor in the sonic hedgehog (Shh) signalling pathway, were identified in most individuals with PHS. Following these discoveries in syndromic HH, the hypothesis that post-zygotic mosaicism in related genes may underly non-syndromic HH was tested. We discuss the identified mosaic variants within individuals with non-syndromic HH, review the analytical methodologies and diagnostic yields, and explore understanding of the functional role of the implicated genes with respect to Shh signalling, and cilia development and function. We also outline future challenges in studying non-syndromic HH and suggest potential novel strategies to interrogate brain mosaicism in HH., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
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41. Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy.

Author

Khoshkhoo S, Wang Y, Chahine Y, Erson-Omay EZ, Robert SM, Kiziltug E, Damisah EC, Nelson-Williams C, Zhu G, Kong W, Huang AY, Stronge E, Phillips HW, Chhouk BH, Bizzotto S, Chen MH, Adikari TN, Ye Z, Witkowski T, Lai D, Lee N, Lokan J, Scheffer IE, Berkovic SF, Haider S, Hildebrand MS, Yang E, Gunel M, Lifton RP, Richardson RM, Blümcke I, Alexandrescu S, Huttner A, Heinzen EL, Zhu J, Poduri A, DeLanerolle N, Spencer DD, Lee EA, Walsh CA, and Kahle KT

Subjects
Humans, Female, Adult, Middle Aged, Male, Mitogen-Activated Protein Kinases metabolism, Retrospective Studies, Hippocampus pathology, Epilepsy, Temporal Lobe surgery, Epilepsy pathology, Drug Resistant Epilepsy, Neocortex
Abstract

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown., Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE., Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022., Exposures: Drug-resistant MTLE., Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex., Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism., Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

Published
2023
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42. Rare Genetic Variation and Outcome of Surgery for Mesial Temporal Lobe Epilepsy.

Author

Perucca P, Stanley K, Harris N, McIntosh AM, Asadi-Pooya AA, Mikati MA, Andrade DM, Dugan P, Depondt C, Choi H, Heinzen EL, Cavalleri GL, Buono RJ, Devinsky O, Sperling MR, Berkovic SF, Delanty N, Goldstein DB, and O'Brien TJ

Abstract

Objective: Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery., Methods: We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls., Results: Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences., Interpretation: Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2022
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43. Somatic variants in diverse genes leads to a spectrum of focal cortical malformations.

Author

Lai D, Gade M, Yang E, Koh HY, Lu J, Walley NM, Buckley AF, Sands TT, Akman CI, Mikati MA, McKhann GM, Goldman JE, Canoll P, Alexander AL, Park KL, Von Allmen GK, Rodziyevska O, Bhattacharjee MB, Lidov HGW, Vogel H, Grant GA, Porter BE, Poduri AH, Crino PB, and Heinzen EL

Subjects
Cadherins, Cell Cycle Proteins, Female, Humans, Malformations of Cortical Development, Group I, Mutation, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Protocadherins, TOR Serine-Threonine Kinases, Epilepsy, Hemimegalencephaly, Malformations of Cortical Development
Abstract

Post-zygotically acquired genetic variants, or somatic variants, that arise during cortical development have emerged as important causes of focal epilepsies, particularly those due to malformations of cortical development. Pathogenic somatic variants have been identified in many genes within the PI3K-AKT-mTOR-signalling pathway in individuals with hemimegalencephaly and focal cortical dysplasia (type II), and more recently in SLC35A2 in individuals with focal cortical dysplasia (type I) or non-dysplastic epileptic cortex. Given the expanding role of somatic variants across different brain malformations, we sought to delineate the landscape of somatic variants in a large cohort of patients who underwent epilepsy surgery with hemimegalencephaly or focal cortical dysplasia. We evaluated samples from 123 children with hemimegalencephaly (n = 16), focal cortical dysplasia type I and related phenotypes (n = 48), focal cortical dysplasia type II (n = 44), or focal cortical dysplasia type III (n = 15). We performed high-depth exome sequencing in brain tissue-derived DNA from each case and identified somatic single nucleotide, indel and large copy number variants. In 75% of individuals with hemimegalencephaly and 29% with focal cortical dysplasia type II, we identified pathogenic variants in PI3K-AKT-mTOR pathway genes. Four of 48 cases with focal cortical dysplasia type I (8%) had a likely pathogenic variant in SLC35A2. While no other gene had multiple disease-causing somatic variants across the focal cortical dysplasia type I cohort, four individuals in this group had a single pathogenic or likely pathogenic somatic variant in CASK, KRAS, NF1 and NIPBL, genes previously associated with neurodevelopmental disorders. No rare pathogenic or likely pathogenic somatic variants in any neurological disease genes like those identified in the focal cortical dysplasia type I cohort were found in 63 neurologically normal controls (P = 0.017), suggesting a role for these novel variants. We also identified a somatic loss-of-function variant in the known epilepsy gene, PCDH19, present in a small number of alleles in the dysplastic tissue from a female patient with focal cortical dysplasia IIIa with hippocampal sclerosis. In contrast to focal cortical dysplasia type II, neither focal cortical dysplasia type I nor III had somatic variants in genes that converge on a unifying biological pathway, suggesting greater genetic heterogeneity compared to type II. Importantly, we demonstrate that focal cortical dysplasia types I, II and III are associated with somatic gene variants across a broad range of genes, many associated with epilepsy in clinical syndromes caused by germline variants, as well as including some not previously associated with radiographically evident cortical brain malformations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Published
2022
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44. Sporadic hypothalamic hamartoma is a ciliopathy with somatic and bi-allelic contributions.

Author

Green TE, Motelow JE, Bennett MF, Ye Z, Bennett CA, Griffin NG, Damiano JA, Leventer RJ, Freeman JL, Harvey AS, Lockhart PJ, Sadleir LG, Boys A, Scheffer IE, Major H, Darbro BW, Bahlo M, Goldstein DB, Kerrigan JF, Heinzen EL, Berkovic SF, and Hildebrand MS

Subjects
Hedgehog Proteins metabolism, Humans, Magnetic Resonance Imaging, Ciliopathies genetics, Hamartoma genetics, Hypothalamic Diseases complications, Hypothalamic Diseases genetics
Abstract

Hypothalamic hamartoma with gelastic seizures is a well-established cause of drug-resistant epilepsy in early life. The development of novel surgical techniques has permitted the genomic interrogation of hypothalamic hamartoma tissue. This has revealed causative mosaic variants within GLI3, OFD1 and other key regulators of the sonic-hedgehog pathway in a minority of cases. Sonic-hedgehog signalling proteins localize to the cellular organelle primary cilia. We therefore explored the hypothesis that cilia gene variants may underlie hitherto unsolved cases of sporadic hypothalamic hamartoma. We performed high-depth exome sequencing and chromosomal microarray on surgically resected hypothalamic hamartoma tissue and paired leukocyte-derived DNA from 27 patients. We searched for both germline and somatic variants under both dominant and bi-allelic genetic models. In hamartoma-derived DNA of seven patients we identified bi-allelic (one germline, one somatic) variants within one of four cilia genes-DYNC2I1, DYNC2H1, IFT140 or SMO. In eight patients, we identified single somatic variants in the previously established hypothalamic hamartoma disease genes GLI3 or OFD1. Overall, we established a plausible molecular cause for 15/27 (56%) patients. Here, we expand the genetic architecture beyond single variants within dominant disease genes that cause sporadic hypothalamic hamartoma to bi-allelic (one germline/one somatic) variants, implicate three novel cilia genes and reconceptualize the disorder as a ciliopathy., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2022
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45. Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery.

Author

Oliver KL, Ellis CA, Scheffer IE, Ganesan S, Leu C, Sadleir LG, Heinzen EL, Mefford HC, Bass AJ, Curtis SW, Harris RV, Whiteman DC, Helbig I, Ottman R, Epstein MP, Bahlo M, and Berkovic SF

Subjects
Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Multifactorial Inheritance genetics, Epilepsy genetics, Epilepsy, Generalized genetics, Epileptic Syndromes
Abstract

Background: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with non-familial (sporadic) epilepsies., Methods: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1,818 from 1,181 families), their unaffected relatives (n = 771), sporadic patients (n = 1,182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalised epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry., Findings: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, p adj  = 5×10 -9 ), sporadic patients (OR 1·11, p adj  = 0.008), and their own unaffected relatives (OR 1·12, p adj  = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (p adj  = 5×10 -11 ). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases., Interpretation: The aggregate effects of common genetic variants, measured as polygenic risk scores, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known genetic etiology., Funding: National Health and Medical Research Council of Australia, National Institutes of Health, American Academy of Neurology, Thomas B and Jeannette E Laws McCabe Fund, Mirowski Family Foundation., Competing Interests: Declaration of interests Samuel Berkovic has received grants from UCB Pharma, Eisai, SciGen; consulting fees from Praxis Precision Medicines, Sequiris; honoraria from Eisai; has a patent for SCN1A testing held by Bionomics Inc licensed to Athena Diagnostics and Genetics Technologies Ltd. Ingrid Scheffer has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, Chiesi, Encoded Therapeutics, Knopp Biosciences and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx, GW Pharma, UCB, Eisai, Xenon Pharmaceuticals, Anavex Life Sciences, Ovid Therapeutics, Epigenyx, Encoded Therapeutics and Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium and UCB; and is a Non-Executive Director of Bellberry Ltd. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID:2012-009). David Whiteman has received speaker fees from Pierre Fabre. Melanie Bahlo has received payment for thesis examination from University of Melbourne, University of Sydney, University of Western Australia; has received support for attending conferences: Genemappers, International Conference on Familial Cortical Myoclonic Tremor Epilepsy and Repeat Expansion Diseases, Lorne Genome, Bioinforsummer, Australian Academy of Science Australia-China symposium on precision medicine; has served as an advisor for ALADIN, Kinghorn Sequencing Center, Murdoch Children's Research Institute, Viertel Foundation; is a committee member for Australian Academy of Health and Medical Sciences, American Epilepsy Society Basic Sciences, Gen V Bioresource Genetics. Costin Leu received conference travel support from the International Epilepsy Congress/ILAE. Ingo Helbig received travel support from the Americal Epilepsy Society. Heather Mefford has received support from CURE Epilepsy and sits on the American Society of Human Genetics Board of Directors. Lynette Sadleir has received consulting fees from the Epilepsy Consortium, Zynerba; is an advisor to Eisai; and is treasurer for the New Zealand League Against Epilepsy., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Published
2022
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46. A pharmacogenomic assessment of psychiatric adverse drug reactions to levetiracetam.

Author

Campbell C, McCormack M, Patel S, Stapleton C, Bobbili D, Krause R, Depondt C, Sills GJ, Koeleman BP, Striano P, Zara F, Sander JW, Lerche H, Kunz WS, Stefansson K, Stefansson H, Doherty CP, Heinzen EL, Scheffer IE, Goldstein DB, O'Brien T, Cotter D, Berkovic SF, Sisodiya SM, Delanty N, and Cavalleri GL

Subjects
Anticonvulsants adverse effects, Case-Control Studies, Genetic Predisposition to Disease genetics, Humans, Levetiracetam adverse effects, Pharmacogenetics, Prospective Studies, Drug-Related Side Effects and Adverse Reactions, Genome-Wide Association Study
Abstract

Objective: Levetiracetam (LEV) is an effective antiseizure medicine, but 10%-20% of people treated with LEV report psychiatric side-effects, and up to 1% may have psychotic episodes. Pharmacogenomic predictors of these adverse drug reactions (ADRs) have yet to be identified. We sought to determine the contribution of both common and rare genetic variation to psychiatric and behavioral ADRs associated with LEV., Methods: This case-control study compared cases of LEV-associated behavioral disorder (n = 149) or psychotic reaction (n = 37) to LEV-exposed people with no history of psychiatric ADRs (n = 920). All samples were of European ancestry. We performed genome-wide association study (GWAS) analysis comparing those with LEV ADRs to controls. We estimated the polygenic risk scores (PRS) for schizophrenia and compared cases with LEV-associated psychotic reaction to controls. Rare variant burden analysis was performed using exome sequence data of cases with psychotic reactions (n = 18) and controls (n = 122)., Results: Univariate GWAS found no significant associations with either LEV-associated behavioural disorder or LEV-psychotic reaction. PRS analysis showed that cases of LEV-associated psychotic reaction had an increased PRS for schizophrenia relative to contr ols (p = .0097, estimate = .4886). The rare-variant analysis found no evidence of an increased burden of rare genetic variants in people who had experienced LEV-associated psychotic reaction relative to controls., Significance: The polygenic burden for schizophrenia is a risk factor for LEV-associated psychotic reaction. To assess the clinical utility of PRS as a predictor, it should be tested in an independent and ideally prospective cohort. Larger sample sizes are required for the identification of significant univariate common genetic signals or rare genetic signals associated with psychiatric LEV ADRs., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Published
2022
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47. Epilepsy Genetics: Advancements in the Field and Impact on Clinical Practice

Author

Hunter SE, Jalazo E, Felton TR, Heinzen EL, Shiloh-Malawsky Y, and Czuczwar SJ

Abstract

During the first decade of the 21 st century, the landscape of epilepsy genetics started to take shape with the discovery of many new genes linked to epilepsy. These genetic discoveries advanced our understanding of the molecular and cellular pathways involved in epilepsy. Over the following ten years, the availability of clinical genetic testing along with rapidly growing knowledge of epilepsy genetics transformed patient care; most profoundly affecting management of childhood-onset epilepsies. This new genomic era offers great opportunities for the advancement of health outcomes and epilepsy research. It has also created new demands and challenges for physicians practicing in this rapidly evolving field, which requires specialized expertise in order to provide best care for patients and their families. This chapter reviews epilepsy genetics advancements and its impact on clinical practice., (Copyright: The Authors.; The authors confirm that the materials included in this chapter do not violate copyright laws. Where relevant, appropriate permissions have been obtained from the original copyright holder(s), and all original sources have been appropriately acknowledged or referenced.)

Published
2022
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48. The benefit of diagnostic whole genome sequencing in schizophrenia and other psychotic disorders.

Author

Alkelai A, Greenbaum L, Docherty AR, Shabalin AA, Povysil G, Malakar A, Hughes D, Delaney SL, Peabody EP, McNamara J, Gelfman S, Baugh EH, Zoghbi AW, Harms MB, Hwang HS, Grossman-Jonish A, Aggarwal V, Heinzen EL, Jobanputra V, Pulver AE, Lerer B, and Goldstein DB

Subjects
Genetic Predisposition to Disease genetics, Humans, Multifactorial Inheritance genetics, Whole Genome Sequencing, Psychotic Disorders genetics, Psychotic Disorders psychology, Schizophrenia diagnosis, Schizophrenia genetics
Abstract

Schizophrenia has a multifactorial etiology, involving a polygenic architecture. The potential benefit of whole genome sequencing (WGS) in schizophrenia and other psychotic disorders is not well studied. We investigated the yield of clinical WGS analysis in 251 families with a proband diagnosed with schizophrenia (N = 190), schizoaffective disorder (N = 49), or other conditions involving psychosis (N = 48). Participants were recruited in Israel and USA, mainly of Jewish, Arab, and other European ancestries. Trio (parents and proband) WGS was performed for 228 families (90.8%); in the other families, WGS included parents and at least two affected siblings. In the secondary analyses, we evaluated the contribution of rare variant enrichment in particular gene sets, and calculated polygenic risk score (PRS) for schizophrenia. For the primary outcome, diagnostic rate was 6.4%; we found clinically significant, single nucleotide variants (SNVs) or small insertions or deletions (indels) in 14 probands (5.6%), and copy number variants (CNVs) in 2 (0.8%). Significant enrichment of rare loss-of-function variants was observed in a gene set of top schizophrenia candidate genes in affected individuals, compared with population controls (N = 6,840). The PRS for schizophrenia was significantly increased in the affected individuals group, compared to their unaffected relatives. Last, we were also able to provide pharmacogenomics information based on CYP2D6 genotype data for most participants, and determine their antipsychotic metabolizer status. In conclusion, our findings suggest that WGS may have a role in the setting of both research and genetic counseling for individuals with schizophrenia and other psychotic disorders and their families., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Published
2022
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49. CSNK2B: A broad spectrum of neurodevelopmental disability and epilepsy severity.

Author

Ernst ME, Baugh EH, Thomas A, Bier L, Lippa N, Stong N, Mulhern MS, Kushary S, Akman CI, Heinzen EL, Yeh R, Bi W, Hanchard NA, Burrage LC, Leduc MS, Chong JSC, Bend R, Lyons MJ, Lee JA, Suwannarat P, Brilstra E, Simon M, Koopmans M, van Binsbergen E, Groepper D, Fleischer J, Nava C, Keren B, Mignot C, Mathieu S, Mancini GMS, Madan-Khetarpal S, Infante EM, Bluvstein J, Seeley A, Bachman K, Klee EW, Schultz-Rogers LE, Hasadsri L, Barnett S, Ellingson MS, Ferber MJ, Narayanan V, Ramsey K, Rauch A, Joset P, Steindl K, Sheehan T, Poduri A, Vasquez A, Ruivenkamp C, White SM, Pais L, Monaghan KG, Goldstein DB, Sands TT, and Aggarwal V

Subjects
Adolescent, Adult, Age of Onset, Child, Child, Preschool, Developmental Disabilities physiopathology, Epilepsies, Myoclonic diagnosis, Epilepsies, Myoclonic etiology, Epilepsies, Myoclonic genetics, Epilepsy, Generalized diagnosis, Epilepsy, Generalized etiology, Exome genetics, Female, Genetic Variation, Humans, Infant, Intellectual Disability etiology, Intellectual Disability genetics, Male, Mutation genetics, Phenotype, Status Epilepticus diagnosis, Status Epilepticus etiology, Status Epilepticus genetics, Young Adult, Developmental Disabilities genetics, Epilepsy, Generalized genetics
Abstract

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures., (© 2021 International League Against Epilepsy.)

Published
2021
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50. Alternating hemiplegia of childhood: evolution over time and mouse model corroboration.

Author

Uchitel J, Wallace K, Tran L, Abrahamsen T, Hunanyan A, Prange L, Jasien J, Caligiuri L, Pratt M, Rikard B, Fons C, De Grandis E, Vezyroglou A, Heinzen EL, Goldstein DB, Vavassori R, Papadopoulou MT, Cocco I, Moré R, Arzimanoglou A, Panagiotakaki E, and Mikati MA

Abstract

Alternating hemiplegia of childhood is a rare neurodevelopmental disorder caused by ATP1A3 mutations. Some evidence for disease progression exists, but there are few systematic analyses. Here, we evaluate alternating hemiplegia of childhood progression in humans and in the D801N knock-in alternating hemiplegia of childhood mouse, Mashlool, model. This study performed an ambidirectional (prospective and retrospective data) analysis of an alternating hemiplegia of childhood patient cohort ( n  = 42, age 10.24 ± 1.48 years) seen at one US centre. To investigate potential disease progression, we used linear mixed effects models incorporating early and subsequent visits, and Wilcoxon Signed Rank test comparing first and last visits. Potential early-life clinical predictors were determined via multivariable regression. We also compared EEG background at first encounter and at last follow-up. We then performed a retrospective confirmation study on a multicentre cohort of alternating hemiplegia of childhood patients from France ( n  = 52). To investigate disease progression in the Mashlool mouse, we performed behavioural testing on a cohort of Mashlool - mice at prepubescent and adult ages ( n  = 11). Results: US patients, over time, demonstrated mild worsening of non-paroxysmal disability index scores, but not of paroxysmal disability index scores. Increasing age was a predictor of worse scores: P  < 0.0001 for the non-paroxysmal disability index, intellectual disability scale and gross motor scores. Earliest non-paroxysmal disability index score was a predictor of last visit non-paroxysmal disability index score ( P  = 0.022), and earliest intellectual disability score was a predictor of last intellectual disability score ( P  = 0.035). More patients with EEG background slowing were noted at last follow-up as compared to initial ( P  = 0.015). Similar worsening of disease with age was also noted in the French cohort: age was a significant predictor of non-paroxysmal disability index score ( P  = 0.001) and first and last non-paroxysmal disability index score scores significantly differed ( P  = 0.002). In animal studies, adult Mashlool mice had, as compared to younger Mashlool mice, (i) worse balance beam performance; (ii) wider base of support; (iii) higher severity of seizures and resultant mortality; and (iv) no increased predisposition to hemiplegic or dystonic spells. In conclusion, (i) non-paroxysmal alternating hemiplegia of childhood manifestations show, on average over time, progression associated with severity of early-life non-paroxysmal disability and age. (ii) Progression also occurs in Mashlool mice, confirming that ATP1A3 disease can lead to age-related worsening. (iii) Clinical findings provide a basis for counselling patients and for designing therapeutic trials. Animal findings confirm a mouse model for investigation of underlying mechanisms of disease progression, and are also consistent with known mechanisms of ATP1A3 -related neurodegeneration., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Published
2021
Full Text
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