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2. Impact of Early Nutritional Intervention During Cancer Treatment on Dietary Intakes and Cardiometabolic Health in Children and Adolescents.

Author

Delorme, Josianne, Dima, Andra, Bélanger, Véronique, Napartuk, Mélanie, Bouchard, Isabelle, Meloche, Caroline, Curnier, Daniel, Sultan, Serge, Laverdière, Caroline, Sinnett, Daniel, and Marcil, Valérie

Subjects
RISK assessment, TUMORS in children, FOOD consumption, RESEARCH funding, EVALUATION of human services programs, CARDIOVASCULAR diseases risk factors, EARLY intervention (Education), SOCIAL support, COMPARATIVE studies, ANTHROPOMETRY, DIET, NUTRITION, PHYSICAL activity, ADOLESCENCE, CHILDREN
Abstract

Simple Summary: Pediatric cancer survivors have a higher risk of developing cardiometabolic complications compared to their peers. This study evaluates the impact of VIE (Valorization, Implication, Education), which is a personalized intervention program that integrates nutrition, physical activity, and psychological support, on dietary intake and cardiometabolic health among children and adolescents following cancer treatment. The participants exposed to the VIE intervention showed specific improved dietary intakes at an average of 1.3 years post-treatment compared to a control group; this was reflected by lower caloric and higher calcium intakes. Furthermore, the participants who were highly involved in the nutritional intervention had greater protein-derived energy intake than the controls. Only the adolescents in the intervention group exhibited a trend toward a lower proportion of cardiometabolic risk factors. While our findings show limited clinical impact, they underscore the importance of exploring additional strategies to improve the diet of all pediatric cancer patients during and after treatment and show the need for further research to assess the long-term impact of such interventions on health. Background/Objectives: Pediatric cancer survivors are at greater risk of cardiometabolic complications than their peers. This study evaluates the preliminary impact of the VIE (Valorization, Implication, Education) intervention, which integrates nutrition, physical activity, and psychological support, on dietary intake and cardiometabolic health among children and adolescents during cancer treatment. Methods: This comparative study includes pediatric cancer patients recruited to either the VIE intervention group or a control group receiving standard care. Post-treatment data on dietary intake, anthropometric measures, blood pressure, and biochemical parameters were compared between groups and stratified by level of involvement in the nutritional intervention and age at diagnosis (children and adolescents). Results: In the intervention group, 45 participants were included (51.1% male, mean age at evaluation 10.2 ± 4.5 years, mean time since end of treatment of 1.3 ± 0.8 years), and the control group comprised 77 participants (44.2% male, mean age at evaluation 12.0 ± 5.6 years, mean time since end of treatment of 1.4 ± 0.8 years). The intervention group had lower total caloric intake (mean: 1759 ± 513 vs. 1997 ± 669 kcal, p = 0.042) and higher calcium intake (mean: 567 ± 240 vs. 432 ± 197 mg/1000 kcal, p = 0.001). The participants who were highly involved in the nutritional intervention had greater protein-derived energy intake than the controls (mean: 17 ± 5 vs. 15 ± 4%, p = 0.029). While there was a tendency for a lesser proportion of cardiometabolic risk factors in the adolescents from the intervention group, the differences did not reach statistical significance. Conclusions: The VIE intervention improved some specific dietary intakes in the medium term after treatment completion but did not significantly impact cardiometabolic health outcomes. Additional strategies are needed to improve the diet of pediatric cancer patients, and further research is warranted to assess the long-term impact of such interventions. [ABSTRACT FROM AUTHOR]

Published
2025
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3. Whole-transcriptome analysis in acute lymphoblastic leukemia: a report from the DFCI ALL Consortium Protocol 16-001

Author

Tran, Thai Hoa, Langlois, Sylvie, Meloche, Caroline, Caron, Maxime, Saint-Onge, Pascal, Rouette, Alexandre, Bataille, Alain R., Jimenez-Cortes, Camille, Sontag, Thomas, Bittencourt, Henrique, Laverdière, Caroline, Lavallée, Vincent-Philippe, Leclerc, Jean-Marie, Cole, Peter D., Gennarini, Lisa M., Kahn, Justine M., Kelly, Kara M., Michon, Bruno, Santiago, Raoul, Stevenson, Kristen E., Welch, Jennifer J.G., Schroeder, Kaitlin M., Koch, Victoria, Cellot, Sonia, Silverman, Lewis B., and Sinnett, Daniel

Published
2022
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5. 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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6. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author

Hamdan, Fadi F., Myers, Candace T., Cossette, Patrick, Lemay, Philippe, Spiegelman, Dan, Laporte, Alexandre Dionne, Nassif, Christina, Diallo, Ousmane, Monlong, Jean, Cadieux-Dion, Maxime, Dobrzeniecka, Sylvia, Meloche, Caroline, Retterer, Kyle, Cho, Megan T., Rosenfeld, Jill A., Bi, Weimin, Massicotte, Christine, Miguet, Marguerite, Brunga, Ledia, Regan, Brigid M., Mo, Kelly, Tam, Cory, Schneider, Amy, Hollingsworth, Georgie, FitzPatrick, David R., Donaldson, Alan, Canham, Natalie, Blair, Edward, Kerr, Bronwyn, Fry, Andrew E., Thomas, Rhys H., Shelagh, Joss, Hurst, Jane A., Brittain, Helen, Blyth, Moira, Lebel, Robert Roger, Gerkes, Erica H., Davis-Keppen, Laura, Stein, Quinn, Chung, Wendy K., Dorison, Sara J., Benke, Paul J., Fassi, Emily, Corsten-Janssen, Nicole, Kamsteeg, Erik-Jan, Mau-Them, Frederic T., Bruel, Ange-Line, Verloes, Alain, Õunap, Katrin, Wojcik, Monica H., Albert, Dara V.F., Venkateswaran, Sunita, Ware, Tyson, Jones, Dean, Liu, Yu-Chi, Mohammad, Shekeeb S., Bizargity, Peyman, Bacino, Carlos A., Leuzzi, Vincenzo, Martinelli, Simone, Dallapiccola, Bruno, Tartaglia, Marco, Blumkin, Lubov, Wierenga, Klaas J., Purcarin, Gabriela, O’Byrne, James J., Stockler, Sylvia, Lehman, Anna, Keren, Boris, Nougues, Marie-Christine, Mignot, Cyril, Auvin, Stéphane, Nava, Caroline, Hiatt, Susan M., Bebin, Martina, Shao, Yunru, Scaglia, Fernando, Lalani, Seema R., Frye, Richard E., Jarjour, Imad T., Jacques, Stéphanie, Boucher, Renee-Myriam, Riou, Emilie, Srour, Myriam, Carmant, Lionel, Lortie, Anne, Major, Philippe, Diadori, Paola, Dubeau, François, D’Anjou, Guy, Bourque, Guillaume, Berkovic, Samuel F., Sadleir, Lynette G., Campeau, Philippe M., Kibar, Zoha, Lafrenière, Ronald G., Girard, Simon L., Mercimek-Mahmutoglu, Saadet, Boelman, Cyrus, Rouleau, Guy A., Scheffer, Ingrid E., Mefford, Heather C., Andrade, Danielle M., Rossignol, Elsa, Minassian, Berge A., and Michaud, Jacques L.

Published
2017
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7. Additional file 2 of Abnormal HDL lipid and protein composition following pediatric cancer treatment: an associative study

Author

Bélanger, Véronique, Morel, Sophia, Napartuk, Mélanie, Bouchard, Isabelle, Meloche, Caroline, Curnier, Daniel, Sultan, Serge, Laverdière, Caroline, Sinnett, Daniel, and Marcil, Valérie

Abstract

Additional file 2: Supplementary Table 2. Plasma lipid profile of post-treatment pediatric cancer patients: comparison based on age group at diagnosis.

Published
2023
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8. Additional file 3 of Abnormal HDL lipid and protein composition following pediatric cancer treatment: an associative study

Author

Bélanger, Véronique, Morel, Sophia, Napartuk, Mélanie, Bouchard, Isabelle, Meloche, Caroline, Curnier, Daniel, Sultan, Serge, Laverdière, Caroline, Sinnett, Daniel, and Marcil, Valérie

Abstract

Additional file 3: Supplementary Table 3. Composition of HDL2 and HDL3 of post-treatment pediatric cancer patients: comparison based on age group at diagnosis.

Published
2023
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10. Needs, Barriers and Facilitators of Adolescents Participating in a Lifestyle Promotion Program in Oncology: Stakeholders, Adolescents and Parents’ Perspective

Author

Kerba, Johanne, primary, Demers, Catherine, additional, Bélanger, Véronique, additional, Napartuk, Mélanie, additional, Bouchard, Isabelle, additional, Meloche, Caroline, additional, Morel, Sophia, additional, Prud’homme, Nicolas, additional, Gélinas, Isabelle, additional, Higgins, Johanne, additional, Curnier, Daniel, additional, Sultan, Serge, additional, Laverdière, Caroline, additional, Sinnett, Daniel, additional, and Marcil, Valérie, additional

Published
2022
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16. SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function

Author

Fassio, Anna, Patry, Lysanne, Congia, Sonia, Onofri, Franco, Piton, Amelie, Gauthier, Julie, Pozzi, Davide, Messa, Mirko, Defranchi, Enrico, Fadda, Manuela, Corradi, Anna, Baldelli, Pietro, Lapointe, Line, St-Onge, Judith, Meloche, Caroline, Mottron, Laurent, Valtorta, Flavia, Khoa Nguyen, Dang, Rouleau, Guy A., Benfenati, Fabio, and Cossette, Patrick

Published
2011
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17. Abstract A57: Feasibility of physical activity in children with cancer: A multidisciplinary program in the context of the VIE study

Author

Caru, Maxime, primary, Duhamel, Gabrielle, additional, Marcil, Valérie, additional, Sultan, Serge, additional, Meloche, Caroline, additional, Bouchard, Isabelle, additional, Drouin, Simon, additional, Bertout, Laurence, additional, Laverdière, Caroline, additional, Sinnett, Daniel, additional, and Curnier, Daniel, additional

Published
2020
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20. The VIE study: feasibility of a physical activity intervention in a multidisciplinary program in children with cancer

Author

Caru, Maxime, primary, Duhamel, Gabrielle, additional, Marcil, Valérie, additional, Sultan, Serge, additional, Meloche, Caroline, additional, Bouchard, Isabelle, additional, Drouin, Simon, additional, Bertout, Laurence, additional, Laverdiere, Caroline, additional, Sinnett, Daniel, additional, and Curnier, Daniel, additional

Published
2019
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22. Global characterization of copy number variants in epilepsy patients from whole genome sequencing

Author

Monlong, Jean, primary, Girard, Simon L., additional, Meloche, Caroline, additional, Cadieux-Dion, Maxime, additional, Andrade, Danielle M., additional, Lafreniere, Ron G., additional, Gravel, Micheline, additional, Spiegelman, Dan, additional, Dionne-Laporte, Alexandre, additional, Boelman, Cyrus, additional, Hamdan, Fadi F., additional, Michaud, Jacques L., additional, Rouleau, Guy, additional, Minassian, Berge A., additional, Bourque, Guillaume, additional, and Cossette, Patrick, additional

Published
2018
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23. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj Reddy, Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Christina 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, Hille, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S., Weber, Yvonne G., 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, Francis, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-François, Cieuta-Walti, Sills, Graeme J., Auce, Pauls, Francin, Ben, Johnson, Michael R., 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, 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, Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Experimental Neurobiology (Balling Group) [research center], University of Luxembourg: High Performance Computing - ULHPC [research center], May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj Reddy, Schubert, Julian, Wolking, Stefan, Becker, Felicitas, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Christina 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, Hille, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S., Weber, Yvonne G., 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, Francis, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-François, Cieuta-Walti, Sills, Graeme J., Auce, Pauls, Francin, Ben, Johnson, Michael R., 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, 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, and Lerche, Holger

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 (O

Published
2018

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

Author

Genetica Groep Koeleman, Zorglijn FNE Medisch, Brain, Child Health, Circulatory Health, Genetica, 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, Kasteleijn-Nolst Trenité, Dorothée, Koeleman, Bobby P.C., Sonsma, Anja C.M., EPICURE Consortium, EuroEPINOMICS CoGIE Consortium, EpiPGX Consortium, Genetica Groep Koeleman, Zorglijn FNE Medisch, Brain, Child Health, Circulatory Health, Genetica, 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, Kasteleijn-Nolst Trenité, Dorothée, Koeleman, Bobby P.C., Sonsma, Anja C.M., EPICURE Consortium, EuroEPINOMICS CoGIE Consortium, and EpiPGX Consortium

Published
2018

25. Global characterization of copy number variants in epilepsy patients from whole genome sequencing

Author

Monlong, Jean, primary, Girard, Simon L., additional, Meloche, Caroline, additional, Cadieux-Dion, Maxime, additional, Andrade, Danielle M., additional, Lafreniere, Ron G., additional, Gravel, Micheline, additional, Spiegelman, Dan, additional, Dionne-Laporte, Alexandre, additional, Boelman, Cyrus, additional, Hamdan, Fadi F., additional, Michaud, Jacques L., additional, Rouleau, Guy, additional, Minassian, Berge A., additional, Bourque, Guillaume, additional, and Cossette, Patrick, additional

Published
2017
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27. Variabilité génétique au niveau des gènes de réparation de l'ADN

Author

Meloche, Caroline and Sinnett, Daniel

Subjects
Leucémie lymphoblastique aiguë, Facteurs de transcription, Polymorphisme, Génétique, Région régulatrice, Cancer, Facteurs de susceptibilité
Abstract

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Published
2003

28. Disruption of AP1S1, Causing a Novel Neurocutaneous Syndrome, Perturbs Development of the Skin and Spinal Cord

Author

Montpetit, Alexandre, primary, Côté, Stéphanie, additional, Brustein, Edna, additional, Drouin, Christian A., additional, Lapointe, Line, additional, Boudreau, Michèle, additional, Meloche, Caroline, additional, Drouin, Régen, additional, Hudson, Thomas J., additional, Drapeau, Pierre, additional, and Cossette, Patrick, additional

Published
2008
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29. Novel α1 and γ2 GABAA receptor subunit mutations in families with idiopathic generalized epilepsy.

Author

Lachance‐Touchette, Pamela, Brown, Patricia, Meloche, Caroline, Kinirons, Peter, Lapointe, Line, Lacasse, Hélène, Lortie, Anne, Carmant, Lionel, Bedford, Fiona, Bowie, Derek, and Cossette, Patrick

Subjects
GABA receptors, GENETIC mutation, EPILEPSY, GENETICS, NEURAL transmission, CHROMOSOMES, ELECTROPHYSIOLOGY, ION channels
Abstract

Epilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, with mutations in several ion‐channel genes being implicated, including those encoding the GABAA receptor. Here, we evaluated the frequency of additional mutations in the GABAA receptor by direct sequencing of the complete open reading frame of the GABRA1 and GABRG2 genes from a cohort of French Canadian families with idiopathic generalized epilepsy (IGE). Using this approach, we have identified three novel mutations that were absent in over 400 control chromosomes. In GABRA1, two mutations were found, with the first being a 25‐bp insertion that was associated with intron retention (i.e. K353delins18X) and the second corresponding to a single point mutation that replaced the aspartate 219 residue with an asparagine (i.e. D219N). Electrophysiological analysis revealed that K353delins18X and D219N altered GABAA receptor function by reducing the total surface expression of mature protein and/or by curtailing neurotransmitter effectiveness. Both defects would be expected to have a detrimental effect on inhibitory control of neuronal circuits. In contrast, the single point mutation identified in the GABRG2 gene, namely P83S, was indistinguishable from the wildtype subunit in terms of surface expression and functionality. This finding was all the more intriguing as the mutation exhibited a high degree of penetrance in three generations of one French Canadian family. Further experimentation will be required to understand how this mutation contributes to the occurrence of IGE in these individuals. [ABSTRACT FROM AUTHOR]

Published
2011
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30. Whole-transcriptome analysis in acute lymphoblastic leukemia: a report from the DFCI ALL Consortium Protocol 16-001

Author

Tran, Thai Hoa, Langlois, Sylvie, Meloche, Caroline, Caron, Maxime, Saint-Onge, Pascal, Rouette, Alexandre, Bataille, Alain R., Jimenez-Cortes, Camille, Sontag, Thomas, Bittencourt, Henrique, Laverdière, Caroline, Lavallée, Vincent-Philippe, Leclerc, Jean-Marie, Cole, Peter D., Gennarini, Lisa M., Kahn, Justine M., Kelly, Kara M., Michon, Bruno, Santiago, Raoul, Stevenson, Kristen E., Welch, Jennifer J.G., Schroeder, Kaitlin M., Koch, Victoria, Cellot, Sonia, Silverman, Lewis B., and Sinnett, Daniel

Abstract

The molecular hallmark of childhood ALL is characterized by recurrent, prognostic genetic alterations, many of which are cryptic by conventional cytogenetics. RNA-seq is a powerful next-generation sequencing technology with the ability to simultaneously identify cryptic gene rearrangements, sequence mutations and gene expression profiles in a single assay. We examined the feasibility and utility of incorporating RNA-seq into a prospective multi-center phase 3 clinical trial for children with newly-diagnosed ALL. Patients enrolled on the DFCI ALL Consortium Protocol 16-001 who consented to optional studies and had available material underwent RNA-seq. RNA-seq was performed in 173 ALL patients. RNA-seq identified at least one alteration in 157 (91%) patients. Fusion detection was 100% concordant with results obtained from conventional cytogenetic analyses. An additional 56 gene fusions were identified by RNA-seq, many of which confer prognostic or therapeutic significance. Gene expression profiling enabled further molecular classification into the followingB-ALL subgroups: Highhyperdiploid (n=36), ETV6-RUNX1/-like(n=31), TCF3-PBX1(n=7), KMT2A-rearranged (n=5), iAMP21 (n=1), hypodiploid (n=1), BCR-ABL1/-like (n=16), DUX4-rearranged (n=11), PAX5alterations (n=11), PAX5P80R (n=1), ZNF384-rearranged (n=4), NUTM1-rearranged (n=1), MEF2D-rearranged (n=1) and Others (n=10).RNA-seq identified 141 nonsynonymous mutations in 93 (54%) patients; the most frequent were RAS-MAPK pathway mutations. Among 79 patients with both low-density array and RNA-seq data for the Ph-like gene signature prediction, results were concordant in 74 (94%) patients. In conclusion, RNA-seqidentified several clinically-relevant genetic alterations not detected by conventional methods, supporting the integration of this technology in frontline pediatric ALL trials.

Published
2021
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31. Association of ultra-rare coding variants with genetic generalized epilepsy: A case–control whole exome sequencing study

Author

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

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

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

Published
2022
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32. 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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33. SYN1loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function

Author

Pietro Baldelli, Davide Pozzi, Dang Khoa Nguyen, Line Lapointe, Patrick Cossette, Manuela Fadda, Mirko Messa, Enrico Defranchi, Flavia Valtorta, Anna Corradi, Lysanne Patry, Franco Onofri, Fabio Benfenati, Guy A. Rouleau, Caroline Meloche, Anna Fassio, Julie Gauthier, Sonia Congia, Judith St-Onge, Amélie Piton, Laurent Mottron, Fassio, Anna, Patry, Lysanne, Congia, Sonia, Onofri, Franco, Piton, Amelie, Gauthier, Julie, Pozzi, Davide, Messa, Mirko, Defranchi, Enrico, Fadda, Manuela, Corradi, Anna, Baldelli, Pietro, Lapointe, Line, St-Onge, Judith, Meloche, Caroline, Mottron, Laurent, Valtorta, Flavia, Khoa Nguyen, Dang, Rouleau, Guy A., Benfenati, Fabio, and Patrick Cossette, And

Subjects
Synapsin I, Immunoblotting, Molecular Sequence Data, Nonsense mutation, Synaptogenesis, Biology, medicine.disease_cause, Gene Knockout Techniques, Epilepsy, chemistry.chemical_compound, Chlorocebus aethiops, Genetics, medicine, Animals, Humans, Missense mutation, SYNAPSIN, Amino Acid Sequence, AUTISM, Autistic Disorder, Phosphorylation, Neurotransmitter, Molecular Biology, EPILEPSY, Genetics (clinical), Neurons, Mutation, Base Sequence, Quebec, Sequence Analysis, DNA, General Medicine, Synapsin, Synapsins, medicine.disease, Pedigree, chemistry, Codon, Nonsense, COS Cells, Synapses, Electrophoresis, Polyacrylamide Gel, Epilepsies, Partial, Lod Score, Mitogen-Activated Protein Kinases
Abstract

Several genes predisposing to autism spectrum disorders (ASDs) with or without epilepsy have been identified, many of which are implicated in synaptic function. Here we report a Q555X mutation in synapsin 1 (SYN1), an X-linked gene encoding for a neuron-specific phosphoprotein implicated in the regulation of neurotransmitter release and synaptogenesis. This nonsense mutation was found in all affected individuals from a large French-Canadian family segregating epilepsy and ASDs. Additional mutations in SYN1 (A51G, A550T and T567A) were found in 1.0 and 3.5% of French-Canadian individuals with autism and epilepsy, respectively. The majority of these SYN1 mutations were clustered in the proline-rich D-domain which is substrate of multiple protein kinases. When expressed in synapsin I (SynI) knockout (KO) neurons, all the D-domain mutants failed in rescuing the impairment in the size and trafficking of synaptic vesicle pools, whereas the wild-type human SynI fully reverted the KO phenotype. Moreover, the nonsense Q555X mutation had a dramatic impact on phosphorylation by MAPK/Erk and neurite outgrowth, whereas the missense A550T and T567A mutants displayed impaired targeting to nerve terminals. These results demonstrate that SYN1 is a novel predisposing gene to ASDs, in addition to epilepsy, and strengthen the hypothesis that a disturbance of synaptic homeostasis underlies the pathogenesis of both diseases.

Published
2011

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