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153. SCN1A duplications and deletions detected in Dravet syndrome: Implications for molecular diagnosis

Author

Marini, Carla, Scheffer, Ingrid E., Nabbout, Rima, Mei, Davide, Cox, Kathy, Dibbens, Leanne M., McMahon, Jacinta M., Iona, Xenia, Carpintero, Rochio Sanchez, Elia, Maurizio, Cilio, Maria Roberta, Specchio, Nicola, Giordano, Lucio, Striano, Pasquale, Gennaro, Elena, Cross, Helen J., Kivity, Sara, Neufeld, Miriam Y., Afawi, Zaid, Andermann, Eva, Keene, Daniel, Dulac, Olivier, Zara, Federico, Berkovic, Samuel F., Guerrini, Renzo, and Mulley, John C.

Published
2009
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156. Development and Validation of a Prediction Model for Early Diagnosis of -Related Epilepsies.

Author

Brunklaus, Andreas, Perez-Palma, Eduardo, Ghanty, Ismael, Xinge, Ji, Brilstra, Eva, Ceulemans, Berten, Chemaly, Nicole, de Lange, Iris, Depienne, Christel, Guerrini, Renzo, Mei, Davide, Moller, Rikke S., Nabbout, Rima, Regan, Brigid M. c, Schneider, Amy L. MGenCouns, Scheffer, Ingrid E., Schoonjans, An-Sofie, Symonds, Joseph D., Weckhuysen, Sarah, and Kattan, Michael W.

Published
2022
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157. Epilepsy Subtype-Specific Copy Number Burden Observed in a Genome-Wide Study of 17 458 Subjects

Author

Niestroj, Lisa-Marie, Perez-Palma, Eduardo, Howrigan, Daniel P., Zhou, Yadi, Cheng, Feixiong, Saarentaus, Elmo, Nürnberg, Peter, Stevelink, Remi, Daly, Mark J., Palotie, Aarno, Lal, Dennis, Feng, Yen-Chen Anne, Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Churchhouse, Claire, Gupta, Namrata, Neale, Benjamin M., Berkovic, Samuel F., Lerche, Holger, Goldstein, David B., Lowenstein, Daniel H., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Dixon-Salazar, Tracy, Guerrini, Renzo, Hakonarson, Hakon, Heinzen, Erin L., Helbig, Ingo, Kwan, Patrick, Marson, Anthony G., Petrovski, Slavé, Kamalakaran, Sitharthan, Sisodiya, Sanjay M., Stewart, Randy, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bellows, Susannah T., Leu, Costin, Bennett, Caitlin A., Johns, Esther C., Macdonald, Alexandra, Shilling, Hannah, Burgess, Rosemary, Weckhuysen, Dorien, Bahlo, Melanie, O’Brien, Terence J., Todaro, Marian, Weckhuysen, Sarah, Stamberger, Hannah, De Jonghe, Peter, Andrade, Danielle M., Sadoway, Tara R., Mo, Kelly, Krestel, Heinz, Gallati, Sabina, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Šterbová, Katalin, Vlcková, Markéta, Sedlácková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Kunz, Wolfram S., Zsurka, Gábor, Elger, Christian E., Bauer, Jürgen, Rademacher, Michael, Pendziwiat, Manuela, Muhle, Hiltrud, Rademacher, Annika, van Baalen, Andreas, von Spiczak, Sarah, Stephani, Ulrich, Afawi, Zaid, Korczyn, Amos D., Kanaan, Moien, Canavati, Christina, Kurlemann, Gerhard, Müller-Schlüter, Karen, Kluger, Gerhard, Häusler, Martin, Blatt, Ilan, Lemke, Johannes R., Krey, Ilona, Weber, Yvonne G., Wolking, Stefan, Becker, Felicitas, Hengsbach, Christian, Rau, Sarah, Maisch, Ana F., Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Schubert-Bast, Susanne, Schreiber, Herbert, Borggräfe, Ingo, Schankin, Christoph J., Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Auvinen, Pia, Saarela, Anni, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Schneider, Natascha, Balestrini, Simona, Zagaglia, Sara, Braatz, Vera, Johnson, Michael R., Auce, Pauls, Sills, Graeme J., Baum, Larry W., Sham, Pak C., Cherny, Stacey S., Lui, Colin H. T., Barišic, Nina, Delanty, Norman, Doherty, Colin P., Shukralla, Arif, McCormack, Mark, El-Naggar, Hany, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Zara, Federico, Iacomino, Michele, Madia, Francesca, Vari, Maria Stella, Mancardi, Maria Margherita, Salpietro, Vincenzo, Bisulli, Francesca, Tinuper, Paolo, Licchetta, Laura, Pippucci, Tommaso, Stipa, Carlotta, Muccioli, Lorenzo, Minardi, Raffaella, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Marini, Carla, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Tumiene, Birute, Mameniskiene, Ruta, Utkus, Algirdas, Praninskiene, Ruta, Grikiniene, Jurgita, Samaitiene, Ruta, Sadleir, Lynette G., King, Chontelle, Mountier, Emily, Caglayan, S. Hande, Arslan, Mutluay, Yapici, Zuhal, Yis, Uluc, Topaloglu, Pinar, Kara, Bulent, Turkdogan, Dilsad, Gundogdu-Eken, Asli, Bebek, Nerses, Ugur-Iseri, Sibel, Baykan, Betül, Salman, Baris, Haryanyan, Garen, Yücesan, Emrah, Kesim, Yesim, Özkara, Çigdem, Sheidley, Beth R., Shain, Catherine, Poduri, Annapurna, Buono, Russell J, Ferraro, Thomas N, Sperling, Michael R., Lo, Warren, Privitera, Michael, French, Jacqueline A., Schachter, Steven, Kuzniecky, Ruben I., Devinsky, Orrin, Hegde, Manu, Khankhanian, Pouya, Helbig, Katherine L., Ellis, Colin A., Spalletta, Gianfranco, Piras, Fabrizio, Piras, Federica, Gili, Tommaso, Ciullo, Valentina, YÜCESAN, EMRAH, Niestroj L.-M., Perez-Palma E., Howrigan D.P., Zhou Y., Cheng F., Saarentaus E., Nurnberg P., Stevelink R., Daly M.J., Palotie A., Lal D, Epi 25 Collaborative, Bisulli F., Tinuper P., Licchetta L., and Epi25 Collaborative

Subjects
Developmental and epileptic encephalopathy, Male, 0301 basic medicine, DNA Copy Number Variations, Disease, Bioinformatics, Genome, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, copy number variation, developmental and epileptic encephalopathy, epilepsy, focal epilepsy, genetic generalized epilepsy, medicine, Humans, Genetic Predisposition to Disease, Copy-number variation, Generalized epilepsy, DNA Copy Number Variation, Copy number variation, business.industry, Breakpoint, Focal epilepsy, Original Articles, medicine.disease, 3. Good health, Genetic generalized epilepsy, 030104 developmental biology, Female, Human medicine, Neurology (clinical), Personalized medicine, business, 030217 neurology & neurosurgery, Genome-Wide Association Study, Human
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 characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

Published
2020
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160. Brain MRI Findings in Severe Myoclonic Epilepsy in Infancy and Genotype–Phenotype Correlations

Author

Striano, Pasquale, Mancardi, Maria Margherita, Biancheri, Roberta, Madia, Francesca, Gennaro, Elena, Paravidino, Roberta, Beccaria, Francesca, Capovilla, Giuseppe, Bernardina, Bernardo Dalla, Darra, Francesca, Elia, Maurizio, Giordano, Lucio, Gobbi, Giuseppe, Granata, Tiziana, Ragona, Francesca, Guerrini, Renzo, Marini, Carla, Mei, Davide, Longaretti, Francesca, Romeo, Antonino, Siri, Laura, Specchio, Nicola, Vigevano, Federico, Striano, Salvatore, Tortora, Fabio, Rossi, Andrea, Minetti, Carlo, Dravet, Charlotte, Gaggero, Roberto, and Zara, Federico

Published
2007

163. Expanding the genetic and phenotypic spectrum of CHD2‐related disease: From early neurodevelopmental disorders to adult‐onset epilepsy.

Author

De Maria, Beatrice, Balestrini, Simona, Mei, Davide, Melani, Federico, Pellacani, Simona, Pisano, Tiziana, Rosati, Anna, Scaturro, Giusi M., Giordano, Lucio, Cantalupo, Gaetano, Fontana, Elena, Zammarchi, Cristina, Said, Edith, Leuzzi, Vincenzo, Mastrangelo, Mario, Galosi, Serena, Parrini, Elena, and Guerrini, Renzo

Abstract

CHD2 encodes the chromodomain helicase DNA‐binding protein 2, an ATP‐dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self‐limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult‐onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2‐related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult‐onset nonsyndromic epilepsy a rare presentation. No clear genotype–phenotype correlation has emerged. [ABSTRACT FROM AUTHOR]

Published
2022
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164. SLC7A3: In Silico Prediction of a Potential New Cause of Childhood Epilepsy.

Author

Sourbron, Jo, Jansen, Katrien, Mei, Davide, Hammer, Trine Bjørg, Møller, Rikke S., Gold, Nina B., O'Grady, Lauren, Guerrini, Renzo, and Lagae, Lieven

Subjects
CHILDHOOD epilepsy, DEVELOPMENTAL disabilities, EPILEPSY, FORECASTING
Abstract

We report an in-depth genetic analysis in an 11-year-old boy with drug-resistant, generalized seizures and developmental disability. Three distinct variants of unknown clinical significance (VUS) were detected by whole exome sequencing (WES) but not by initial genetic analyses (microarray and epilepsy gene panel). These variants involve the SLC7A3 , CACNA1H, and IGLON5 genes, which were subsequently evaluated by computational analyses using the InterVar tool and MutationTaster. While future functional studies are necessary to prove the pathogenicity of a certain VUS, segregation analyses over three generations and in silico predictions suggest the X-linked gene SLC7A3 (transmembrane solute carrier transporter) as the likely culprit gene in this patient. In addition, a search via GeneMatcher unveiled two additional patients with a VUS in SLC7A3. We propose SLC7A3 as a likely candidate gene for epilepsy and/or developmental/cognitive delay and provide an overview of the 27 SLC genes related to epilepsy by other preclinical and/or clinical studies. [ABSTRACT FROM AUTHOR]

Published
2022
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165. Distinct epilepsy phenotypes and response to drugs in KCNA1 gain‐ and loss‐of function variants.

Author

Miceli, Francesco, Guerrini, Renzo, Nappi, Mario, Soldovieri, Maria Virginia, Cellini, Elena, Gurnett, Christina A., Parmeggiani, Lucio, Mei, Davide, and Taglialatela, Maurizio

Subjects
EPILEPSY, PARTIAL epilepsy, PHENOTYPES, SODIUM channels, NEUROLOGICAL disorders, SYMPTOMS
Abstract

A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine‐responsive, focal epilepsy. Patch‐clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild‐type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1‐mediated currents, exerting loss‐of‐function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain‐of‐function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1‐related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored. [ABSTRACT FROM AUTHOR]

Published
2022
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167. Clinical spectrum of -related epileptic disorders

Author

Wolking, Stefan, May, Patrick, Mei, Davide, Møller, Rikke S, Balestrini, Simona, Helbig, Katherine L, Altuzarra, Cecilia Desmettre, Chatron, Nicolas, Kaiwar, Charu, Stöhr, Katharina, Widdess-Walsh, Peter, Mendelsohn, Bryce A, Numis, Adam, Cilio, Maria-Roberta, Van Paesschen, Wim, Svendsen, Lene L, Oates, Stephanie, Hughes, Elaine, Goyal, Sushma, Brown, Kathleen, Sifuentes Saenz, Margarita, Dorn, Thomas, Muhle, Hiltrud, Pagnamenta, Alistair T, Vavoulis, Dimitris V, Knight, Samantha J L, Taylor, Jenny C, Canevini, Maria Paola, Darra, Francesca, Gavrilova, Ralitza H, Powis, Zöe, Tang, Shan, Marquetand, Justus, Armstrong, Martin, McHale, Duncan, Klee, Eric W, Kluger, Gerhard J, Lowenstein, Daniel H, Weckhuysen, Sarah, Pal, Deb K, Helbig, Ingo, Guerrini, Renzo, Thomas, Rhys H, Rees, Mark I, Lesca, Gaetan, Sisodiya, Sanjay M, Weber, Yvonne G, Lal, Dennis, Marini, Carla, Lerche, Holger, Schubert, Julian, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique

Subjects
Male, Drug Resistant Epilepsy, Adolescent, Learning Disabilities, Developmental Disabilities, Infant, Newborn, Mutation, Missense, High-Throughput Nucleotide Sequencing, Infant, Syntaxin 1, Electroencephalography, Sequence Analysis, DNA, Seizures, Febrile, Young Adult, Phenotype, Loss of Function Mutation, Child, Preschool, Humans, Anticonvulsants, Female, Epilepsies, Partial, Child, Epileptic Syndromes
Abstract

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Published
2019

168. Neurologic phenotypes associated with COL4A1 / 2 mutations

Author

Zagaglia, Sara, Selch, Christina, Radić Nišević, Jelena, Mei, Davide, Michalak, Zuzanna, Hernandez-Hernandez, Laura, Krithika, S., Vezyroglou, Katharina, Varadkar, Sophia M., Pepler, Alexander, Biskup, Saskia, Leão, Miguel, Gärtner, Jutta, Merkenschlager, Andreas, Jaksch, Michaela, Møller, Rikke S., Gardella, Elena, Kristiansen, Britta Schlott, Hansen, Lars Kjærsgaard, Vari, Maria Stella, Helbig, Katherine L., Desai, Sonal, Smith-Hicks, Constance L., Hino-Fukuyo, Naomi, Talvik, Tiina, Laugesaar, Rael, Ilves, Pilvi, Õunap, Katrin, Körber, Ingrid, Hartlieb, Till, Kudernatsch, Manfred, Winkler, Peter, Schimmel, Mareike, Hasse, Anette, Knuf, Markus, Heinemeyer, Jan, Makowski, Christine, Ghedia, Sondhya, Subramanian, Gopinath M., Striano, Pasquale, Thomas, Rhys H., Micallef, Caroline, Thom, Maria, Werring, David J., Kluger, Gerhard Josef, Cross, J. Helen, Guerrini, Renzo, Balestrini, Simona, and Sisodiya, Sanjay M.

Subjects
Adult, Collagen Type IV, Male, Epilepsy, Adolescent, BIOMEDICINA I ZDRAVSTVO. Kliničke medicinske znanosti. Neurologija, Young Adult, BIOMEDICINE AND HEALTHCARE. Clinical Medical Sciences. Neurology, Child, Preschool, Mutation, Humans, Female, Nervous System Diseases, Child, Genetic Association Studies
Abstract

Objective To characterize the neurologic phenotypes associated with COL4A1/2 mutations and to seek genotype–phenotype correlation. Methods We analyzed clinical, EEG, and neuroimaging data of 44 new and 55 previously reported patients with COL4A1/COL4A2 mutations. Results Childhood-onset focal seizures, frequently complicated by status epilepticus and resistance to antiepileptic drugs, was the most common phenotype. EEG typically showed focal epileptiform discharges in the context of other abnormalities, including generalized sharp waves or slowing. In 46.4% of new patients with focal seizures, porencephalic cysts on brain MRI colocalized with the area of the focal epileptiform discharges. In patients with porencephalic cysts, brain MRI frequently also showed extensive white matter abnormalities, consistent with the finding of diffuse cerebral disturbance on EEG. Notably, we also identified a subgroup of patients with epilepsy as their main clinical feature, in which brain MRI showed nonspecific findings, in particular periventricular leukoencephalopathy and ventricular asymmetry. Analysis of 15 pedigrees suggested a worsening of the severity of clinical phenotype in succeeding generations, particularly when maternally inherited. Mutations associated with epilepsy were spread across COL4A1 and a clear genotype–phenotype correlation did not emerge. Conclusion COL4A1/COL4A2 mutations typically cause a severe neurologic condition and a broader spectrum of milder phenotypes, in which epilepsy is the predominant feature. Early identification of patients carrying COL4A1/COL4A2 mutations may have important clinical consequences, while for research efforts, omission from large-scale epilepsy sequencing studies of individuals with abnormalities on brain MRI may generate misleading estimates of the genetic contribution to the epilepsies overall.

Published
2018
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171. Biallelic DMXL2 mutations impair autophagy and cause Ohtahara syndrome with progressive course

Author

Esposito, Alessandro, primary, Falace, Antonio, additional, Wagner, Matias, additional, Gal, Moran, additional, Mei, Davide, additional, Conti, Valerio, additional, Pisano, Tiziana, additional, Aprile, Davide, additional, Cerullo, Maria Sabina, additional, De Fusco, Antonio, additional, Giovedì, Silvia, additional, Seibt, Annette, additional, Magen, Daniella, additional, Polster, Tilman, additional, Eran, Ayelet, additional, Stenton, Sarah L, additional, Fiorillo, Chiara, additional, Ravid, Sarit, additional, Mayatepek, Ertan, additional, Hafner, Hava, additional, Wortmann, Saskia, additional, Levanon, Erez Y, additional, Marini, Carla, additional, Mandel, Hanna, additional, Benfenati, Fabio, additional, Distelmaier, Felix, additional, Fassio, Anna, additional, and Guerrini, Renzo, additional

Published
2019
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172. Enhanced targeted resequencing by optimizing the combination of enrichment technology and DNA fragment length

Author

Iadarola, Barbara, primary, Xumerle, Luciano, additional, Lavezzari, Denise, additional, Paterno, Marta, additional, Marcolungo, Luca, additional, Beltrami, Cristina, additional, Fortunati, Elisabetta, additional, Mei, Davide, additional, Vetro, Annalisa, additional, Guerrini, Renzo, additional, Parrini, Elena, additional, Rossato, Marzia, additional, and Delledonne, Massimo, additional

Published
2019
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173. TBC1D24-TLDc-related epilepsy exercise-induced dystonia: rescue by antioxidants in a disease model

Author

Lüthy, Kevin, primary, Mei, Davide, additional, Fischer, Baptiste, additional, De Fusco, Maurizio, additional, Swerts, Jef, additional, Paesmans, Jone, additional, Parrini, Elena, additional, Lubarr, Naomi, additional, Meijer, Inge A, additional, Mackenzie, Katherine M, additional, Lee, Wang-Tso, additional, Cittaro, Davide, additional, Aridon, Paolo, additional, Schoovaerts, Nils, additional, Versées, Wim, additional, Verstreken, Patrik, additional, Casari, Giorgio, additional, and Guerrini, Renzo, additional

Published
2019
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174. Clinical spectrum of STX1B-related epileptic disorders

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Wolking, Stefan, May, Patrick, Mei, Davide, Møller, Rikke S., Balestrini, Simona, Helbig, Katherine L., Altuzurra, Cecilia D., Chatron, Nicolas, Kaiwar, Charu, Stöhr, Katharina, Widdess-Walsh, Peter, Mendelsohn, Bryce A., Numis, Adam, Cilio, Maria R., Van Paesschen, Wim, Svendsen, Lene L., Oates, Stephanie, Hughes, Elaine, Goyal, Sushma, Brown, Kathleen, Sifuentes Saenz, Dorn, Thomas, Muhle, Hiltrud, Pagnamenta, Alistair T., Vavoulis, Dimitris V., Knight, Samantha J.L., Taylor, Jenny C., Canevini, Maria P., Darra, Franchesca, Gavrilova, Ralitza H., Powis, Zöe, Tang, Shan, Marquetand, Justus, Armstrong, Martin, McHale, Duncan, Klee, Ernst W., Kluger, Gerhard J., Lowenstein, Daniel H., Weckhuysen, Sarah, Pal, Deb K., Helbig, Ingo, Guerrini, Renzo, Thomas, Rhys H., Rees, Mark I., Lesca, Gaetan, Sisodiya, Sanjay M., Weber, Yvonne G., Lal, Dennis, Marini, Carla, Lerche, Holger, Schubert, Julian, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Wolking, Stefan, May, Patrick, Mei, Davide, Møller, Rikke S., Balestrini, Simona, Helbig, Katherine L., Altuzurra, Cecilia D., Chatron, Nicolas, Kaiwar, Charu, Stöhr, Katharina, Widdess-Walsh, Peter, Mendelsohn, Bryce A., Numis, Adam, Cilio, Maria R., Van Paesschen, Wim, Svendsen, Lene L., Oates, Stephanie, Hughes, Elaine, Goyal, Sushma, Brown, Kathleen, Sifuentes Saenz, Dorn, Thomas, Muhle, Hiltrud, Pagnamenta, Alistair T., Vavoulis, Dimitris V., Knight, Samantha J.L., Taylor, Jenny C., Canevini, Maria P., Darra, Franchesca, Gavrilova, Ralitza H., Powis, Zöe, Tang, Shan, Marquetand, Justus, Armstrong, Martin, McHale, Duncan, Klee, Ernst W., Kluger, Gerhard J., Lowenstein, Daniel H., Weckhuysen, Sarah, Pal, Deb K., Helbig, Ingo, Guerrini, Renzo, Thomas, Rhys H., Rees, Mark I., Lesca, Gaetan, Sisodiya, Sanjay M., Weber, Yvonne G., Lal, Dennis, Marini, Carla, Lerche, Holger, and Schubert, Julian

Abstract

Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and to establish genotype-phenotype correlations by identifying further disease-related variants. Methods: We used next generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. Results: We describe fifteen new variants in STX1B which are distributed across the whole gene. We discerned four different phenotypic groups across the newly identified and previously published patients (49 in 23 families): 1) Six sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development and without permanent neurological deficits; 2) two patients of genetic generalized epilepsy without febrile seizures and cognitive deficits; 3) thirteen patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; 4) two patients with focal epilepsy. Nonsense mutations were found more often in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. Conclusion: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the ILAE classification. Variants in STX1B are protean, and able to contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

Published
2019

175. Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3

Author

Florian, Rahel T., Kraft, Florian, Leitao, Elsa, Kaya, Sabine, Klebe, Stephan, Magnin, Eloi, van Rootselaar, Anne-Fleur, Buratti, Julien, Kuehnel, Theresa, Schroeder, Christopher, Giesselmann, Sebastian, Tschernoster, Nikolai, Altmueller, Janine, lamiral, AnaiDe, Keren, Boris, Nava, Caroline, Bouteiller, Delphine, Forlani, Sylvie, Jornea, Ludmila, Kubica, Regina, Ye, Tao, Plassard, Damien, Jost, Bernard, Meyer, Vincent, Deleuze, Jean-Francois, Delpu, Yannick, Avarello, Mario D. M., Vijfhuizen, Lisanne S., Rudolf, Gabrielle, Hirsch, Edouard, Kroes, Thessa, Reif, Philipp S., Rosenow, Felix, Ganos, Christos, Vidailhet, Marie, Thivard, Lionel, Mathieu, Alexandre, Bourgeron, Thomas, Kurth, Ingo, Rafehi, Haloom, Steenpass, Laura, Horsthemke, Bernhard, Berkovic, Samuel F., Bisulli, Francesca, Brancati, Francesco, Canafoglia, Laura, Casari, Giorgio, Guerrini, Renzo, Ishiura, Hiroyuki, Licchetta, Laura, Mei, Davide, Pippucci, Tommaso, Sadleir, Lynette, Scheffer, Ingrid E., Striano, Pasquale, Tinuper, Paolo, Tsuji, Shoji, Zara, Federico, LeGuern, Eric, Klein, Karl Martin, Labauge, Pierre, Bennett, Mark F., Bahlo, Melanie, Gecz, Jozef, Corbett, Mark A., Tijssen, Marina A. J., van den Maagdenberg, Arn M. J. M., Depienne, Christel, Florian, Rahel T., Kraft, Florian, Leitao, Elsa, Kaya, Sabine, Klebe, Stephan, Magnin, Eloi, van Rootselaar, Anne-Fleur, Buratti, Julien, Kuehnel, Theresa, Schroeder, Christopher, Giesselmann, Sebastian, Tschernoster, Nikolai, Altmueller, Janine, lamiral, AnaiDe, Keren, Boris, Nava, Caroline, Bouteiller, Delphine, Forlani, Sylvie, Jornea, Ludmila, Kubica, Regina, Ye, Tao, Plassard, Damien, Jost, Bernard, Meyer, Vincent, Deleuze, Jean-Francois, Delpu, Yannick, Avarello, Mario D. M., Vijfhuizen, Lisanne S., Rudolf, Gabrielle, Hirsch, Edouard, Kroes, Thessa, Reif, Philipp S., Rosenow, Felix, Ganos, Christos, Vidailhet, Marie, Thivard, Lionel, Mathieu, Alexandre, Bourgeron, Thomas, Kurth, Ingo, Rafehi, Haloom, Steenpass, Laura, Horsthemke, Bernhard, Berkovic, Samuel F., Bisulli, Francesca, Brancati, Francesco, Canafoglia, Laura, Casari, Giorgio, Guerrini, Renzo, Ishiura, Hiroyuki, Licchetta, Laura, Mei, Davide, Pippucci, Tommaso, Sadleir, Lynette, Scheffer, Ingrid E., Striano, Pasquale, Tinuper, Paolo, Tsuji, Shoji, Zara, Federico, LeGuern, Eric, Klein, Karl Martin, Labauge, Pierre, Bennett, Mark F., Bahlo, Melanie, Gecz, Jozef, Corbett, Mark A., Tijssen, Marina A. J., van den Maagdenberg, Arn M. J. M., and Depienne, Christel

Abstract

Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.

Published
2019

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

Author

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

Abstract

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABAA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

Published
2019

177. Neurologic phenotypes associated with COL4A1/2 mutations

Author

Zagaglia, Sara, Selch, Christina, Nisevic, Jelena Radic, Mei, Davide, Michalak, Zuzanna, Hernandez-Hernandez, Laura, Krithika, S., Vezyroglou, Katharina, Varadkar, Sophia M., Pepler, Alexander, Biskup, Saskia, Leão, Miguel, Gärtner, Jutta, Merkenschlager, Andreas, Jaksch, Michaela, Møller, Rikke S., Gardella, Elena, Kristiansen, Britta Schlott, Hansen, Lars Kjærsgaard, Vari, Maria Stella, Helbig, Katherine L., Desai, Sonal, Smith-Hicks, Constance L., Hino-Fukuyo, Naomi, Talvik, Tiina, Laugesaar, Rael, Ilves, Pilvi, Õunap, Katrin, Körber, Ingrid, Hartlieb, Till, Kudernatsch, Manfred, Winkler, Peter, Schimmel, Mareike, Hasse, Anette, Knuf, Markus, Heinemeyer, Jan, Makowski, Christine, Ghedia, Sondhya, Subramanian, Gopinath M., Striano, Pasquale, Thomas, Rhys H., Micallef, Caroline, Thom, Maria, Werring, David J., Kluger, Gerhard Josef, Cross, J. Helen, Guerrini, Renzo, Balestrini, Simona, and Sisodiya, Sanjay M.

Subjects
ddc
Published
2018

178. Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects

Author

Marini, Carla, Hardies, Katia, Pisano, Tiziana, May, Patrick, Weckhuysen, Sarah, Cellini, Elena, Suls, Arvid, Mei, Davide, Balling, Rudi, Jonghe, Peter D., Helbig, Ingo, Garozzo, Domenico, Guerrini, Renzo, Afawi, Zaid, Barišić, Nina, Baulac, Stéphanie, Brilstra, Eva H., Caglayan, Hande, Dana, Craiu, Hageman, Gerard, Helle, Hjalgrim, Jähn, Johanna, Klein, Karl Martin, Leguern, Eric, Lemke, Johannes R., Møller, Rikke S., Muhle, Hiltrud, Rosenow, Felix, Serratosa, Jose, Schelhaas, Jurgen H., Sterbova, Katalin, von Spiczak, Sarah, Szczepanik, Elzbieta, Yis, Uluc, Lerche, Holger, Striano, Pasquale, Weber, Yvonne, and Zara, Federico

Subjects
epileptic encephalopathy, Journal Article, genetics, suppression burst, skeletal abnormalities, infantile spasms
Published
2017

179. Dravet syndrome as part of the clinical and genetic spectrum of sodium channel epilepsies and encephalopathies.

Author

Mei, Davide, Cetica, Valentina, Marini, Carla, and Guerrini, Renzo

Subjects
*SODIUM channels, *BRUGADA syndrome, *GENETIC disorders, *COGNITION disorders, *FEBRILE seizures, *GENETIC mutation
Abstract

Dravet syndrome is the most studied form of genetic epilepsy. It has now been clarified that the clinical spectrum of the syndrome does not have firmly established boundaries. The core phenotype is characterized by intractable, mainly clonic, seizures precipitated by increased body temperature with onset in the first year of life and subsequent appearance of multiple seizures types still precipitated by, but not confined to, hyperthermia. Cognitive impairment is invariably present when the full syndrome is manifested. This complex of symptoms is related to mutations in the SCN1A gene, which are often de novo and constitutional but can also be inherited from a parent with less severe clinical manifestations or be present as somatic mosaicism. Inheritance from less severely affected individuals, at times only having experienced a few febrile seizures, and differences in severity, even within the same family, with a subset of patients only showing fragments of the syndrome, testify to a remarkable phenotypic heterogeneity as far as severity, but less so clinical phenomenology, are concerned. This characteristic, together with underascertainment of SCN1A mutations due to human errors or technical limitations in uncovering alternative pathogenic molecular mechanisms, such as genomic rearrangements or poison exons, has contributed to making clinicians and geneticists suspicious that Dravet syndrome may be caused by more than one gene. This opinion has been further amplified by the description of other genetic disorders, such as PCDH19‐ or CHD2‐related epilepsy, whose phenotypes have included fragments of the Dravet phenotypic spectrum, and by the suboptimal characterization of phenotypes associated with mutations in SCN1B, HCN1, KCN2A, GABRA1, GABRG2, and STXBP1. The SCN1A gene–Dravet syndrome association is in our opinion highly specific. However, because the syndrome spectrum is wide, fragments of it can at times also be manifested in other genetic epilepsy syndromes, thereby leading to overdiagnosis of Dravet syndrome beyond SCN1A. Dravet syndrome is in turn a severe SCN1A phenotype within a continuum of SCN1A‐related clinical phenomenology. [ABSTRACT FROM AUTHOR]

Published
2020
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180. Corrigendum to “Pyridoxine-5′-phosphate oxidase (Pnpo) deficiency: Clinical and biochemical alterations associated with the C.347g > A (P.·Arg116gln) mutation” [Mol. Genet. Metab. 122/1–2 (2017) 135–142]

Author

di Salvo, Martino L., primary, Mastrangelo, Mario, additional, Nogués, Isabel, additional, Tolve, Manuela, additional, Paiardini, Alessandro, additional, Carducci, Carla, additional, Mei, Davide, additional, Montomoli, Martino, additional, Tramonti, Angela, additional, Guerrini, Renzo, additional, Contestabile, Roberto, additional, and Leuzzi, Vincenzo, additional

Published
2018
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181. Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study

Author

Trivisano, Marina, primary, Pietrafusa, Nicola, additional, Terracciano, Alessandra, additional, Marini, Carla, additional, Mei, Davide, additional, Darra, Francesca, additional, Accorsi, Patrizia, additional, Battaglia, Domenica, additional, Caffi, Lorella, additional, Canevini, Maria P., additional, Cappelletti, Simona, additional, Cesaroni, Elisabetta, additional, de Palma, Luca, additional, Costa, Paola, additional, Cusmai, Raffaella, additional, Giordano, Lucio, additional, Ferrari, Annarita, additional, Freri, Elena, additional, Fusco, Lucia, additional, Granata, Tiziana, additional, Martino, Tommaso, additional, Mastrangelo, Massimo, additional, Bova, Stefania M., additional, Parmeggiani, Lucio, additional, Ragona, Francesca, additional, Sicca, Federico, additional, Striano, Pasquale, additional, Specchio, Luigi M., additional, Tondo, Ilaria, additional, Zambrelli, Elena, additional, Zamponi, Nelia, additional, Zanus, Caterina, additional, Boniver, Clementina, additional, Vecchi, Marilena, additional, Avolio, Carlo, additional, Dalla Bernardina, Bernardo, additional, Bertini, Enrico, additional, Guerrini, Renzo, additional, Vigevano, Federico, additional, and Specchio, Nicola, additional

Published
2018
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182. Neurologic phenotypes associated with COL4A1/2 mutations

Author

Zagaglia, Sara, primary, Selch, Christina, additional, Nisevic, Jelena Radic, additional, Mei, Davide, additional, Michalak, Zuzanna, additional, Hernandez-Hernandez, Laura, additional, Krithika, S., additional, Vezyroglou, Katharina, additional, Varadkar, Sophia M., additional, Pepler, Alexander, additional, Biskup, Saskia, additional, Leão, Miguel, additional, Gärtner, Jutta, additional, Merkenschlager, Andreas, additional, Jaksch, Michaela, additional, Møller, Rikke S., additional, Gardella, Elena, additional, Kristiansen, Britta Schlott, additional, Hansen, Lars Kjærsgaard, additional, Vari, Maria Stella, additional, Helbig, Katherine L., additional, Desai, Sonal, additional, Smith-Hicks, Constance L., additional, Hino-Fukuyo, Naomi, additional, Talvik, Tiina, additional, Laugesaar, Rael, additional, Ilves, Pilvi, additional, Õunap, Katrin, additional, Körber, Ingrid, additional, Hartlieb, Till, additional, Kudernatsch, Manfred, additional, Winkler, Peter, additional, Schimmel, Mareike, additional, Hasse, Anette, additional, Knuf, Markus, additional, Heinemeyer, Jan, additional, Makowski, Christine, additional, Ghedia, Sondhya, additional, Subramanian, Gopinath M., additional, Striano, Pasquale, additional, Thomas, Rhys H., additional, Micallef, Caroline, additional, Thom, Maria, additional, Werring, David J., additional, Kluger, Gerhard Josef, additional, Cross, J. Helen, additional, Guerrini, Renzo, additional, Balestrini, Simona, additional, and Sisodiya, Sanjay M., additional

Published
2018
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183. Analysis of 17 genes detects mutations in 81% of 811 patients with lissencephaly

Author

Di Donato, Nataliya, primary, Timms, Andrew E., additional, Aldinger, Kimberly A., additional, Mirzaa, Ghayda M., additional, Bennett, James T., additional, Collins, Sarah, additional, Olds, Carissa, additional, Mei, Davide, additional, Chiari, Sara, additional, Carvill, Gemma, additional, Myers, Candace T., additional, Rivière, Jean-Baptiste, additional, Zaki, Maha S., additional, Gleeson, Joseph G., additional, Rump, Andreas, additional, Conti, Valerio, additional, Parrini, Elena, additional, Ross, M.Elizabeth, additional, Ledbetter, David H., additional, Guerrini, Renzo, additional, and Dobyns, William B., additional

Published
2018
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184. HCN1mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Author

Marini, Carla, primary, Porro, Alessandro, additional, Rastetter, Agnès, additional, Dalle, Carine, additional, Rivolta, Ilaria, additional, Bauer, Daniel, additional, Oegema, Renske, additional, Nava, Caroline, additional, Parrini, Elena, additional, Mei, Davide, additional, Mercer, Catherine, additional, Dhamija, Radhika, additional, Chambers, Chelsea, additional, Coubes, Christine, additional, Thévenon, Julien, additional, Kuentz, Paul, additional, Julia, Sophie, additional, Pasquier, Laurent, additional, Dubourg, Christèle, additional, Carré, Wilfrid, additional, Rosati, Anna, additional, Melani, Federico, additional, Pisano, Tiziana, additional, Giardino, Maria, additional, Innes, A Micheil, additional, Alembik, Yves, additional, Scheidecker, Sophie, additional, Santos, Manuela, additional, Figueiroa, Sonia, additional, Garrido, Cristina, additional, Fusco, Carlo, additional, Frattini, Daniele, additional, Spagnoli, Carlotta, additional, Binda, Anna, additional, Granata, Tiziana, additional, Ragona, Francesca, additional, Freri, Elena, additional, Franceschetti, Silvana, additional, Canafoglia, Laura, additional, Castellotti, Barbara, additional, Gellera, Cinzia, additional, Milanesi, Raffaella, additional, Mancardi, Maria Margherita, additional, Clark, Damien R, additional, Kok, Fernando, additional, Helbig, Katherine L, additional, Ichikawa, Shoji, additional, Sadler, Laurie, additional, Neupauerová, Jana, additional, Laššuthova, Petra, additional, Štěrbová, Katalin, additional, Laridon, Annick, additional, Brilstra, Eva, additional, Koeleman, Bobby, additional, Lemke, Johannes R, additional, Zara, Federico, additional, Striano, Pasquale, additional, Soblet, Julie, additional, Smits, Guillaume, additional, Deconinck, Nicolas, additional, Barbuti, Andrea, additional, DiFrancesco, Dario, additional, LeGuern, Eric, additional, Guerrini, Renzo, additional, Santoro, Bina, additional, Hamacher, Kay, additional, Thiel, Gerhard, additional, Moroni, Anna, additional, DiFrancesco, Jacopo C, additional, and Depienne, Christel, additional

Published
2018
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187. HCN1 mutation spectrum: From neonatal epileptic encephalopathy to benign generalized epilepsy and beyond

Author

Genetica Klinische Genetica, Brain, Child Health, Genetica Groep Koeleman, Circulatory Health, Marini, Carla, Porro, Alessandro, Rastetter, Agnès, Dalle, Carine, Rivolta, Ilaria, Bauer, Daniel, Oegema, Renske, Nava, Caroline, Parrini, Elena, Mei, Davide, Mercer, Catherine, Dhamija, Radhika, Chambers, Chelsea, Coubes, Christine, Thévenon, Julien, Kuentz, Paul, Julia, Sophie, Pasquier, Laurent, Dubourg, Christèle, Carré, Wilfrid, Rosati, Anna, Melani, Federico, Pisano, Tiziana, Giardino, Maria, Innes, A. Micheil, Alembik, Yves, Scheidecker, Sophie, Santos, Manuela, Figueiroa, Sonia, Garrido, Cristina, Fusco, Carlo, Frattini, Daniele, Spagnoli, Carlotta, Binda, Anna, Granata, Tiziana, Ragona, Francesca, Freri, Elena, Franceschetti, Silvana, Canafoglia, Laura, Castellotti, Barbara, Gellera, Cinzia, Milanesi, Raffaella, Mancardi, Maria Margherita, Clark, Damien R., Kok, Fernando, Helbig, Katherine L., Ichikawa, Shoji, Sadler, Laurie, Neupauerová, Jana, Laššuthova, Petra, Štěrbová, Katalin, Laridon, Annick, Brilstra, Eva, Koeleman, Bobby, Lemke, Johannes R., Zara, Federico, Striano, Pasquale, Soblet, Julie, Smits, Guillaume, Deconinck, Nicolas, Barbuti, Andrea, Difrancesco, Dario, Leguern, Eric, Guerrini, Renzo, Santoro, Bina, Hamacher, Kay, Thiel, Gerhard, Moroni, Anna, Difrancesco, Jacopo C., Depienne, Christel, Genetica Klinische Genetica, Brain, Child Health, Genetica Groep Koeleman, Circulatory Health, Marini, Carla, Porro, Alessandro, Rastetter, Agnès, Dalle, Carine, Rivolta, Ilaria, Bauer, Daniel, Oegema, Renske, Nava, Caroline, Parrini, Elena, Mei, Davide, Mercer, Catherine, Dhamija, Radhika, Chambers, Chelsea, Coubes, Christine, Thévenon, Julien, Kuentz, Paul, Julia, Sophie, Pasquier, Laurent, Dubourg, Christèle, Carré, Wilfrid, Rosati, Anna, Melani, Federico, Pisano, Tiziana, Giardino, Maria, Innes, A. Micheil, Alembik, Yves, Scheidecker, Sophie, Santos, Manuela, Figueiroa, Sonia, Garrido, Cristina, Fusco, Carlo, Frattini, Daniele, Spagnoli, Carlotta, Binda, Anna, Granata, Tiziana, Ragona, Francesca, Freri, Elena, Franceschetti, Silvana, Canafoglia, Laura, Castellotti, Barbara, Gellera, Cinzia, Milanesi, Raffaella, Mancardi, Maria Margherita, Clark, Damien R., Kok, Fernando, Helbig, Katherine L., Ichikawa, Shoji, Sadler, Laurie, Neupauerová, Jana, Laššuthova, Petra, Štěrbová, Katalin, Laridon, Annick, Brilstra, Eva, Koeleman, Bobby, Lemke, Johannes R., Zara, Federico, Striano, Pasquale, Soblet, Julie, Smits, Guillaume, Deconinck, Nicolas, Barbuti, Andrea, Difrancesco, Dario, Leguern, Eric, Guerrini, Renzo, Santoro, Bina, Hamacher, Kay, Thiel, Gerhard, Moroni, Anna, Difrancesco, Jacopo C., and Depienne, Christel

Published
2018

188. Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects

Author

Muhle, Hiltrud, Sterbova, Katalin, von Spiczak, Sarah, Szczepanik, Elzbieta, Yis, Uluc, Baulac, Stéphanie, Barišić, Nina, Lerche, Holger, Striano, Pasquale, Weber, Yvonne, Zara, Federico, Garozzo, Domenico, Jonghe, Peter D., Balling, Rudi, Mei, Davide, Cellini, Elena, Klein, Karl Martin, Suls, Arvid, Jähn, Johanna, Helle, Hjalgrim, Marini, Carla, Hardies, Katia, Pisano, Tiziana, May, Patrick, Weckhuysen, Sarah, Hageman, Gerard, Dana, Craiu, Caglayan, Hande, Schelhaas, Jurgen H., Brilstra, Eva H., Serratosa, Jose, Rosenow, Felix, Afawi, Zaid, Guerrini, Renzo, Helbig, Ingo, Møller, Rikke S., Lemke, Johannes R, and Leguern, Eric

Subjects
Arthrogryposis, Male, Heterozygote, Glycosylation, Siblings, Gene Expression, Electroencephalography, skeletal abnormalities, Quadriplegia, Bone and Bones, epileptic encephalopathy, genetics, infantile spasms, suppression burst, Intellectual Disability, Mutation, Nucleotide Transport Proteins, Microcephaly, Humans, Female, Child, Spasms, Infantile
Abstract

© 2017 Wiley Periodicals, Inc.We describe the clinical and whole genome sequencing (WGS) study of a non-consanguineous Italian family in which two siblings, a boy and a girl, manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities, carried novel SLC35A3 compound heterozygous mutations. Both siblings exhibited infantile spasms, associated with focal, and tonic vibratory seizures from early infancy. EEG recordings showed a suppression-burst (SB) pattern and multifocal paroxysmal activity in both. In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability. General examination showed distal arthrogryposis predominant in the hands in both siblings and severe left dorso-lumbar convex scoliosis in one. WGS of the siblings-parents quartet identified novel compound heterozygous mutations in SLC35A3 in both children. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine transporter. With this study, we add SLC35A3 to the gene list of epilepsies. Neurological symptoms and skeletal abnormalities might result from impaired glycosylation of proteins involved in normal development and function of the central nervous system and skeletal apparatus.

Published
2016

189. Pitfalls in genetic testing : the story of missed SCN1A mutations

Author

Djémié, Tania, Weckhuysen, Sarah, von Spiczak, Sarah, Carvill, Gemma L, Jaehn, Johanna, Anttonen, Anna-Kaisa, Brilstra, Eva, Caglayan, Hande S, de Kovel, Carolien G, Depienne, Christel, Gaily, Eija, Gennaro, Elena, Giraldez, Beatriz G, Gormley, Padhraig, Guerrero-López, Rosa, Guerrini, Renzo, Hämäläinen, Eija, Hartmann, Corinna, Hernandez-Hernandez, Laura, Hjalgrim, Helle, Koeleman, Bobby P C, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R, Leu, Costin, Marini, Carla, McMahon, Jacinta M, Mei, Davide, Møller, Rikke S, Muhle, Hiltrud, Myers, Candace T, Nava, Caroline, Serratosa, Jose M, Sisodiya, Sanjay M, Stephani, Ulrich, Striano, Pasquale, van Kempen, Marjan J A, Verbeek, Nienke E, Usluer, Sunay, Zara, Federico, Palotie, Aarno, Mefford, Heather C, Scheffer, Ingrid E, De Jonghe, Peter, Helbig, Ingo, Suls, Arvid, and EuroEPINOMICS‐RES Dravet working group

Subjects
Sanger sequencing, Journal Article, epilepsy, next-generation sequencing, genetic screening, Dravet syndrome
Abstract

BACKGROUND: Sanger sequencing, still the standard technique for genetic testing in most diagnostic laboratories and until recently widely used in research, is gradually being complemented by next-generation sequencing (NGS). No single mutation detection technique is however perfect in identifying all mutations. Therefore, we wondered to what extent inconsistencies between Sanger sequencing and NGS affect the molecular diagnosis of patients. Since mutations in SCN1A, the major gene implicated in epilepsy, are found in the majority of Dravet syndrome (DS) patients, we focused on missed SCN1A mutations. METHODS: We sent out a survey to 16 genetic centers performing SCN1A testing. RESULTS: We collected data on 28 mutations initially missed using Sanger sequencing. All patients were falsely reported as SCN1A mutation-negative, both due to technical limitations and human errors. CONCLUSION: We illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated.

Published
2016

191. Use of epilepsy gene panels for early diagnosis of epilepsy in children 2-4 years of age: expert considerations on current and future practices in Europe

Author

Izzo, Emanuela, primary, Barroso, Eva, additional, Bailey, Mitch, additional, Griesbach, Stefan, additional, Lerche, Holger, additional, Jenkins, Lucy, additional, Le Guern, Eric, additional, Mei, Davide, additional, Mikhaylova, Svetlana, additional, Santorelli, Filippo, additional, and Miller, Nicole, additional

Published
2018
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192. Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients

Author

de Kovel, Carolien G.F., Brilstra, Eva H., van Kempen, Marjan J.A., van‘t Slot, Ruben, Nijman, Isaac J., Afawi, Zaid, De Jonghe, Peter, Djémié, Tania, Guerrini, Renzo, Hardies, Katia, Helbig, Ingo, Hendrickx, Rik, Kanaan, Moine, Kramer, Uri, Lehesjoki, Anna‐Elina E., Lemke, Johannes R., Marini, Carla, Mei, Davide, Møller, Rikke S., Pendziwiat, Manuela, Stamberger, Hannah, Suls, Arvid, Weckhuysen, Sarah, Koeleman, Bobby P.C., R, Balling, N, Barisic, S, Baulac, HS, Caglayan, DC, Craiu, C, Depienne, P, Gormley, H, Hjalgrim, D, Hoffman‐Zacharska, J, Jähn, KM, Klein, V, Komarek, E, LeGuern, H, Lerche, P, May, H, Muhle, D, Pal, A, Palotie, F, Rosenow, K, Selmer, JM, Serratosa, SM, Sisodiya, U, Stephani, K, Sterbova, P, Striano, T, Talvik, M, van Haelst, N, Verbeek, S, von Spiczak, YG, Weber, Other departments, Amsterdam Reproduction & Development (AR&D), Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, EuroEPINOMICS RES Consortium, Neuroscience Center, Research Programs Unit, Department of Medical and Clinical Genetics, Anna-Elina Lehesjoki / Principal Investigator, and Research Programme for Molecular Neurology

Subjects
0301 basic medicine, Candidate gene, education, EEF1A2, Genomics, targeted panel sequencing, Biology, Frameshift mutation, loss-of-function, 03 medical and health sciences, Genotype, Journal Article, Genetics, De novo, HNRNPU, X‐linked, epileptic encephalopathy, loss‐of‐function, prioritization, recessive, Molecular Biology, Gene, Genetics (clinical), Loss function, X-linked, 3112 Neurosciences, Original Articles, Phenotype, 3. Good health, 030104 developmental biology, Original Article, Human medicine
Abstract

BACKGROUND: Many genes are candidates for involvement in epileptic encephalopathy (EE) because one or a few possibly pathogenic variants have been found in patients, but insufficient genetic or functional evidence exists for a definite annotation.METHODS: To increase the number of validated EE genes, we sequenced 26 known and 351 candidate genes for EE in 360 patients. Variants in 25 genes known to be involved in EE or related phenotypes were followed up in 41 patients. We prioritized the candidate genes, and followed up 31 variants in this prioritized subset of candidate genes.RESULTS: Twenty-nine genotypes in known genes for EE (19) or related diseases (10), dominant as well as recessive or X-linked, were classified as likely pathogenic variants. Among those, likely pathogenic de novo variants were found in EE genes that act dominantly, including the recently identified genes EEF1A2, KCNB1 and the X-linked gene IQSEC2. A de novo frameshift variant in candidate gene HNRNPU was the only de novo variant found among the followed-up candidate genes, and the patient's phenotype was similar to a few recent publications.CONCLUSION: Mutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss-of-function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life.

Published
2016
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193. Phenotypic spectrum of GABRA1

Author

Johannesen, Katrine, Marini, Carla, Pfeffer, Siona, Møller, Rikke S., Dorn, Thomas, Niturad, Christina, Gardella, Elena, Weber, Yvonne, Søndergård, Marianne, Hjalgrim, Helle, Nikanorova, Mariana, Becker, Felicitas, Larsen, Line H. G., Dahl, Hans A., Maier, Oliver, Mei, Davide, Biskup, Saskia, Klein, Karl M., Reif, Philipp S., Rosenow, Felix, Elias, Abdallah F., Hudson, Cindy, Helbig, Katherine L., Schubert Bast, Susanne, Scordo, Maria R., Craiu, Dana, Djémié, Tania, Hoffman Zacharska, Dorota, Caglayan, Hande, Helbig, Ingo, Serratosa, Jose, Striano, Pasquale, De Jonghe, Peter, Weckhuysen, Sarah, Suls, Arvid, Muru, Kai, Talvik, Inga, Talvik, Tiina, Muhle, Hiltrud, Borggraefe, Ingo, Rost, Imma, Guerrini, Renzo, Lerche, Holger, Lemke, Johannes R., Rubboli, Guido, and Maljevic, Snezana

Subjects
Neurology (clinical)
Published
2016

194. Biochemical data from the characterization of a new pathogenic mutation of human pyridoxine-5'-phosphate oxidase (PNPO)

Author

di Salvo, Martino L., primary, Mastrangelo, Mario, additional, Nogués, Isabel, additional, Tolve, Manuela, additional, Paiardini, Alessandro, additional, Carducci, Carla, additional, Mei, Davide, additional, Montomoli, Martino, additional, Tramonti, Angela, additional, Guerrini, Renzo, additional, Contestabile, Roberto, additional, and Leuzzi, Vincenzo, additional

Published
2017
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195. A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations

Author

Zhu, Xiaolin, primary, Padmanabhan, Raghavendra, additional, Copeland, Brett, additional, Bridgers, Joshua, additional, Ren, Zhong, additional, Kamalakaran, Sitharthan, additional, O'Driscoll-Collins, Ailbhe, additional, Berkovic, Samuel F., additional, Scheffer, Ingrid E., additional, Poduri, Annapurna, additional, Mei, Davide, additional, Guerrini, Renzo, additional, Lowenstein, Daniel H., additional, Allen, Andrew S., additional, Heinzen, Erin L., additional, and Goldstein, David B., additional

Published
2017
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196. Pyridoxine-5′-phosphate oxidase (Pnpo) deficiency: Clinical and biochemical alterations associated with the C.347g > A (P.·Arg116gln) mutation

Author

di Salvo, Martino L., primary, Mastrangelo, Mario, additional, Nogués, Isabel, additional, Tolve, Manuela, additional, Paiardini, Alessandro, additional, Carducci, Carla, additional, Mei, Davide, additional, Montomoli, Martino, additional, Tramonti, Angela, additional, Guerrini, Renzo, additional, Contestabile, Roberto, additional, and Leuzzi, Vincenzo, additional

Published
2017
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198. Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Marini, Carla, Hardies, Katia, Pisano, Tiziana, May, Patrick, Weckhuysen, Sarah, Cellini, Elena, Suls, Arvid, Mei, Davide, Balling, Rudi, De Jonghe, Peter, Helbig, Ingo, Garozzo, Domenico, EuroEPINOMICS consortium AR working group, Guerrini, Renzo, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], Marini, Carla, Hardies, Katia, Pisano, Tiziana, May, Patrick, Weckhuysen, Sarah, Cellini, Elena, Suls, Arvid, Mei, Davide, Balling, Rudi, De Jonghe, Peter, Helbig, Ingo, Garozzo, Domenico, EuroEPINOMICS consortium AR working group, and Guerrini, Renzo

Abstract

We describe the clinical and whole genome sequencing (WGS) study of a non-consanguineous Italian family in which two siblings, a boy and a girl, manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities, carried novel SLC35A3 compound heterozy- gous mutations. Both siblings exhibited infantile spasms, associated with focal, and tonic vibratory seizures from early infancy. EEG recordings showed a suppression-burst (SB) pattern and multifocal paroxysmal activity in both. In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability. General examination showed distal arthrog- ryposis predominant in the hands in both siblings and severe left dorso-lumbar convex scoliosis in one. WGS of the siblings-parents quartet identified novel compound heterozygous mutations in SLC35A3 in both children. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine transporter. With this study, we add SLC35A3 to the gene list of epilepsies. Neurological symptoms and skeletal abnormalities might result from impaired glycosylation of proteins involved in normal development and function of the central nervous system and skeletal apparatus.

Published
2017

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

Author

Zhu, Xiaolin, Cooper, Gregory M1, Zhu, Xiaolin, Padmanabhan, Raghavendra, Copeland, Brett, Bridgers, Joshua, Ren, Zhong, Kamalakaran, Sitharthan, O'Driscoll-Collins, Ailbhe, Berkovic, Samuel F, Scheffer, Ingrid E, Poduri, Annapurna, Mei, Davide, Guerrini, Renzo, Lowenstein, Daniel H, Allen, Andrew S, Heinzen, Erin L, Goldstein, David B, Zhu, Xiaolin, Cooper, Gregory M1, Zhu, Xiaolin, Padmanabhan, Raghavendra, Copeland, Brett, Bridgers, Joshua, Ren, Zhong, Kamalakaran, Sitharthan, O'Driscoll-Collins, Ailbhe, Berkovic, Samuel F, Scheffer, Ingrid E, Poduri, Annapurna, Mei, Davide, Guerrini, Renzo, Lowenstein, Daniel H, Allen, Andrew S, Heinzen, Erin L, and Goldstein, David B

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

200. Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects

Author

Genetica Klinische Genetica, Brain, UMC Utrecht, Marini, Carla, Hardies, Katia, Pisano, Tiziana, May, Patrick, Weckhuysen, Sarah, Cellini, Elena, Suls, Arvid, Mei, Davide, Balling, Rudi, Jonghe, Peter D., Helbig, Ingo, Garozzo, Domenico, Guerrini, Renzo, Afawi, Zaid, Barišić, Nina, Baulac, Stéphanie, Brilstra, Eva H., Caglayan, Hande, Dana, Craiu, Hageman, Gerard, Helle, Hjalgrim, Jähn, Johanna, Klein, Karl Martin, Leguern, Eric, Lemke, Johannes R., Møller, Rikke S., Muhle, Hiltrud, Rosenow, Felix, Serratosa, Jose, Schelhaas, Jurgen H., Sterbova, Katalin, von Spiczak, Sarah, Szczepanik, Elzbieta, Yis, Uluc, Lerche, Holger, Striano, Pasquale, Weber, Yvonne, Zara, Federico, Genetica Klinische Genetica, Brain, UMC Utrecht, Marini, Carla, Hardies, Katia, Pisano, Tiziana, May, Patrick, Weckhuysen, Sarah, Cellini, Elena, Suls, Arvid, Mei, Davide, Balling, Rudi, Jonghe, Peter D., Helbig, Ingo, Garozzo, Domenico, Guerrini, Renzo, Afawi, Zaid, Barišić, Nina, Baulac, Stéphanie, Brilstra, Eva H., Caglayan, Hande, Dana, Craiu, Hageman, Gerard, Helle, Hjalgrim, Jähn, Johanna, Klein, Karl Martin, Leguern, Eric, Lemke, Johannes R., Møller, Rikke S., Muhle, Hiltrud, Rosenow, Felix, Serratosa, Jose, Schelhaas, Jurgen H., Sterbova, Katalin, von Spiczak, Sarah, Szczepanik, Elzbieta, Yis, Uluc, Lerche, Holger, Striano, Pasquale, Weber, Yvonne, and Zara, Federico

Published
2017

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