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1. Dominant NARS1 mutations causing axonal Charcot–Marie–Tooth disease expand NARS1-associated diseases.

Author: Beijer, Danique, Marte, Sheila, Li, Jiaxin C, Ridder, Willem De, Chen, Jessie Z, Tadenev, Abigail L D, Miers, Kathy E, Deconinck, Tine, Macdonell, Richard, Marques, Wilson, Jonghe, Peter De, Pratt, Samia L, Meyer-Schuman, Rebecca, Züchner, Stephan, Antonellis, Anthony, Burgess, Robert W, and Baets, Jonathan
Published: 2024
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2. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author: May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Dennis, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, De Jonghe, Peter, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerses, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, François, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-François, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Pauls, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L, Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Arfan Ikram, M, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thomas, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, Sonsma, Anja C.M., Jonghe, Peter De, and Ikram, M Arfan
Published: 2018
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3. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Author: Steward, Charles A., Roovers, Jolien, Suner, Marie-Marthe, Gonzalez, Jose M., Uszczynska-Ratajczak, Barbara, Pervouchine, Dmitri, Fitzgerald, Stephen, Viola, Margarida, Stamberger, Hannah, Hamdan, Fadi F., Ceulemans, Berten, Leroy, Patricia, Nava, Caroline, Lepine, Anne, Tapanari, Electra, Keiller, Don, Abbs, Stephen, Sanchis-Juan, Alba, Grozeva, Detelina, Rogers, Anthony S., Diekhans, Mark, Guigó, Roderic, Petryszak, Robert, Minassian, Berge A., Cavalleri, Gianpiero, Vitsios, Dimitrios, Petrovski, Slavé, Harrow, Jennifer, Flicek, Paul, Lucy Raymond, F., Lench, Nicholas J., Jonghe, Peter De, Mudge, Jonathan M., Weckhuysen, Sarah, Sisodiya, Sanjay M., and Frankish, Adam
Published: 2019
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4. Mutant HSPB8 causes protein aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal hereditary motor neuropathy patients

Author: Irobi, Joy, Holmgren, Anne, Winter, Vicky De, Asselbergh, Bob, Gettemans, Jan, Adriaensen, Dirk, Groote, Chantal Ceuterick-de, Coster, Rudy Van, Jonghe, Peter De, and Timmerman, Vincent
Published: 2012
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5. Sub-genic intolerance, ClinVar, and the epilepsies: A whole-exome sequencing study of 29,165 individuals

Author: Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, 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, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, 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, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, 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., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., 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, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., Goldstein, David B., Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Motelow, Joshua E., Povysil, Gundula, Dhindsa, Ryan S., Stanley, Kate E., Allen, Andrew S., Feng, Yen-Chen Anne, Howrigan, Daniel P., Abbott, Liam E., Tashman, Katherine, Cerrato, Felecia, Cusick, Caroline, Singh, Tarjinder, Heyne, Henrike, Byrnes, Andrea E., Churchhouse, Claire, Watts, Nick, Solomonson, Matthew, Lal, Dennis, Gupta, Namrata, Neale, Benjamin M., Cavalleri, Gianpiero L., Cossette, Patrick, Cotsapas, Chris, Jonghe, Peter De, 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, Weckhuysen, Sarah, Depondt, Chantal, Dlugos, Dennis J., Scheffer, Ingrid E., Striano, Pasquale, Freyer, Catharine, Krause, Roland, May, Patrick, McKenna, Kevin, Regan, Brigid M., Bennett, Caitlin A., Leu, Costin, Leech, Stephanie L., O’Brien, Terence J., Todaro, Marian, Stamberger, Hannah, Andrade, Danielle M., Ali, Quratulain Zulfiqar, Sadoway, Tara R., Krestel, Heinz, Schaller, André, Papacostas, Savvas S., Kousiappa, Ioanna, Tanteles, George A., Christou, Yiolanda, Štěrbová, Katalin, Vlčková, Markéta, Sedláčková, Lucie, Laššuthová, Petra, Klein, Karl Martin, Rosenow, Felix, Reif, Philipp S., Knake, Susanne, Neubauer, Bernd A., Zimprich, Friedrich, Feucht, Martha, Reinthaler, Eva M., Kunz, Wolfram S., Zsurka, Gábor, Surges, Rainer, Baumgartner, Tobias, Wrede, Randi Von, 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, Lauxmann, Stephan, Boßelmann, Christian, Kegele, Josua, Hengsbach, Christian, Rau, Sarah, Steinhoff, Bernhard J., Schulze-Bonhage, Andreas, Borggräfe, Ingo, Schankin, Christoph J., Schubert-Bast, Susanne, Schreiber, Herbert, Mayer, Thomas, Korinthenberg, Rudolf, Brockmann, Knut, Wolff, Markus, Dennig, Dieter, Madeleyn, Rene, Kälviäinen, Reetta, Saarela, Anni, Timonen, Oskari, Linnankivi, Tarja, Lehesjoki, Anna-Elina, Rheims, Sylvain, Lesca, Gaetan, Ryvlin, Philippe, Maillard, Louis, Valton, Luc, Derambure, Philippe, Bartolomei, Fabrice, Hirsch, Edouard, Michel, Véronique, Chassoux, Francine, Rees, Mark I., Chung, Seo-Kyung, Pickrell, William O., Powell, Robert, Baker, Mark D., Fonferko-Shadrach, Beata, Lawthom, Charlotte, Anderson, Joseph, 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., Delanty, Norman, Doherty, Colin P., Shukralla, Arif, El-Naggar, Hany, Widdess-Walsh, Peter, Barišić, Nina, Canafoglia, Laura, Franceschetti, Silvana, Castellotti, Barbara, Granata, Tiziana, Ragona, Francesca, Zara, Federico, Iacomino, Michele, Riva, Antonella, Madia, Francesca, Vari, Maria Stella, Salpietro, Vincenzo, Scala, Marcello, Mancardi, Maria Margherita, Nobili, Lino, Amadori, Elisabetta, Giacomini, Thea, Bisulli, Francesca, Pippucci, Tommaso, Licchetta, Laura, Minardi, Raffaella, Tinuper, Paolo, Muccioli, Lorenzo, Mostacci, Barbara, Gambardella, Antonio, Labate, Angelo, Annesi, Grazia, Manna, Lorella, Gagliardi, Monica, Parrini, Elena, Mei, Davide, Vetro, Annalisa, Bianchini, Claudia, Montomoli, Martino, Doccini, Viola, Barba, Carmen, Hirose, Shinichi, Ishii, Atsushi, Suzuki, Toshimitsu, Inoue, Yushi, Yamakawa, Kazuhiro, Beydoun, Ahmad, Nasreddine, Wassim, Zgheib, Nathalie Khoueiry, Tumiene, Birute, Utkus, Algirdas, Sadleir, Lynette G., King, Chontelle, Caglayan, S. Hande, Arslan, Mutluay, Yapıcı, Zuhal, Topaloglu, Pınar, Kara, Bulent, Yis, Uluc, Turkdogan, Dilsad, Gundogdu-Eken, Aslı, Bebek, Nerses, Tsai, Meng-Han, Ho, Chen-Jui, Lin, Chih-Hsiang, Lin, Kuang-Lin, Chou, I.-Jun, Poduri, Annapurna, Shiedley, Beth R., Shain, Catherine, Noebels, Jeffrey L., Goldman, Alicia, Busch, Robyn M., Jehi, Lara, Najm, Imad M., Ferguson, Lisa, Khoury, Jean, Glauser, Tracy A., Clark, Peggy O., 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, Greenberg, David A., Ellis, Colin A., Goldberg, Ethan, Helbig, Katherine L., Cosico, Mahgenn, Vaidiswaran, Priya, Fitch, Eryn, Berkovic, Samuel F., Lerche, Holger, Lowenstein, Daniel H., and Goldstein, David B.
Abstract: Summary Both mild and severe epilepsies are influenced by variants in the same genes, yet an explanation for the resulting phenotypic variation is unknown. As part of the ongoing Epi25 Collaboration, we performed a whole-exome sequencing analysis of 13,487 epilepsy-affected individuals and 15,678 control individuals. While prior Epi25 studies focused on gene-based collapsing analyses, we asked how the pattern of variation within genes differs by epilepsy type. Specifically, we compared the genetic architectures of severe developmental and epileptic encephalopathies (DEEs) and two generally less severe epilepsies, genetic generalized epilepsy and non-acquired focal epilepsy (NAFE). Our gene-based rare variant collapsing analysis used geographic ancestry-based clustering that included broader ancestries than previously possible and revealed novel associations. Using the missense intolerance ratio (MTR), we found that variants in DEE-affected individuals are in significantly more intolerant genic sub-regions than those in NAFE-affected individuals. Only previously reported pathogenic variants absent in available genomic datasets showed a significant burden in epilepsy-affected individuals compared with control individuals, and the ultra-rare pathogenic variants associated with DEE were located in more intolerant genic sub-regions than variants associated with non-DEE epilepsies. MTR filtering improved the yield of ultra-rare pathogenic variants in affected individuals compared with control individuals. Finally, analysis of variants in genes without a disease association revealed a significant burden of loss-of-function variants in the genes most intolerant to such variation, indicating additional epilepsy-risk genes yet to be discovered. Taken together, our study suggests that genic and sub-genic intolerance are critical characteristics for interpreting the effects of variation in genes that influence epilepsy.
Published: 2021

6. Mutations in the ER-shaping protein reticulon 2 cause the axon-degenerative disorder hereditary spastic paraplegia type 12

Author: Montenegro, Gladys, Rebelo, Adriana P., Connell, James, Allison, Rachel, Babalini, Carla, D'Aloia, Michela, Montieri, Pasqua, Schule, Rebecca, Ishiura, Hiroyuki, Price, Justin, Strickland, Alleene, Gonzalez, Michael A., Baumbach-Reardon, Lisa, Deconinck, Tine, Huang, Jia, Bernardi, Giorgio, Vance, Jeffery M., Rogers, Mark T., Tsuji, Shoji, Jonghe, Peter De, Pericak-Vance, Margaret A., Schols, Ludger, Orlacchio, Antonio, Reid, Evan, and Zuchner, Stephan
Subjects: Gene mutations -- Health aspects, Heat shock proteins -- Physiological aspects -- Genetic aspects -- Research, Paralysis, Spastic -- Genetic aspects -- Risk factors -- Research, Health care industry
Abstract: Hereditary spastic paraplegias (HSPs) are a group of genetically heterogeneous neurodegenerative conditions. They are characterized by progressive spastic paralysis of the legs as a result of selective, length-dependent degeneration of the axons of the corticospinal tract. Mutations in 3 genes encoding proteins that work together to shape the ER into sheets and tubules--receptor accessory protein 1 (REEP1), atlastin-1 (ATL1), and spastin (SPAST)--have been found to underlie many cases of HSP in Northern Europe and North America. Applying Sanger and exome sequencing, we have now identified 3 mutations in reticulon 2 (RTN2), which encodes a member of the reticulon family of prototypic ER-shaping proteins, in families with spastic paraplegia 12 (SPG12). These autosomal dominant mutations included a complete deletion of RTN2 and a frameshift mutation predicted to produce a highly truncated protein. Wild-type reticulon 2, but not the truncated protein potentially encoded by the frameshift allele, localized to the ER. RTN2 interacted with spastin, and this interaction required a hydrophobic region in spastin that is involved in ER localization and that is predicted to form a curvature-inducing/sensing hairpin loop domain. Our results directly implicate a reticulon protein in axonopathy, show that this protein participates in a network of interactions among HSP proteins involved in ER shaping, and further support the hypothesis that abnormal ER morphogenesis is a pathogenic mechanism in HSP., Introduction The ER is a continuous membrane system comprising the nuclear envelope and a dynamic network of proximal sheets and peripheral tubules. Proteins of 2 classes--the reticulons and the REEP/DP1/yop1p [...]
Published: 2012
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7. De novo FZR1 loss-of-function variants cause developmental and epileptic encephalopathies.

Author: Manivannan, Sathiya N, Roovers, Jolien, Smal, Noor, Myers, Candace T, Turkdogan, Dilsad, Roelens, Filip, Kanca, Oguz, Chung, Hyung-Lok, Scholz, Tasja, Hermann, Katharina, Bierhals, Tatjana, Caglayan, Hande S, Stamberger, Hannah, Consortium, MAE Working Group of EuroEPINOMICS RES, Mefford, Heather, Jonghe, Peter de, Yamamoto, Shinya, Weckhuysen, Sarah, Bellen, Hugo J, and MAE Working Group of EuroEPINOMICS RES Consortium
Subjects: RESEARCH, EPILEPSY, CRANIOFACIAL abnormalities, CELL cycle proteins, EVALUATION research, COMPARATIVE studies, RESEARCH funding, PHENOTYPES, ATAXIA
Abstract: FZR1, which encodes the Cdh1 subunit of the anaphase-promoting complex, plays an important role in neurodevelopment by regulating the cell cycle and by its multiple post-mitotic functions in neurons. In this study, evaluation of 250 unrelated patients with developmental and epileptic encephalopathies and a connection on GeneMatcher led to the identification of three de novo missense variants in FZR1. Whole-exome sequencing in 39 patient-parent trios and subsequent targeted sequencing in an additional cohort of 211 patients was performed to identify novel genes involved in developmental and epileptic encephalopathy. Functional studies in Drosophila were performed using three different mutant alleles of the Drosophila homologue of FZR1 fzr. All three individuals carrying de novo variants in FZR1 had childhood-onset generalized epilepsy, intellectual disability, mild ataxia and normal head circumference. Two individuals were diagnosed with the developmental and epileptic encephalopathy subtype myoclonic atonic epilepsy. We provide genetic-association testing using two independent statistical tests to support FZR1 association with developmental and epileptic encephalopathies. Further, we provide functional evidence that the missense variants are loss-of-function alleles using Drosophila neurodevelopment assays. Using three fly mutant alleles of the Drosophila homologue fzr and overexpression studies, we show that patient variants can affect proper neurodevelopment. With the recent report of a patient with neonatal-onset with microcephaly who also carries a de novo FZR1 missense variant, our study consolidates the relationship between FZR1 and developmental and epileptic encephalopathy and expands the associated phenotype. We conclude that heterozygous loss-of-function of FZR1 leads to developmental and epileptic encephalopathies associated with a spectrum of neonatal to childhood-onset seizure types, developmental delay and mild ataxia. Microcephaly can be present but is not an essential feature of FZR1-encephalopathy. In summary, our approach of targeted sequencing using novel gene candidates and functional testing in Drosophila will help solve undiagnosed myoclonic atonic epilepsy or developmental and epileptic encephalopathy cases. [ABSTRACT FROM AUTHOR]
Published: 2022
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8. Additional file 1 of Gene family information facilitates variant interpretation and identification of disease-associated genes in neurodevelopmental disorders

Author: Lal, Dennis, May, Patrick, Perez-Palma, Eduardo, Samocha, Kaitlin E., Kosmicki, Jack A., Robinson, Elise B., Møller, Rikke S., Krause, Roland, Nürnberg, Peter, Weckhuysen, Sarah, Jonghe, Peter De, Guerrini, Renzo, Niestroj, Lisa M., Du, Juliana, Marini, Carla, Ware, James S., Kurki, Mitja, Padhraig Gormley, Tang, Sha, Sitao Wu, Biskup, Saskia, Annapurna Poduri, Neubauer, Bernd A., Koeleman, Bobby P. C., Helbig, Katherine L., Weber, Yvonne G., Helbig, Ingo, Majithia, Amit R., Palotie, Aarno, and Daly, Mark J.
Subjects: ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, ComputingMilieux_COMPUTERSANDEDUCATION, Data_FILES, ComputerApplications_COMPUTERSINOTHERSYSTEMS
Abstract: Additional file 1: Supplementary methods, figures, and table.
Published: 2020
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9. Clinico-genetic, imaging and molecular delineation of COQ8A-ataxia: a multicenter study of 59 patients

Author: Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Traschuetz, Andreas; Schirinzi, Tommaso; Laugwitz, Lucia; Murray, Nathan H.; Bingman, Craig A.; Reich, Selina; Kern, Jan; Heinzmann, Anna; Vasco, Gessica; Bertini, Enrico; Zanni, Ginevra; Durr, Alexandra; Magri, Stefania; Taroni, Franco; Malandrini, Alessandro; Baets, Jonathan; de Jonghe, Peter; de Ridder, Willem; Bereau, Matthieu; Demuth, Stephanie; Ganos, Christos; Hanagasi, Hasmet; Kurul, Semra Hız; Bender, Benjamin; Schoels, Ludger; Grasshoff, Ute; Klopstock, Thomas; Horvath, Rita; van de Warrenburg, Bart; Burglen, Lydie; Rougeot, Christelle; Ewenczyk, Claire; Koenig, Michel; Santorelli, Filippo M.; Anheim, Mathieu; Munhoz, Renato P.; Haack, Tobias; Distelmaier, Felix; Pagliarini, David J.; Puccio, Helene; Synofzik, Matthis, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine, Başak, Ayşe Nazlı (ORCID 0000-0001-9257-3540 & YÖK ID 1512), Traschuetz, Andreas; Schirinzi, Tommaso; Laugwitz, Lucia; Murray, Nathan H.; Bingman, Craig A.; Reich, Selina; Kern, Jan; Heinzmann, Anna; Vasco, Gessica; Bertini, Enrico; Zanni, Ginevra; Durr, Alexandra; Magri, Stefania; Taroni, Franco; Malandrini, Alessandro; Baets, Jonathan; de Jonghe, Peter; de Ridder, Willem; Bereau, Matthieu; Demuth, Stephanie; Ganos, Christos; Hanagasi, Hasmet; Kurul, Semra Hız; Bender, Benjamin; Schoels, Ludger; Grasshoff, Ute; Klopstock, Thomas; Horvath, Rita; van de Warrenburg, Bart; Burglen, Lydie; Rougeot, Christelle; Ewenczyk, Claire; Koenig, Michel; Santorelli, Filippo M.; Anheim, Mathieu; Munhoz, Renato P.; Haack, Tobias; Distelmaier, Felix; Pagliarini, David J.; Puccio, Helene; Synofzik, Matthis, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine
Abstract: Objective: to foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). Methods: cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. Results: fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that >= 48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. Interpretation: this study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia., European Union (European Union); Horizon 2020; European Union's Horizon 2020 Research and Innovation Program by the BMBF, E-Rare-3 network PREPARE; European Union's Horizon 2020 Research and Innovation Program, Solve-RD; German Bundesministerium fur Bildung und Forschung (BMBF), in der Systemmedizin "mitOmics; University of Tubingen, Medical Faculty, for the Clinician Scientist; Italian Ministry of Health; German Research Foundation/Deutsche Forschungsgemeinschaft; NIH; NSF; Wellcome Trust Investigator; ; Medical Research Council (UK); European Research Council (ERC); Wellcome Trust Pathfinder Scheme; Newton Fund; Senior Clinical Researcher mandate of the Research Fund - Flanders (FWO); ZonMW, Hersenstichting, Gossweiler Foundation; Radboud University Medical Centre; VolkswagenStiftung (Freigeist Fellowship; Deutsche Forschungsgemeinschaft; German Parkinson Society and Actelion Pharmaceuticals; Italian Ministry of Health Ricerca Finalizzata Suna and İnan Kıraç Foundation and Koç University School of Medicine
Published: 2020

10. Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies

Author: Zimoń, Magdalena, Baets, Jonathan, Auer-Grumbach, Michaela, Berciano, José, Garcia, Antonio, Lopez-Laso, Eduardo, Merlini, Luciano, Hilton-Jones, David, McEntagart, Meriel, Crosby, Andrew H., Barisic, Nina, Boltshauser, Eugen, Shaw, Christopher E., Landouré, Guida, Ludlow, Christy L., Gaudet, Rachelle, Houlden, Henry, Reilly, Mary M., Fischbeck, Kenneth H., Sumner, Charlotte J., Timmerman, Vincent, Jordanova, Albena, and Jonghe, Peter De
Published: 2010
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11. Diagnostic implications of genetic copy number variation in epilepsy plus

Author: Coppola, Antonietta, Cellini, Elena, Stamberger, Hannah, Saarentaus, Elmo, Cetica, Valentina, Lal, Dennis, Djemie, Tania, Bartnik-Glaska, Magdalena, Ceulemans, Berten, Cross, J. Helen, Deconinck, Tine, De Masi, Salvatore, Dorn, Thomas, Guerrini, Renzo, Hoffman-Zacharska, Dorotha, Kooy, Frank, Lagae, Lieven, Lench, Nicholas, Lemke, Johannes R., Lucenteforte, Ersilia, Madia, Francesca, Mefford, Heather C., Morrogh, Deborah, Nuernberg, Peter, Palotie, Aarno, Schoonjans, An-Sofie, Striano, Pasquale, Szczepanik, Elzbieta, Tostevin, Anna, Vermeesch, Joris R., Van Esch, Hilde, Van Paesschen, Wim, Waters, Jonathan J., Weckhuysen, Sarah, Zara, Federico, Jonghe, Peter De, Sisodiya, Sanjay M., Marini, Carla, Moller, Rikke S., and Hjalgrim, Helle
Subjects: epilepsy genes, Phenotype, Genotype, DNA Copy Number Variations, mental disorders, array CGH, Humans, Genetic Predisposition to Disease, Comorbidity, SNP array, Epilepsy/complications, copy number variants
Abstract: Objective: Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods: We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results: Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10 −9). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance: The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.
Published: 2019

12. Genes and Loci Involved in Febrile Seizures and Related Epilepsy Syndromes

Author: Audenaert, Dominique, Van Broeckhoven, Christine, and Jonghe, Peter De
Published: 2006
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13. 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

14. novoSNP, a novel computational tool for sequence variation discovery

Author: Weckx, Stefan, Rademakers, Rosa, Claes, Lieve, Jonghe, Peter De, Rijk, Peter De, Del-Favero, Jurgen, Cruts, Marc, and Broeckhoven, Christine Van
Subjects: Genetic markers -- Research, Single nucleotide polymorphisms -- Research, Nucleotide sequence -- Research, Genetic research, Health
Abstract: A software package called the novoSNP that provides a fast, reliable, and accurate strategy for the discovery of single nucleotide polymorphisms (SNPs) and insertion-deletion polymorphisms (INDELs) from sequence trace files are developed. Sequence-variation-finding programs like Polyphred and PolyBayes have shown limitations regarding correct SNP and/or INDEL discovery.
Published: 2005

15. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Author: Wiessner, Manuela, Maroofian, Reza, Ni, Meng-Yuan, Pedroni, Andrea, Müller, Juliane S, Stucka, Rolf, Beetz, Christian, Efthymiou, Stephanie, Santorelli, Filippo M, Alfares, Ahmed A, Zhu, Changlian, Meszarosova, Anna Uhrova, Alehabib, Elham, Bakhtiari, Somayeh, Janecke, Andreas R, Otero, Maria Gabriela, Chen, Jin Yun Helen, Peterson, James T, Strom, Tim M, and Jonghe, Peter De
Subjects: FAMILIAL spastic paraplegia, NEUROLOGICAL disorders, NERVOUS system, JUVENILE diseases, DEVELOPMENTAL delay, RESEARCH, GENETIC mutation, ANIMAL experimentation, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, RATS, COMPARATIVE studies, FISHES, RESEARCH funding, OXIDOREDUCTASES, GENETIC techniques, MICE, GENEALOGY
Abstract: Human 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) is a putative iron-containing non-heme oxygenase of unknown specificity and biological significance. We report 25 families containing 34 individuals with neurological disease associated with biallelic HPDL variants. Phenotypes ranged from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spasticity and global developmental delays, sometimes complicated by episodes of neurological and respiratory decompensation. Variants included bona fide pathogenic truncating changes, although most were missense substitutions. Functionality of variants could not be determined directly as the enzymatic specificity of HPDL is unknown; however, when HPDL missense substitutions were introduced into 4-hydroxyphenylpyruvate dioxygenase (HPPD, an HPDL orthologue), they impaired the ability of HPPD to convert 4-hydroxyphenylpyruvate into homogentisate. Moreover, three additional sets of experiments provided evidence for a role of HPDL in the nervous system and further supported its link to neurological disease: (i) HPDL was expressed in the nervous system and expression increased during neural differentiation; (ii) knockdown of zebrafish hpdl led to abnormal motor behaviour, replicating aspects of the human disease; and (iii) HPDL localized to mitochondria, consistent with mitochondrial disease that is often associated with neurological manifestations. Our findings suggest that biallelic HPDL variants cause a syndrome varying from juvenile-onset pure hereditary spastic paraplegia to infantile-onset spastic tetraplegia associated with global developmental delays. [ABSTRACT FROM AUTHOR]
Published: 2021
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16. Additional file 1: Table S1. of Sporadic late-onset nemaline myopathy: clinico-pathological characteristics and review of 76 cases

Author: Schnitzler, Lukas, Schreckenbach, Tobias, Nadaj-Pakleza, Aleksandra, Stenzel, Werner, Rushing, Elisabeth, Damme, Philip Van, Ferbert, Andreas, Petri, Susanne, Hartmann, Christian, Bornemann, Antje, Meisel, Andreas, Petersen, Jens, Tousseyn, Thomas, Thal, Dietmar, Reimann, Jens, Jonghe, Peter De, Jean-Jacques Martin, Bergh, Peter Van Den, JĂśrg Schulz, Weis, Joachim, and Claeys, Kristl
Abstract: Genetic variants identified in patients with SLONM using NGS and a panel of 283 genes. (DOC 72 kb)
Published: 2017
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17. Additional file 1: of STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations

Author: Hayer, Stefanie, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, ZĂźchner, Stephan, Reich, Selina, SchĂśls, Ludger, SchĂźle, Rebecca, Jonghe, Peter De, Baets, Jonathan, and Synofzik, Matthis
Abstract: Protein network analysis. (DOCX 1176Â kb)
Published: 2017
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18. Additional file 2: of STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations

Author: Hayer, Stefanie, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, Züchner, Stephan, Reich, Selina, Schöls, Ludger, Schüle, Rebecca, Jonghe, Peter De, Baets, Jonathan, and Synofzik, Matthis
Abstract: Western blots of CHIP in mutation carriers. (DOCX 241 kb)
Published: 2017
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19. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies.

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], Appenzeller, Silke, Balling, Rudi, Barisic, Nina, Baulac, Stéphanie, Caglayan, Hande, Craiu, Dana, Jonghe, Peter De, Depienne, Christel, Dimova, Petia, Djémié, Tania, Gormley, Padhraig, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jähn, Johanna, Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Kuhlenbäumer, Gregor, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R., Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Møller, Rikke S., Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Pendziwiat, Manuela, Robbiano, Angela, Roelens, Filip, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M., Sisodiya, Sanjay, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, Spiczak, Sarah Von, Weber, Yvonne, Weckhuysen, Sarah, Zara, Federico, Abou-Khalil, Bassel, Alldredge, Brian K., Andermann, Eva, Andermann, Frederick, Amrom, Dina, Bautista, Jocelyn F., Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Cascino, Gregory, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Fiol, Miguel, Fountain, Nathan B., French, Jacqueline, Friedman, Daniel, Geller, Eric B., Glauser, Tracy, Glynn, Simon, Haas, Kevin, Haut, Sheryl R., Hayward, Jean, Helmers, Sandra L., Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Knowlton, Robert C., Kossoff, Eric H., Kuperman, Rachel, Kuzniecky, Ruben, Lowenstein, Daniel H., McGuire, Shannon M., Motika, Paul V., Novotny, Edward J., Ottman, Ruth, Paolicchi, Juliann M., Parent, Jack, Park, Kristen, Poduri, Annapurna, Sadleir, Lynette, Scheffer, Ingrid E., Shellhaas, Renée A., Sherr, Elliott, Shih, Jerry J., Singh, Rani, Sirven, Joseph, Smith, Michael C., Sullivan, Joe, Thio, Liu Lin, Venkat, Anu, Vining, Eileen P. G., Allmen, Gretchen K. Von, Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Allen, Andrew S., Cossette, Patrick, Delanty, Norman, Eichler, Evan E., Goldstein, David B., Han, Yujun, Heinzen, Erin L., Johnson, Michael R., Marson, Anthony G., Mefford, Heather C., Nieh, Sahar Esmaeeli, O’Brien, Terence J., Petrou, Stephen, Petrovski, Slavé, Ruzzo, Elizabeth K., 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], Appenzeller, Silke, Balling, Rudi, Barisic, Nina, Baulac, Stéphanie, Caglayan, Hande, Craiu, Dana, Jonghe, Peter De, Depienne, Christel, Dimova, Petia, Djémié, Tania, Gormley, Padhraig, Guerrini, Renzo, Helbig, Ingo, Hjalgrim, Helle, Hoffman-Zacharska, Dorota, Jähn, Johanna, Klein, Karl Martin, Koeleman, Bobby, Komarek, Vladimir, Krause, Roland, Kuhlenbäumer, Gregor, Leguern, Eric, Lehesjoki, Anna-Elina, Lemke, Johannes R., Lerche, Holger, Linnankivi, Tarja, Marini, Carla, May, Patrick, Møller, Rikke S., Muhle, Hiltrud, Pal, Deb, Palotie, Aarno, Pendziwiat, Manuela, Robbiano, Angela, Roelens, Filip, Rosenow, Felix, Selmer, Kaja, Serratosa, Jose M., Sisodiya, Sanjay, Stephani, Ulrich, Sterbova, Katalin, Striano, Pasquale, Suls, Arvid, Talvik, Tiina, Spiczak, Sarah Von, Weber, Yvonne, Weckhuysen, Sarah, Zara, Federico, Abou-Khalil, Bassel, Alldredge, Brian K., Andermann, Eva, Andermann, Frederick, Amrom, Dina, Bautista, Jocelyn F., Berkovic, Samuel F., Bluvstein, Judith, Boro, Alex, Cascino, Gregory, Consalvo, Damian, Crumrine, Patricia, Devinsky, Orrin, Dlugos, Dennis, Epstein, Michael P., Fiol, Miguel, Fountain, Nathan B., French, Jacqueline, Friedman, Daniel, Geller, Eric B., Glauser, Tracy, Glynn, Simon, Haas, Kevin, Haut, Sheryl R., Hayward, Jean, Helmers, Sandra L., Joshi, Sucheta, Kanner, Andres, Kirsch, Heidi E., Knowlton, Robert C., Kossoff, Eric H., Kuperman, Rachel, Kuzniecky, Ruben, Lowenstein, Daniel H., McGuire, Shannon M., Motika, Paul V., Novotny, Edward J., Ottman, Ruth, Paolicchi, Juliann M., Parent, Jack, Park, Kristen, Poduri, Annapurna, Sadleir, Lynette, Scheffer, Ingrid E., Shellhaas, Renée A., Sherr, Elliott, Shih, Jerry J., Singh, Rani, Sirven, Joseph, Smith, Michael C., Sullivan, Joe, Thio, Liu Lin, Venkat, Anu, Vining, Eileen P. G., Allmen, Gretchen K. Von, Weisenberg, Judith L., Widdess-Walsh, Peter, Winawer, Melodie R., Allen, Andrew S., Cossette, Patrick, Delanty, Norman, Eichler, Evan E., Goldstein, David B., Han, Yujun, Heinzen, Erin L., Johnson, Michael R., Marson, Anthony G., Mefford, Heather C., Nieh, Sahar Esmaeeli, O’Brien, Terence J., Petrou, Stephen, Petrovski, Slavé, and Ruzzo, Elizabeth K.
Abstract: In the list of consortium members for the Epilepsy Phenome/Genome Project, member Dina Amrom’s name was misspelled as Amron. The authors regret the error.
Published: 2017

20. Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies

Author: Zimoń, Magdalena, Baets, Jonathan, Auer-Grumbach, Michaela, Berciano, José, Garcia, Antonio, Lopez-Laso, Eduardo, Merlini, Luciano, Hilton-Jones, David, McEntagart, Meriel, Crosby, Andrew H., Barisic, Nina, Boltshauser, Eugen, Shaw, Christopher E., Landouré, Guida, Ludlow, Christy L., Gaudet, Rachelle, Houlden, Henry, Reilly, Mary M., Fischbeck, Kenneth H., Sumner, Charlotte J., Timmerman, Vincent, Jordanova, Albena, Jonghe, Peter De, Zimoń, Magdalena, Baets, Jonathan, Auer-Grumbach, Michaela, Berciano, José, Garcia, Antonio, Lopez-Laso, Eduardo, Merlini, Luciano, Hilton-Jones, David, McEntagart, Meriel, Crosby, Andrew H., Barisic, Nina, Boltshauser, Eugen, Shaw, Christopher E., Landouré, Guida, Ludlow, Christy L., Gaudet, Rachelle, Houlden, Henry, Reilly, Mary M., Fischbeck, Kenneth H., Sumner, Charlotte J., Timmerman, Vincent, Jordanova, Albena, and Jonghe, Peter De
Abstract: Hereditary neuropathies form a heterogeneous group of disorders for which over 40 causal genes have been identified to date. Recently, dominant mutations in the transient receptor potential vanilloid 4 gene were found to be associated with three distinct neuromuscular phenotypes: hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. Transient receptor potential vanilloid 4 encodes a cation channel previously implicated in several types of dominantly inherited bone dysplasia syndromes. We performed DNA sequencing of the coding regions of transient receptor potential vanilloid 4 in a cohort of 145 patients with various types of hereditary neuropathy and identified five different heterozygous missense mutations in eight unrelated families. One mutation arose de novo in an isolated patient, and the remainder segregated in families. Two of the mutations were recurrent in unrelated families. Four mutations in transient receptor potential vanilloid 4 targeted conserved arginine residues in the ankyrin repeat domain, which is believed to be important in protein-protein interactions. Striking phenotypic variability between and within families was observed. The majority of patients displayed a predominantly, or pure, motor neuropathy with axonal characteristics observed on electrophysiological testing. The age of onset varied widely, ranging from congenital to late adulthood onset. Various combinations of additional features were present in most patients including vocal fold paralysis, scapular weakness, contractures and hearing loss. We identified six asymptomatic mutation carriers, indicating reduced penetrance of the transient receptor potential vanilloid 4 defects. This finding is relatively unusual in the context of hereditary neuropathies and has important implications for diagnostic testing and genetic counselling
Published: 2017

21. Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy.

Author: Beijer, Danique, Deconinck, Tine, Bleecker, Jan L De, Dotti, Maria Teresa, Malandrini, Alessandro, Urtizberea, J Andoni, Zulaica, Miren, Munain, Adolfo López de, Asselbergh, Bob, Jonghe, Peter De, Baets, Jonathan, De Bleecker, Jan L, López de Munain, Adolfo, and De Jonghe, Peter
Subjects: NONSENSE mutation, LEBER'S hereditary optic atrophy, SPECTRIN, MOTOR neurons, SENSORY neurons, NEUROPATHY
Abstract: Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the αII-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative αII-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes. [ABSTRACT FROM AUTHOR]
Published: 2019
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22. Burden analysis of rare microdeletions suggests a strong impact of neurodevelopmental genes in genetic generalised epilepsies

Author: Lal, Dennis, Ruppert, Ann-Kathrin, Trucks, Holger, Schulz, Herbert, Kovel, Carolien G. de, Kasteleijn-Nolst Trenité, Dorothée G., Sonsma, Anja C. M., Koeleman, Bobby P., Lindhout, Dick, Weber, Yvonne G., Lerche, Holger, Kapser, Claudia, Schankin, Christoph Josef, Kunz, Wolfram S., Surges, Rainer, Elger, Christian Erich, Gaus, Verena, Schmitz, Bettina, Helbig, Ingo, Muhle, Hiltrud, Stephani, Ulrich, Klein, Karl Martin, Rosenow, Felix, Neubauer, Bernd Axel, Reinthaler, Eva Maria, Zimprich, Fritz, Feucht, Martha, Møller, Rikke S., Hjalgrim, Helle, Jonghe, Peter De, Suls, Arvid, Lieb, Wolfgang, Franke, Andre, Strauch, Konstantin, Gieger, Christian, Schurmann, Claudia, Schminke, Ulf, Nürnberg, Peter, Sander, Thomas, Lal, Dennis, Ruppert, Ann-Kathrin, Trucks, Holger, Schulz, Herbert, Kovel, Carolien G. de, Kasteleijn-Nolst Trenité, Dorothée G., Sonsma, Anja C. M., Koeleman, Bobby P., Lindhout, Dick, Weber, Yvonne G., Lerche, Holger, Kapser, Claudia, Schankin, Christoph Josef, Kunz, Wolfram S., Surges, Rainer, Elger, Christian Erich, Gaus, Verena, Schmitz, Bettina, Helbig, Ingo, Muhle, Hiltrud, Stephani, Ulrich, Klein, Karl Martin, Rosenow, Felix, Neubauer, Bernd Axel, Reinthaler, Eva Maria, Zimprich, Fritz, Feucht, Martha, Møller, Rikke S., Hjalgrim, Helle, Jonghe, Peter De, Suls, Arvid, Lieb, Wolfgang, Franke, Andre, Strauch, Konstantin, Gieger, Christian, Schurmann, Claudia, Schminke, Ulf, Nürnberg, Peter, and Sander, Thomas
Abstract: Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
Published: 2015

23. GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia.

Author: Eidhof, Ilse, Baets, Jonathan, Kamsteeg, Erik-Jan, Deconinck, Tine, Ninhuijs, Lisa van, Martin, Jean-Jacques, Schüle, Rebecca, Züchner, Stephan, Jonghe, Peter De, Schenck, Annette, van Ninhuijs, Lisa, De Jonghe, Peter, and van de Warrenburg, Bart P
Subjects: CEREBELLAR ataxia, SPASTICITY, DROSOPHILA melanogaster genetics, DEMENTIA, GENETIC mutation, EXOMES, GENETICS, CEREBELLUM physiology, INSECT physiology, ANIMAL experimentation, ATAXIA, COMPARATIVE studies, DISEASE susceptibility, GENES, GENETIC techniques, INSECTS, RESEARCH methodology, MEDICAL cooperation, NERVE tissue proteins, PROTEINS, RESEARCH, PHYSIOLOGICAL stress, PHENOTYPES, EVALUATION research
Abstract: Autosomal recessive cerebellar ataxias are a group of rare disorders that share progressive degeneration of the cerebellum and associated tracts as the main hallmark. Here, we report two unrelated patients with a new subtype of autosomal recessive cerebellar ataxia caused by biallelic, gene-disruptive mutations in GDAP2, a gene previously not implicated in disease. Both patients had onset of ataxia in the fourth decade. Other features included progressive spasticity and dementia. Neuropathological examination showed degenerative changes in the cerebellum, olive inferior, thalamus, substantia nigra, and pyramidal tracts, as well as tau pathology in the hippocampus and amygdala. To provide further evidence for a causative role of GDAP2 mutations in autosomal recessive cerebellar ataxia pathophysiology, its orthologous gene was investigated in the fruit fly Drosophila melanogaster. Ubiquitous knockdown of Drosophila Gdap2 resulted in shortened lifespan and motor behaviour anomalies such as righting defects, reduced and uncoordinated walking behaviour, and compromised flight. Gdap2 expression levels responded to stress treatments in control flies, and Gdap2 knockdown flies showed increased sensitivity to deleterious effects of stressors such as reactive oxygen species and nutrient deprivation. Thus, Gdap2 knockdown in Drosophila and GDAP2 loss-of-function mutations in humans lead to locomotor phenotypes, which may be mediated by altered responses to cellular stress. [ABSTRACT FROM AUTHOR]
Published: 2018
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24. Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis

Author: Bogaert, Elke, Goris, An, Van Damme, Philip, Geelen, Veerle, Lemmens, Robin, van Es, Michael A, van den Berg, Leonard H, Sleegers, Kristel, Verpoorten, Nathalie, Timmerman, Vincent, Jonghe, Peter De, Van Broeckhoven, Christine, Traynor, Bryan J, Landers, John E, Brown, Robert H, Glass, Jonathan D, Al-Chalabi, Ammar, Shaw, Christopher E, Birve, Anna, Andersen, Peter M, Slowik, Agnieszka, Tomik, Barbara, Melki, Judith, Robberecht, Wim, Van Den Bosch, Ludo, Bogaert, Elke, Goris, An, Van Damme, Philip, Geelen, Veerle, Lemmens, Robin, van Es, Michael A, van den Berg, Leonard H, Sleegers, Kristel, Verpoorten, Nathalie, Timmerman, Vincent, Jonghe, Peter De, Van Broeckhoven, Christine, Traynor, Bryan J, Landers, John E, Brown, Robert H, Glass, Jonathan D, Al-Chalabi, Ammar, Shaw, Christopher E, Birve, Anna, Andersen, Peter M, Slowik, Agnieszka, Tomik, Barbara, Melki, Judith, Robberecht, Wim, and Van Den Bosch, Ludo
Abstract: Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca(2+) permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no nonsynonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility, age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.
Published: 2012
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25. Peripheral neuropathy and 46XY gonadal dysgenesis: A heterogeneous entity

Author: Baets, Jonathan, Dierick, Ines, Groote, Chantal Ceuterick-de, Ende, Jenneke van den, Martin, Jean-Jacques, Geens, Karin, Robberecht, Wim, Nelis, Eva, Timmerman, Vincent, and Jonghe, Peter De
Published: 2009
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26. Pelizaeus-Merzbacher–Like Disease in a Family With Variable Phenotype and a Novel Splicing GJC2 Mutation

Author: Al-Yahyaee, Said Ali, primary, Al-Kindi, Mohammed, additional, Jonghe, Peter De, additional, Al-Asmi, Abdulah, additional, Al-Futaisi, Amna, additional, Vriendt, Els De, additional, Deconinck, Tine, additional, and Chand, Pratap, additional
Published: 2012
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27. Simultaneous mutation and copy number variation (CNV) detection by multiplex PCR-based GS-FLX sequencing

Author: Goossens, Dirk, primary, Moens, Lotte N., additional, Nelis, Eva, additional, Lenaerts, An-Sofie, additional, Glassee, Wim, additional, Kalbe, Andreas, additional, Frey, Bruno, additional, Kopal, Guido, additional, Jonghe, Peter De, additional, Rijk, Peter De, additional, and Del-Favero, Jurgen, additional
Published: 2008
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28. Genotype–phenotype analysis in patients with giant axonal neuropathy (GAN)

Author: Koop, Olga, primary, Schirmacher, Anja, additional, Nelis, Eva, additional, Timmerman, Vincent, additional, Jonghe, Peter De, additional, Ringelstein, Bernd, additional, Rasic, Vedrana Milic, additional, Evrard, Philippe, additional, Gärtner, Jutta, additional, Claeys, Kristl G., additional, Appenzeller, Silke, additional, Rautenstrauss, Bernd, additional, Hühne, Kathrin, additional, Ramos-Arroyo, Maria A., additional, Wörle, Helmut, additional, Moilanen, Jukka S., additional, Hammans, Simon, additional, and Kuhlenbäumer, Gregor, additional
Published: 2007
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29. Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV

Author: Verpoorten, Nathalie, primary, Claeys, Kristl G., additional, Deprez, Liesbet, additional, Jacobs, An, additional, Gerwen, Veerle Van, additional, Lagae, Lieven, additional, Arts, Willem Frans, additional, Meirleir, Linda De, additional, Keymolen, Kathelijn, additional, Groote, Chantal Ceuterick-de, additional, Jonghe, Peter De, additional, Timmerman, Vincent, additional, and Nelis, Eva, additional
Published: 2006
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30. Mutations in SEPT9 cause hereditary neuralgic amyotrophy

Author: Kuhlenbäumer, Gregor, primary, Hannibal, Mark C, additional, Nelis, Eva, additional, Schirmacher, Anja, additional, Verpoorten, Nathalie, additional, Meuleman, Jan, additional, Watts, Giles D J, additional, Vriendt, Els De, additional, Young, Peter, additional, Stögbauer, Florian, additional, Halfter, Hartmut, additional, Irobi, Joy, additional, Goossens, Dirk, additional, Del-Favero, Jurgen, additional, Betz, Benjamin G, additional, Hor, Hyun, additional, Kurlemann, Gert, additional, Bird, Thomas D, additional, Airaksinen, Eila, additional, Mononen, Tarja, additional, Serradell, Adolfo Pou, additional, Prats, José M, additional, Broeckhoven, Christine Van, additional, Jonghe, Peter De, additional, Timmerman, Vincent, additional, Ringelstein, E Bernd, additional, and Chance, Phillip F, additional
Published: 2005
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31. Absence of mutations in the prion-protein gene in a large cohort of HMSN patients

Author: Koop, Olga, primary, Timmerman, Vincent, additional, Jonghe, Peter de, additional, Ringelstein, Bernd, additional, Young, Peter, additional, and Kuhlenbäumer, Gregor, additional
Published: 2005
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32. Mutations in the pleckstrin homology domain of dynamin 2 cause dominant intermediate Charcot-Marie-Tooth disease

Author: Züchner, Stephan, primary, Noureddine, Maher, additional, Kennerson, Marina, additional, Verhoeven, Kristien, additional, Claeys, Kristl, additional, Jonghe, Peter De, additional, Merory, John, additional, Oliveira, Sofia A, additional, Speer, Marcy C, additional, Stenger, Judith E, additional, Walizada, Gina, additional, Zhu, Danqing, additional, Pericak-Vance, Margaret A, additional, Nicholson, Garth, additional, Timmerman, Vincent, additional, and Vance, Jeffery M, additional
Published: 2005
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33. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy

Author: Irobi, Joy, primary, Impe, Katrien Van, additional, Seeman, Pavel, additional, Jordanova, Albena, additional, Dierick, Ines, additional, Verpoorten, Nathalie, additional, Michalik, Andrej, additional, Vriendt, Els De, additional, Jacobs, An, additional, Gerwen, Veerle Van, additional, Vennekens, Krist'l, additional, Mazanec, Radim, additional, Tournev, Ivailo, additional, Hilton-Jones, David, additional, Talbot, Kevin, additional, Kremensky, Ivo, additional, Bosch, Ludo Van Den, additional, Robberecht, Wim, additional, Vandekerckhove, Joël, additional, Broeckhoven, Christine Van, additional, Gettemans, Jan, additional, Jonghe, Peter De, additional, and Timmerman, Vincent, additional
Published: 2004
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34. Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A

Author: Züchner, Stephan, primary, Mersiyanova, Irina V, additional, Muglia, Maria, additional, Bissar-Tadmouri, Nisrine, additional, Rochelle, Julie, additional, Dadali, Elena L, additional, Zappia, Mario, additional, Nelis, Eva, additional, Patitucci, Alessandra, additional, Senderek, Jan, additional, Parman, Yesim, additional, Evgrafov, Oleg, additional, Jonghe, Peter De, additional, Takahashi, Yuji, additional, Tsuji, Shoij, additional, Pericak-Vance, Margaret A, additional, Quattrone, Aldo, additional, Battologlu, Esra, additional, Polyakov, Alexander V, additional, Timmerman, Vincent, additional, Schröder, J Michael, additional, and Vance, Jeffery M, additional
Published: 2004
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35. Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome

Author: Windpassinger, Christian, primary, Auer-Grumbach, Michaela, additional, Irobi, Joy, additional, Patel, Heema, additional, Petek, Erwin, additional, Hörl, Gerd, additional, Malli, Roland, additional, Reed, Johanna A, additional, Dierick, Ines, additional, Verpoorten, Nathalie, additional, Warner, Thomas T, additional, Proukakis, Christos, additional, den Bergh, Peter Van, additional, Verellen, Christine, additional, Maldergem, Lionel Van, additional, Merlini, Luciano, additional, Jonghe, Peter De, additional, Timmerman, Vincent, additional, Crosby, Andrew H, additional, and Wagner, Klaus, additional
Published: 2004
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36. A novel connexin 32 missense mutation (E208G) causing Charcot-Marie-Tooth disease Communicated by Mark H. Paalman Online Citation: Human Mutation, Mutation and Polymorphism Report #212 (2000) Online http://journals.wiley.com/1059-7794/pdf/mutation/mpr212.pdf Acknowledgments: This work was supported by the Polish State Committee for Scientific Research (grants 4p05E00815 and 2266/ IA/167/97) and the Fund for Scientific Research (FWO - Flanders, Belgium).

Author: Kochanski, Andrzej, primary, Lofgren, Ann, additional, Jedrzejowska, Hanna, additional, Ryniewicz, Barbara, additional, Czarny-Ratajczak, Malwina, additional, Barciszewska, Anna-Maria, additional, Samocko, Joanna, additional, Hausmanowa-Petrusewicz, Irena, additional, Jonghe, Peter De, additional, Timmerman, Vincent, additional, and Latos-Bielenska, Anna, additional
Published: 2001
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37. Pelizaeus-Merzbacher–Like Disease in a Family With Variable Phenotype and a Novel Splicing GJC2 Mutation.

Author: Al-Yahyaee, Said Ali, Al-Kindi, Mohammed, Jonghe, Peter De, Al-Asmi, Abdulah, Al-Futaisi, Amna, Vriendt, Els De, Deconinck, Tine, and Chand, Pratap
Subjects: PELIZAEUS-merzbacher disease, PHENOTYPES, AUTOSOMAL recessive polycystic kidney, NYSTAGMUS, BRAIN imaging, MAGNETIC resonance imaging, CONNEXINS
Abstract: Pelizaeus-Merzbacher–like disease is an autosomal recessive disorder characterized by neonatal nystagmus, ataxia, progressive spasticity, and development delay and is rarely caused by GJC2 mutations. We report 7 patients from a large consanguineous family who had variable severity of Pelizaeus-Merzbacher–like disease. The 3 youngest of branch A were bedridden by their first year because of permanent scissoring of their legs and had severe frontal lobe epilepsy. The single patient from branch B was the least affected, being able to walk until 12 years of age and had no epilepsy. Brain magnetic resonance imaging (MRI) showed hypomyelination. The patients had a novel canonical splicing GJC2 c.-20+1G>C mutation with a predicted loss of the coding connexin 47 protein. The exceptionally large number of patients in this unique family enabled to describe the intrafamilial variability of Pelizaeus-Merzbacher–like disease. The predicted functional loss of connexin 47 might be associated with a severe form of Pelizaeus-Merzbacher–like disease. [ABSTRACT FROM AUTHOR]
Published: 2013
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38. Origin of the de novo duplication in Charcot — Marie — Tooth disease type 1A: unequal nonsister chromatid exchange during spermatogenesis

Author: Palau, Francisco, primary, Löfgren, Ann, additional, Jonghe, Peter De, additional, Bort, Sylvia, additional, Nelis, Eva, additional, Sevilla, Teresa, additional, Martin, Jean-Jacques, additional, Vilchez, Juan, additional, Prieto, Felix, additional, and Broeckhoven, Christine Van, additional
Published: 1993
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39. Glucose Transporter 1 Deficiency as a Treatable Cause of Myoclonic Astatic Epilepsy.

Author: Mullen, Saul A., Marini, Carla, Suls, Arvid, Mei, Davide, Giustina, Elvio Della, Buti, Daniela, Arsov, Todor, Damiano, John, Lawrence, Kate, Jonghe, Peter De, Berkovic, Samuel F., Scheffer, Ingrid E., and Guerrini, Renzo
Abstract: Objective: To determine if a significant proportion of patients with myoclonic-astatic epilepsy (MAE) have glucose transporter 1 (GLUT1) deficiency. Design: Genetic analysis. Setting: Ambulatory and hospitalized care. Patients: Eighty-four unrelated probands with MAE were phenotyped and SLC2A1 was sequenced and analyzed by multiplex ligation-dependent probe amplification. Any identified mutations were then screened in controls. Main Outcome Measure: Any SLC2A1 mutations. Results: Four of 84 probands with MAE had a mutation of SLC2A1 on sequencing. Multiplex ligation-dependent probe amplification analysis did not reveal any genomic rearrangements in 75 of the remaining cases; 5 could not be tested. Two patients with MAE with SLC2A1 mutations also developed paroxysmal exertional dyskinesia in childhood. Conclusions: Five percent of our patients with MAE had SLC2A1 mutations, suggesting that patients with MAE should be tested for GLUT1 deficiency. Diagnosis of GLUT1 deficiency is a strong indication for early use of the ketogenic diet, which may substantially improve outcome of this severe disorder. [ABSTRACT FROM AUTHOR]
Published: 2011
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40. Simultaneous mutation and copy number variation (CNV) detection by multiplex PCR-based GS-FLX sequencing.

Author: Goossens, Dirk, Moens, Lotte N., Nelis, Eva, Lenaerts, An-Sofie, Glassee, Wim, Kalbe, Andreas, Frey, Bruno, Kopal, Guido, Jonghe, Peter De, Rijk, Peter De, and Del-Favero, Jurgen
Abstract: We evaluated multiplex PCR amplification as a front-end for high-throughput sequencing, to widen the applicability of massive parallel sequencers for the detailed analysis of complex genomes. Using multiplex PCR reactions, we sequenced the complete coding regions of seven genes implicated in peripheral neuropathies in 40 individuals on a GS-FLX genome sequencer (Roche). The resulting dataset showed highly specific and uniform amplification. Comparison of the GS-FLX sequencing data with the dataset generated by Sanger sequencing confirmed the detection of all variants present and proved the sensitivity of the method for mutation detection. In addition, we showed that we could exploit the multiplexed PCR amplicons to determine individual copy number variation (CNV), increasing the spectrum of detected variations to both genetic and genomic variants. We conclude that our straightforward procedure substantially expands the applicability of the massive parallel sequencers for sequencing projects of a moderate number of amplicons (50-500) with typical applications in resequencing exons in positional or functional candidate regions and molecular genetic diagnostics. Hum Mutat 0,1-6, 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
Published: 2009
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41. Erratum to: Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia.

Author: Wiessner, Manuela, Maroofian, Reza, Ni, Meng-Yuan, Pedroni, Andrea, Müller, Juliane S, Stucka, Rolf, Beetz, Christian, Efthymiou, Stephanie, Santorelli, Filippo M, Alfares, Ahmed A, Zhu, Changlian, Meszarosova, Anna Uhrova, Alehabib, Elham, Bakhtiari, Somayeh, Janecke, Andreas R, Otero, Maria Gabriela, Chen, Jin Yun Helen, Peterson, James T, Strom, Tim M, and Jonghe, Peter De
Subjects: FAMILIAL spastic paraplegia
Published: 2021
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42. SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve

Author: Bennett, Craig L., Shirk, Andrew J., Huynh, Huy M., Street, Valerie A., Nelis, Eva, Maldergem, Lionel Van, Jonghe, Peter De, Jordanova, Albena, Guergueltcheva, Velina, Tournev, Ivailo, Bergh, Peter Van den, Seeman, Pavel, Mazanec, Radim, Prochazka, Tomas, Kremensky, Ivo, Haberlova, Jana, Weiss, Michael D., and Timmerman, Vincent
Abstract: CharcotMarieTooth neuropathy type 1C (CMT1C) is an autosomal dominant demyelinating peripheral neuropathy caused by missense mutations in the small integral membrane protein of lysosome/late endosome (SIMPLE) gene. To investigate the prevalence of SIMPLE mutations, we screened a cohort of 152 probands with various types of demyelinating or axonal and pure motor or sensory inherited neuropathies. SIMPLE mutations were found only in CMT1 patients, including one G112S and one W116G missense mutations. A novel I74I polymorphism was identified, yet no splicing defect of SIMPLE is likely. Haplotype analysis of STR markers and intragenic SNPs linked to the gene demonstrated that families with the same mutation are unlikely to be related. The clustering of the G112S, T115N, and W116G mutations within five amino acids suggests this domain may be critical to peripheral nerve myelination. Electrophysiological studies showed that CMT1C patients from six pedigrees (n = 38) had reduced nerve conduction velocities ranging from 7.5 to 27.0m/sec (peroneal). Two patients had temporal dispersion of nerve conduction and irregularity of conduction slowing, which is unusual for CMT1 patients. We report the expression of SIMPLE in various cell types of the sciatic nerve, including Schwann cells, the affected cell type in CMT1C.
Published: 2004
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43. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Author: Steward, Charles A., Roovers, Jolien, Suner, Marie-Marthe, Gonzalez, Jose M., Uszczynska-Ratajczak, Barbara, Pervouchine, Dmitri, Fitzgerald, Stephen, Viola, Margarida, Stamberger, Hannah, Hamdan, Fadi F., Ceulemans, Berten, Leroy, Patricia, Nava, Caroline, Lepine, Anne, Tapanari, Electra, Keiller, Don, Abbs, Stephen, Sanchis-Juan, Alba, Grozeva, Detelina, Rogers, Anthony S., Diekhans, Mark, Guigó, Roderic, Petryszak, Robert, Minassian, Berge A., Cavalleri, Gianpiero, Vitsios, Dimitrios, Petrovski, Slavé, Harrow, Jennifer, Flicek, Paul, Lucy Raymond, F., Lench, Nicholas J., Jonghe, Peter De, Mudge, Jonathan M., Weckhuysen, Sarah, Sisodiya, Sanjay M., and Frankish, Adam
Subjects: 631/61/212/2301, article, ComputingMilieux_LEGALASPECTSOFCOMPUTING, 3. Good health, 692/4017
Abstract: Funder: Agency for Innovation by Science and Technology, IWT, Funder: U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI), Funder: BOF-University of Antwerp (FFB180053) and FWO (1861419N)., The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60–65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional ‘footprint’ of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.

44. Additional file 3: of STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations

Author: Hayer, Stefanie, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, Züchner, Stephan, Reich, Selina, Schöls, Ludger, Schüle, Rebecca, Jonghe, Peter De, Baets, Jonathan, and Synofzik, Matthis
Subjects: 3. Good health
Abstract: Case vignettes. Detailed medical history and clinical examination data of the three STUB1 patients. (DOCX 14 kb)

45. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

Author: Steward, Charles A, Roovers, Jolien, Suner, Marie-Marthe, Gonzalez, Jose M, Uszczynska-Ratajczak, Barbara, Pervouchine, Dmitri, Fitzgerald, Stephen, Viola, Margarida, Stamberger, Hannah, Hamdan, Fadi F, Ceulemans, Berten, Leroy, Patricia, Nava, Caroline, Lepine, Anne, Tapanari, Electra, Keiller, Don, Abbs, Stephen, Sanchis-Juan, Alba, Grozeva, Detelina, Rogers, Anthony S, Diekhans, Mark, Guigó, Roderic, Petryszak, Robert, Minassian, Berge A, Cavalleri, Gianpiero, Vitsios, Dimitrios, Petrovski, Slavé, Harrow, Jennifer, Flicek, Paul, Lucy Raymond, F, Lench, Nicholas J, Jonghe, Peter De, Mudge, Jonathan M, Weckhuysen, Sarah, Sisodiya, Sanjay M, and Frankish, Adam
Subjects: Molecular Medicine, FOS: Basic medicine, Medical Genomics, 3. Good health
Abstract: The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using SCN1A as a case study, due to its close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.

46. Additional file 3: of STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations

Author: Hayer, Stefanie, Deconinck, Tine, Bender, Benjamin, Smets, Katrien, Züchner, Stephan, Reich, Selina, Schöls, Ludger, Schüle, Rebecca, Jonghe, Peter De, Baets, Jonathan, and Synofzik, Matthis
Subjects: 3. Good health
Abstract: Case vignettes. Detailed medical history and clinical examination data of the three STUB1 patients. (DOCX 14 kb)

47. Dominant mutations in the cation channel gene transient receptor potential vanilloid 4 cause an unusual spectrum of neuropathies

Author: Zimoń, Magdalena, Baets, Jonathan, Auer-Grumbach, Michaela, Berciano, José, Garcia, Antonio, Lopez-Laso, Eduardo, Merlini, Luciano, Hilton-Jones, David, McEntagart, Meriel, Crosby, Andrew H., Barisic, Nina, Boltshauser, Eugen, Shaw, Christopher E., Landouré, Guida, Ludlow, Christy L., Gaudet, Rachelle, Houlden, Henry, Reilly, Mary M., Fischbeck, Kenneth H., Sumner, Charlotte J., Timmerman, Vincent, Jordanova, Albena, Jonghe, Peter De, Zimoń, Magdalena, Baets, Jonathan, Auer-Grumbach, Michaela, Berciano, José, Garcia, Antonio, Lopez-Laso, Eduardo, Merlini, Luciano, Hilton-Jones, David, McEntagart, Meriel, Crosby, Andrew H., Barisic, Nina, Boltshauser, Eugen, Shaw, Christopher E., Landouré, Guida, Ludlow, Christy L., Gaudet, Rachelle, Houlden, Henry, Reilly, Mary M., Fischbeck, Kenneth H., Sumner, Charlotte J., Timmerman, Vincent, Jordanova, Albena, and Jonghe, Peter De
Abstract: Hereditary neuropathies form a heterogeneous group of disorders for which over 40 causal genes have been identified to date. Recently, dominant mutations in the transient receptor potential vanilloid 4 gene were found to be associated with three distinct neuromuscular phenotypes: hereditary motor and sensory neuropathy 2C, scapuloperoneal spinal muscular atrophy and congenital distal spinal muscular atrophy. Transient receptor potential vanilloid 4 encodes a cation channel previously implicated in several types of dominantly inherited bone dysplasia syndromes. We performed DNA sequencing of the coding regions of transient receptor potential vanilloid 4 in a cohort of 145 patients with various types of hereditary neuropathy and identified five different heterozygous missense mutations in eight unrelated families. One mutation arose de novo in an isolated patient, and the remainder segregated in families. Two of the mutations were recurrent in unrelated families. Four mutations in transient receptor potential vanilloid 4 targeted conserved arginine residues in the ankyrin repeat domain, which is believed to be important in protein-protein interactions. Striking phenotypic variability between and within families was observed. The majority of patients displayed a predominantly, or pure, motor neuropathy with axonal characteristics observed on electrophysiological testing. The age of onset varied widely, ranging from congenital to late adulthood onset. Various combinations of additional features were present in most patients including vocal fold paralysis, scapular weakness, contractures and hearing loss. We identified six asymptomatic mutation carriers, indicating reduced penetrance of the transient receptor potential vanilloid 4 defects. This finding is relatively unusual in the context of hereditary neuropathies and has important implications for diagnostic testing and genetic counselling

48. DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4).

Author: Chen, Ying-Zhang, Bennett, Craig L., Huynh, Huy M., Blair, Ian P., Puls, Imke, Irobi, Joy, Dierick, Ines, Abel, Anneuie, Kennerson, Marina L., Rabi, Bruce A., Nicholson, Garth A., Auer-Grumbach, Michaela, Wagner, Klaus, Jonghe, Peter De, Griffin, John W., Fischbeck, Kenneth H., Timmerman, Vincent, Cornblath, David R., and Chance, Phillip F.
Subjects: *AMYOTROPHIC lateral sclerosis, *NEUROMUSCULAR diseases, *MOTOR neuron diseases, *NUCLEIC acids, *DNA helicases, *ISOMERASES
Abstract: Juvenile amyotrophic lateral sclerosis (ALS4) is a rare autosomal dominant form of juvenile amyotrophic lateral sclerosis (ALS) characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs. Individuals affected with ALS4 usually have an onset of symptoms at age <25 years, a slow rate of progression, and a normal life span. The ALS4 locus maps to a 1.7-Mb interval on chromosome 9q34 flanked by D9S64 and D9S1198. To identify the molecular basis of ALS4, we tested 19 genes within the ALS4 interval and detected missense mutations (T3I, L389S, and R2136H) in the Senataxin gene (SETX). The SETX gene encodes a novel 302.8-kD protein. Although its function remains unknown, SETX contains a DNA/RNA helicase domain with strong homology to human RENT1 and IGHMBP2, two genes encoding proteins known to have roles in RNA processing. These observations of ALS4 suggest that mutations in SETX may cause neuronal degeneration through dysfunction of the helicase activity or other steps in RNA processing. [ABSTRACT FROM AUTHOR]
Published: 2004
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49. Diagnostic implications of genetic copy number variation in epilepsy plus

Author: Coppola, A., Cellini, E., Stamberger, H., Saarentaus, E., Cetica, V., Lal, D., Djemie, T., Bartnik-Glaska, M., Ceulemans, B., Helen Cross, J., Deconinck, T., Masi, S. D., Dorn, T., Guerrini, R., Hoffman-Zacharska, D., Kooy, F., Lagae, L., Lench, N., Lemke, J. R., Lucenteforte, E., Madia, F., Mefford, H. C., Morrogh, D., Nuernberg, P., Palotie, A., Schoonjans, A. -S., Striano, P., Szczepanik, E., Tostevin, A., Vermeesch, J. R., Van Esch, H., Van Paesschen, W., Waters, J. J., Weckhuysen, S., Zara, F., Jonghe, P. D., Sisodiya, S. M., Marini, C., Lehesjioki, A. -E., Craiu, D., Talvik, T., Caglayan, H., Serratosa, J., Sterbova, K., Moller, R. S., Hjalgrim, H., Lerche, H., Weber, Y., Helbig, I., von Spiczak, S., Barba, C., Bogaerts, A., Boni, A., Galizia, E. C., Chiari, S., Di Gacomo, G., Ferrari, A., Guarducci, S., Giglio, S., Holmgren, P., Leu, C., Melani, F., Novara, F., Pantaleo, M., Peeters, E., Pisano, T., Rosati, A., Sander, J., Schoeler, N., Stankiewicz, P., Striano, S., Suls, A., Traverso, M., Vandeweyer, G., Van Dijck, A., Zuffardi, O., Coppola, Antonietta, Cellini, Elena, Stamberger, Hannah, Saarentaus, Elmo, Cetica, Valentina, Lal, Denni, Djémié, Tania, Bartnik-Glaska, Magdalena, Ceulemans, Berten, Helen Cross, J., Deconinck, Tine, Masi, Salvatore De, Dorn, Thoma, Guerrini, Renzo, Hoffman-Zacharska, Dorotha, Kooy, Frank, Lagae, Lieven, Lench, Nichola, Lemke, Johannes R., Lucenteforte, Ersilia, Madia, Francesca, Mefford, Heather C., Morrogh, Deborah, Nuernberg, Peter, Palotie, Aarno, Schoonjans, An-Sofie, Striano, Pasquale, Szczepanik, Elzbieta, Tostevin, Anna, Vermeesch, Joris R., Van Esch, Hilde, Van Paesschen, Wim, Waters, Jonathan J, Weckhuysen, Sarah, Zara, Federico, Jonghe, Peter De, Sisodiya, Sanjay M., Marini, Carla, Lehesjioki, Anna-Elina, Craiu, Dana, Talvik, Tiina, Caglayan, Hande, Serratosa, Jose, Sterbova, Katalin, Møller, Rikke S., Hjalgrim, Helle, Lerche, Holger, Weber, Yvonne, Helbig, Ingo, von Spiczak, Sarah, Barba, Carmen, Bogaerts, Anneleen, Boni, Antonella, Galizia, Elisabeth Caruana, Chiari, Sara, Di Gacomo, Gianpiero, Ferrari, Annarita, Guarducci, Silvia, Giglio, Sabrina, Holmgren, Philip, Leu, Costin, Melani, Federico, Novara, Francesca, Pantaleo, Marilena, Peeters, Elke, Pisano, Tiziana, Rosati, Anna, Sander, Josemir, Schoeler, Natasha, Stankiewicz, Pawel, Striano, Salvatore, Suls, Arvid, Traverso, Monica, Vandeweyer, Geert, Van Dijck, Anke, and Zuffardi, Orsetta
Subjects: epilepsy gene, Epilepsy, DNA Copy Number Variations, Genotype, Comorbidity, array CGH, copy number variants, epilepsy genes, SNP array, Phenotype, Neurology, mental disorders, Full‐length Original Research, Humans, copy number variant, Genetic Predisposition to Disease, Neurology (clinical)
Abstract: Summary Objective Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. Methods We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had “epilepsy plus,” defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. Results Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51‐6.68; P = 2.34 × 10−9). Meta‐analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. Significance The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large‐scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes.
Published: 2019

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

Author: Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.
Subjects: 0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract: BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
Published: 2018

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