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1. Phenotypic effects of genetic variants associated with autism

Author

Rolland, Thomas, Cliquet, Freddy, Anney, Richard J. L., Moreau, Clara, Traut, Nicolas, Mathieu, Alexandre, Huguet, Guillaume, Duan, Jinjie, Warrier, Varun, Portalier, Swan, Dry, Louise, Leblond, Claire S., Douard, Elise, Amsellem, Frédérique, Malesys, Simon, Maruani, Anna, Toro, Roberto, Børglum, Anders D., Grove, Jakob, Baron-Cohen, Simon, Packer, Alan, Chung, Wendy K., Jacquemont, Sébastien, Delorme, Richard, and Bourgeron, Thomas

Published
2023
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2. Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism

Author

Pretzsch, Charlotte M., Floris, Dorothea L., Schäfer, Tim, Bletsch, Anke, Gurr, Caroline, Lombardo, Michael V., Chatham, Chris H., Tillmann, Julian, Charman, Tony, Arenella, Martina, Jones, Emily, Ambrosino, Sara, Bourgeron, Thomas, Dumas, Guillaume, Cliquet, Freddy, Leblond, Claire S., Loth, Eva, Oakley, Bethany, Buitelaar, Jan K., Baron-Cohen, Simon, Beckmann, Christian F., Persico, Antonio M., Banaschewski, Tobias, Durston, Sarah, Freitag, Christine M., Murphy, Declan G. M., and Ecker, Christine

Published
2023
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3. Genetic correlates of phenotypic heterogeneity in autism

Author

Warrier, Varun, Zhang, Xinhe, Reed, Patrick, Havdahl, Alexandra, Moore, Tyler M., Cliquet, Freddy, Leblond, Claire S., Rolland, Thomas, Rosengren, Anders, Rowitch, David H., Hurles, Matthew E., Geschwind, Daniel H., Børglum, Anders D., Robinson, Elise B., Grove, Jakob, Martin, Hilary C., Bourgeron, Thomas, and Baron-Cohen, Simon

Published
2022
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4. European Autism GEnomics Registry (EAGER): protocol for a multicentre cohort study and registry

Author

Bloomfield, Madeleine, primary, Lautarescu, Alexandra, additional, Heraty, Síofra, additional, Douglas, Sarah, additional, Violland, Pierre, additional, Plas, Roderik, additional, Ghosh, Anjuli, additional, Van den Bosch, Katrien, additional, Eaton, Eliza, additional, Absoud, Michael, additional, Battini, Roberta, additional, Blázquez Hinojosa, Ana, additional, Bolshakova, Nadia, additional, Bölte, Sven, additional, Bonanni, Paolo, additional, Borg, Jacqueline, additional, Calderoni, Sara, additional, Calvo Escalona, Rosa, additional, Castelo-Branco, Miguel, additional, Castro-Fornieles, Josefina, additional, Caro, Pilar, additional, Cliquet, Freddy, additional, Danieli, Alberto, additional, Delorme, Richard, additional, Elia, Maurizio, additional, Hempel, Maja, additional, Leblond, Claire S, additional, Madeira, Nuno, additional, McAlonan, Grainne, additional, Milone, Roberta, additional, Molloy, Ciara J, additional, Mouga, Susana, additional, Montiel, Virginia, additional, Pina Rodrigues, Ana, additional, Schaaf, Christian P, additional, Serrano, Mercedes, additional, Tammimies, Kristiina, additional, Tye, Charlotte, additional, Vigevano, Federico, additional, Oliveira, Guiomar, additional, Mazzone, Beatrice, additional, O’Neill, Cara, additional, Pender, Julie, additional, Romero, Verena, additional, Tillmann, Julian, additional, Oakley, Bethany, additional, Murphy, Declan G M, additional, Gallagher, Louise, additional, Bourgeron, Thomas, additional, Chatham, Christopher, additional, and Charman, Tony, additional

Published
2024
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6. Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features

Author

Rafiq, Muhammad Arshad, Leblond, Claire S, Saqib, Muhammad Arif Nadeem, Vincent, Akshita K, Ambalavanan, Amirthagowri, Khan, Falak Sher, Ayaz, Muhammad, Shaheen, Naseema, Spiegelman, Dan, Ali, Ghazanfar, Amin-ud-din, Muhammad, Laurent, Sandra, Mahmood, Huda, Christian, Mehtab, Ali, Nadir, Fennell, Alanna, Nanjiani, Zohair, Egger, Gerald, Caron, Chantal, Waqas, Ahmed, Ayub, Muhammad, Rasheed, Saima, Forgeot d’Arc, Baudouin, Johnson, Amelie, So, Joyce, Brohi, Muhammad Qasim, Mottron, Laurent, Ansar, Muhammad, Vincent, John B, and Xiong, Lan

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Mental Health, Pediatric, Rare Diseases, Clinical Research, Intellectual and Developmental Disabilities (IDD), Autism, Brain Disorders, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Congenital, Mental health, Abnormalities, Multiple, Autistic Disorder, Base Sequence, Developmental Disabilities, Female, Fingers, Genes, Recessive, Genotype, Haplotypes, Homozygote, Humans, Intellectual Disability, Male, Microcephaly, Molecular Sequence Data, Muscle Hypotonia, Myopia, Obesity, Pakistan, Pedigree, Phenotype, Retinal Degeneration, Sequence Analysis, DNA, Sequence Deletion, Vesicular Transport Proteins, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

BackgroundCohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits.MethodsClinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations.ResultsWe identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population.ConclusionWe suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.

Published
2015

8. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis

Author

Kaneb, Hannah M, Folkmann, Andrew W, Belzil, Véronique V, Jao, Li-En, Leblond, Claire S, Girard, Simon L, Daoud, Hussein, Noreau, Anne, Rochefort, Daniel, Hince, Pascale, Szuto, Anna, Levert, Annie, Vidal, Sabrina, André-Guimont, Catherine, Camu, William, Bouchard, Jean-Pierre, Dupré, Nicolas, Rouleau, Guy A, Wente, Susan R, and Dion, Patrick A

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Rare Diseases, Neurosciences, Brain Disorders, ALS, Neurodegenerative, Orphan Drug, 2.1 Biological and endogenous factors, Aetiology, Neurological, Amyotrophic Lateral Sclerosis, Animals, Arthrogryposis, Codon, Nonsense, DNA-Binding Proteins, Disease Models, Animal, Haploinsufficiency, HeLa Cells, Humans, Microscopy, Confocal, Motor Neurons, Mutation, Missense, Nuclear Pore, Nucleocytoplasmic Transport Proteins, Pedigree, Protein Processing, Post-Translational, RNA Splicing, RNA, Messenger, Zebrafish, Hela Cells, Medical and Health Sciences, Genetics & Heredity
Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1. In this study, we carried out the first screening of GLE1 in ALS patients (173 familial and 760 sporadic) and identified 2 deleterious mutations (1 splice site and 1 nonsense mutation) and 1 missense mutation. Functional analysis of the deleterious mutants revealed them to be unable to rescue motor neuron pathology in zebrafish morphants lacking Gle1. Furthermore, in HeLa cells, both mutations caused a depletion of hGle1 at the nuclear pore where it carries out an essential role in nuclear export of mRNA. These results suggest a haploinsufficiency mechanism and point to a causative role for GLE1 mutations in ALS patients. This further supports the involvement of global defects in RNA metabolism in ALS.

Published
2015

11. Dissecting the 22q13 region to explore the genetic and phenotypic diversity of patients with Phelan-McDermid syndrome

Author

Vitrac, Aline, primary, Leblond, Claire S., additional, Rolland, Thomas, additional, Cliquet, Freddy, additional, Mathieu, Alexandre, additional, Maruani, Anna, additional, Delorme, Richard, additional, Schön, Michael, additional, Grabrucker, Andreas M., additional, van Ravenswaaij-Arts, Conny, additional, Phelan, Katy, additional, Tabet, Anne-Claude, additional, and Bourgeron, Thomas, additional

Published
2023
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12. Both rare and common genetic variants contribute to autism in the Faroe Islands

Author

Leblond, Claire S, Cliquet, Freddy, Carton, Coralie, Huguet, Guillaume, Mathieu, Alexandre, Kergrohen, Thomas, Buratti, Julien, Lemière, Nathalie, Cuisset, Laurence, Bienvenu, Thierry, Boland, Anne, Deleuze, Jean-François, Stora, Tormodur, Biskupstoe, Rannva, Halling, Jónrit, Andorsdóttir, Guðrið, Billstedt, Eva, Gillberg, Christopher, and Bourgeron, Thomas

Published
2019
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13. Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations

Author

Gouder, Laura, Vitrac, Aline, Goubran-Botros, Hany, Danckaert, Anne, Tinevez, Jean-Yves, André-Leroux, Gwenaëlle, Atanasova, Ekaterina, Lemière, Nathalie, Biton, Anne, Leblond, Claire S., Poulet, Aurélie, Boland, Anne, Deleuze, Jean-François, Benchoua, Alexandra, Delorme, Richard, Bourgeron, Thomas, and Cloëz-Tayarani, Isabelle

Published
2019
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16. Author Correction: A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author

Tabet, Anne-Claude, Rolland, Thomas, Ducloy, Marie, Lévy, Jonathan, Buratti, Julien, Mathieu, Alexandre, Haye, Damien, Perrin, Laurence, Dupont, Céline, Passemard, Sandrine, Capri, Yline, Verloes, Alain, Drunat, Séverine, Keren, Boris, Mignot, Cyril, Marey, Isabelle, Jacquette, Aurélia, Whalen, Sandra, Pipiras, Eva, Benzacken, Brigitte, Chantot-Bastaraud, Sandra, Afenjar, Alexandra, Héron, Delphine, Le Caignec, Cédric, Beneteau, Claire, Pichon, Olivier, Isidor, Bertrand, David, Albert, El Khattabi, Laila, Kemeny, Stephan, Gouas, Laetitia, Vago, Philippe, Mosca-Boidron, Anne-Laure, Faivre, Laurence, Missirian, Chantal, Philip, Nicole, Sanlaville, Damien, Edery, Patrick, Satre, Véronique, Coutton, Charles, Devillard, Françoise, Dieterich, Klaus, Vuillaume, Marie-Laure, Rooryck, Caroline, Lacombe, Didier, Pinson, Lucile, Gatinois, Vincent, Puechberty, Jacques, Chiesa, Jean, Lespinasse, James, Dubourg, Christèle, Quelin, Chloé, Fradin, Mélanie, Journel, Hubert, Toutain, Annick, Martin, Dominique, Benmansour, Abdelamdjid, Leblond, Claire S., Toro, Roberto, Amsellem, Frédérique, Delorme, Richard, and Bourgeron, Thomas

Published
2019
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20. Genetic markers of Restless Legs Syndrome in Parkinson disease

Author

Gan-Or, Ziv, Alcalay, Roy N., Bar-Shira, Anat, Leblond, Claire S., Postuma, Ronald B., Ben-Shachar, Shay, Waters, Cheryl, Johnson, Amelie, Levy, Oren, Mirelman, Anat, Gana-Weisz, Mali, Dupré, Nicolas, Montplaisir, Jacques, Giladi, Nir, Fahn, Stanley, Xiong, Lan, Dion, Patrick A., Orr-Urtreger, Avi, and Rouleau, Guy A.

Published
2015
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21. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Author

FALS Sequencing Consortium, Cirulli, Elizabeth T., Lasseigne, Brittany N., Petrovski, Slavé, Sapp, Peter C., Dion, Patrick A., Leblond, Claire S., Couthouis, Julien, Lu, Yi-Fan, Wang, Quanli, Krueger, Brian J., Ren, Zhong, Keebler, Jonathan, Han, Yujun, Levy, Shawn E., Boone, Braden E., Wimbish, Jack R., Waite, Lindsay L., Jones, Angela L., Carulli, John P., Day-Williams, Aaron G., Staropoli, John F., Xin, Winnie W., Chesi, Alessandra, Raphael, Alya R., McKenna-Yasek, Diane, Cady, Janet, de Jong, J. M. B. Vianney, Kenna, Kevin P., Smith, Bradley N., Topp, Simon, Miller, Jack, Gkazi, Athina, Al-Chalabi, Ammar, van den Berg, Leonard H., Veldink, Jan, Silani, Vincenzo, Ticozzi, Nicola, Shaw, Christopher E., Baloh, Robert H., Appel, Stanley, Simpson, Ericka, Lagier-Tourenne, Clotilde, Pulst, Stefan M., Gibson, Summer, Trojanowski, John Q., Elman, Lauren, McCluskey, Leo, Grossman, Murray, Shneider, Neil A., Chung, Wendy K., Ravits, John M., Glass, Jonathan D., Sims, Katherine B., Van Deerlin, Vivianna M., Maniatis, Tom, Hayes, Sebastian D., Ordureau, Alban, Swarup, Sharan, Landers, John, Baas, Frank, Allen, Andrew S., Bedlack, Richard S., Harper, J. Wade, Gitler, Aaron D., Rouleau, Guy A., Brown, Robert, Harms, Matthew B., Cooper, Gregory M., Harris, Tim, Myers, Richard M., and Goldstein, David B.

Published
2015

23. Stratifying the autistic phenotype using electrophysiological indices of social perception

Author

Mason, Luke, primary, Moessnang, Carolin, additional, Chatham, Christopher, additional, Ham, Lindsay, additional, Tillmann, Julian, additional, Dumas, Guillaume, additional, Ellis, Claire, additional, Leblond, Claire S., additional, Cliquet, Freddy, additional, Bourgeron, Thomas, additional, Beckmann, Christian, additional, Charman, Tony, additional, Oakley, Beth, additional, Banaschewski, Tobias, additional, Meyer-Lindenberg, Andreas, additional, Baron-Cohen, Simon, additional, Bölte, Sven, additional, Buitelaar, Jan K., additional, Durston, Sarah, additional, Loth, Eva, additional, Oranje, Bob, additional, Persico, Antonio, additional, Dell’Acqua, Flavio, additional, Ecker, Christine, additional, Johnson, Mark H., additional, Murphy, Declan, additional, and Jones, Emily J. H., additional

Published
2022
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25. ALS GENES: Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Author

Cirulli, Elizabeth T., Lasseigne, Brittany N., Petrovski, Slavé, Sapp, Peter C., Dion, Patrick A., Leblond, Claire S., Couthouis, Julien, Lu, Yi-Fan, Wang, Quanli, Krueger, Brian J., Ren, Zhong, Keebler, Jonathan, Han, Yujun, Levy, Shawn E., Boone, Braden E., Wimbish, Jack R., Waite, Lindsay L., Jones, Angela L., Carulli, John P., Day-Williams, Aaron G., Staropoli, John F., Xin, Winnie W., Chesi, Alessandra, Raphael, Alya R., McKenna-Yasek, Diane, Cady, Janet, Vianney de Jong, J. M. B., Kenna, Kevin P., Smith, Bradley N., Topp, Simon, Miller, Jack, Gkazi, Athina, Sequencing Consortium, FALS, Al-Chalabi, Ammar, van den Berg, Leonard H., Veldink, Jan, Silani, Vincenzo, Ticozzi, Nicola, Shaw, Christopher E., Baloh, Robert H., Appel, Stanley, Simpson, Ericka, Lagier-Tourenne, Clotilde, Pulst, Stefan M., Gibson, Summer, Trojanowski, John Q., Elman, Lauren, McCluskey, Leo, Grossman, Murray, Shneider, Neil A., Chung, Wendy K., Ravits, John M., Glass, Jonathan D., Sims, Katherine B., Van Deerlin, Vivianna M., Maniatis, Tom, Hayes, Sebastian D., Ordureau, Alban, Swarup, Sharan, Landers, John, Baas, Frank, Allen, Andrew S., Bedlack, Richard S., Wade Harper, J., Gitler, Aaron D., Rouleau, Guy A., Brown, Robert, Harms, Matthew B., Cooper, Gregory M., Harris, Tim, Myers, Richard M., and Goldstein, David B.

Published
2015

27. Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2

Author

Schmeisser, Michael J., Ey, Elodie, Wegener, Stephanie, Bockmann, Juergen, Stempel, A. Vanessa, Kuebler, Angelika, Janssen, Anna-Lena, Udvardi, Patrick T., Shiban, Ehab, Spilker, Christina, Balschun, Detlef, Skryabin, Boris V., tom Dieck, Susanne, Smalla, Karl-Heinz, Montag, Dirk, Leblond, Claire S., Faure, Philippe, Torquet, Nicolas, Le Sourd, Anne-Marie, Toro, Roberto, Grabrucker, Andreas M., Shoichet, Sarah A., Schmitz, Dietmar, Kreutz, Michael R., Bourgeron, Thomas, Gundelfinger, Eckart D., and Boeckers, Tobias M.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour (1). Mutations in synaptic proteins such as neuroligins (2,3), neurexins (4), GKAPs/SAPAPs (5) and ProSAPs/ Shanks (6-10) were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/ Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion (11,12). Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/[Shank.sup.-/-] mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced JV-methyl-D-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/[Shank.sup.-/-] mutants with ProSAP2/ Shank3α[β.sup.-/-] mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype., Many of the recently identified autism spectrum disorders (ASD) candidate genes code for proteins of excitatory synapses (13-15), suggesting that these disorders may arise from molecular imbalances of synaptic connections. [...]

Published
2012
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28. A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories

Author

Akimoto, Chizuru, Volk, Alexander E, van Blitterswijk, Marka, Van den Broeck, Marleen, Leblond, Claire S, Lumbroso, Serge, Camu, William, Neitzel, Birgit, Onodera, Osamu, van Rheenen, Wouter, Pinto, Susana, Weber, Markus, Smith, Bradley, Proven, Melanie, Talbot, Kevin, Keagle, Pamela, Chesi, Alessandra, Ratti, Antonia, van der Zee, Julie, Alstermark, Helena, Birve, Anna, Calini, Daniela, Nordin, Angelica, Tradowsky, Daniela C, Just, Walter, Daoud, Hussein, Angerbauer, Sabrina, DeJesus-Hernandez, Mariely, Konno, Takuya, Lloyd-Jani, Anjali, de Carvalho, Mamede, Mouzat, Kevin, Landers, John E, Veldink, Jan H, Silani, Vincenzo, Gitler, Aaron D, Shaw, Christopher E, Rouleau, Guy A, van den Berg, Leonard H, Van Broeckhoven, Christine, Rademakers, Rosa, Andersen, Peter M, and Kubisch, Christian

Published
2014
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29. Neurobiological Correlates of Change in Adaptive Behavior in Autism.

Author

Pretzsch, Charlotte M., Schäfer, Tim, Lombardo, Michael V., Warrier, Varun, Mann, Caroline, Bletsch, Anke, Chatham, Chris H., Floris, Dorothea L., Tillmann, Julian, Yousaf, Afsheen, Jones, Emily, Charman, Tony, Ambrosino, Sara, Bourgeron, Thomas, Dumas, Guillaume, Loth, Eva, Oakley, Bethany, Buitelaar, Jan K., Cliquet, Freddy, and Leblond, Claire S.

Subjects
MAGNETIC resonance imaging, AUTISM, RESEARCH funding, PSYCHOLOGICAL adaptation, LONGITUDINAL method
Abstract

Objective: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is associated with significant difficulties in adaptive behavior and variation in clinical outcomes across the life span. Some individuals with ASD improve, whereas others may not change significantly, or regress. Hence, the development of "personalized medicine" approaches is essential. However, this requires an understanding of the biological processes underpinning differences in clinical outcome, at both the individual and subgroup levels, across the lifespan.Methods: The authors conducted a longitudinal follow-up study of 483 individuals (204 with ASD and 279 neurotypical individuals, ages 6-30 years), with assessment time points separated by ∼12-24 months. Data collected included behavioral data (Vineland Adaptive Behavior Scale-II), neuroanatomical data (structural MRI), and genetic data (DNA). Individuals with ASD were grouped into clinically meaningful "increasers," "no-changers," and "decreasers" in adaptive behavior. First, the authors compared neuroanatomy between outcome groups. Next, they examined whether deviations from the neurotypical neuroanatomical profile were associated with outcome at the individual level. Finally, they explored the observed neuroanatomical differences' potential genetic underpinnings.Results: Outcome groups differed in neuroanatomical features (cortical volume and thickness, surface area), including in "social brain" regions previously implicated in ASD. Also, deviations of neuroanatomical features from the neurotypical profile predicted outcome at the individual level. Moreover, neuroanatomical differences were associated with genetic processes relevant to neuroanatomical phenotypes (e.g., synaptic development).Conclusions: This study demonstrates, for the first time, that variation in clinical (adaptive) outcome is associated with both group- and individual-level variation in anatomy of brain regions enriched for genes relevant to ASD. This may facilitate the move toward better targeted/precision medicine approaches. [ABSTRACT FROM AUTHOR]

Published
2022
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30. Sub-diagnostic effects of genetic variants associated with autism

Author

Rolland, Thomas, primary, Cliquet, Freddy, additional, Anney, Richard J.L., additional, Moreau, Clara, additional, Traut, Nicolas, additional, Mathieu, Alexandre, additional, Huguet, Guillaume, additional, Duan, Jinjie, additional, Warrier, Varun, additional, Portalier, Swan, additional, Dry, Louise, additional, Leblond, Claire S., additional, Douard, Elise, additional, Amsellem, Frédérique, additional, Malesys, Simon, additional, Maruani, Anna, additional, Toro, Roberto, additional, Børglum, Anders D., additional, Grove, Jakob, additional, Baron-Cohen, Simon, additional, Packer, Alan, additional, Chung, Wendy K., additional, Jacquemont, Sébastien, additional, Delorme, Richard, additional, and Bourgeron, Thomas, additional

Published
2021
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32. Genetic correlates of phenotypic heterogeneity in autism

Author

Warrier, Varun, Zhang, Xinhe, Reed, Patrick, Havdahl, Alexandra, Moore, Tyler M., Cliquet, Freddy, Leblond, Claire S., Rolland, Thomas, Rosengren, Anders, Caceres, Antonia San Jose, Hayward, Hannah, Crawley, Daisy, Faulkner, Jessica, Sabet, Jessica, Ellis, Claire, Oakley, Bethany, Loth, Eva, Charman, Tony, Murphy, Declan, Holt, Rosemary, Waldman, Jack, Upadhyay, Jessica, Gunby, Nicola, Lai, Meng-Chuan, Renouf, Gwilym, Ruigrok, Amber, Taylor, Emily, Ziauddeen, Hisham, Deakin, Julia, di Bruttopilo, Sara Ambrosino, van Dijk, Sarai, Rijks, Yvonne, Koops, Tabitha, Douma, Miriam, Spaan, Alyssia, Selten, Iris, Steffers, Maarten, van Themaat, Anna Ver Loren, Bast, Nico, Baumeister, Sarah, O’Dwyer, Larry, Bours, Carsten, Rausch, Annika, von Rhein, Daniel, Cornelissen, Ineke, de Bruin, Yvette, Graauwmans, Maartje, Kostrzewa, Elzbieta, Cauvet, Elodie, Tammimies, Kristiina, Sitnikow, Rouslan, Dumas, Guillaume, Kim, Yang-Min, Bourgeron, Thomas, Hougaard, David M., Bybjerg-Grauholm, Jonas, Werge, Thomas, Mortensen, Preben Bo, Mors, Ole, Nordentoft, Merete, Adhya, Dwaipayan, Alamanza, Armandina, Allison, Carrie, Garvey, Isabelle, Parsons, Tracey, Smith, Paula, Tsompanidis, Alex, Burton, Graham J., Heazell, Alexander E. P., Gabis, Lidia V., Biron-Shental, Tal, Lancaster, Madeline A., Srivastava, Deepak P., Mill, Jonathan, Rowitch, David H., Hurles, Matthew E., Geschwind, Daniel H., Børglum, Anders D., Robinson, Elise B., Grove, Jakob, Martin, Hilary C., Baron-Cohen, Simon, University of Cambridge [UK] (CAM), Lovisenberg Diakonale Sykehus - Lovisenberg Diaconal Hospital [Oslo], Norwegian Institute of Public Health [Oslo] (NIPH), University of Oslo (UiO), University of Pennsylvania [Philadelphia], Children’s Hospital of Philadelphia (CHOP ), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen University Hospital, The Wellcome Trust Sanger Institute [Cambridge], University of California [Los Angeles] (UCLA), University of California, Aarhus University [Aarhus], Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Massachusetts General Hospital [Boston], Harvard T.H. Chan School of Public Health, V.W. is funded by St. Catharine’s College, Cambridge. This study was funded by grants to SBC from the Medical Research Council, the Wellcome Trust, the Autism Research Trust, the Templeton World Charity Foundation, and to T.B. from the Institut Pasteur, the CNRS, The Bettencourt-Schueller and the Cognacq-Jay Foundations, the APHP and the Université de Paris. SBC was funded by the Autism Research Trust, the Wellcome Trust, the Templeton World Charitable Foundation, and the NIHR Biomedical Research Centre in Cambridge, during the period of this work. The Medical Research Council (MRC) funded the Cambridge Autism Research Database (CARD) that made this study possible. SBC also received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 777394. The JU receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. His research was also supported by the National Institute of Health Research (NIHR) Applied Research Collaboration East of England (ARC EoE) programme. T.M.M. is supported by U.S. National Institutes of Mental Health (NIMH) grant MH117014. The views expressed are those of the authors, and not necessarily those of the NIHR, NHS or Department of Health and Social Care. We acknowledge with gratitude the generous support of Drs Dennis and Mireille Gillings in strengthening the collaboration between S.B.-C. and T.B., and between Cambridge University and the Institut Pasteur. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The AIMS-2-TRIALS LEAP receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA and AUTISM SPEAKS, Autistica, SFARI. A full list of the authors and affiliations in the AIMS-2-TRIALS LEAP group is provided in the Supplementary Information. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), NIMH (1U01MH109514-01 to ADB) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to ADB). We thank Jonathan Sebat for sharing the de novo variant calls in the SPARK and SSC datasets., Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Warrier, Varun [0000-0003-4532-8571], Havdahl, Alexandra [0000-0002-9268-0423], Moore, Tyler M [0000-0002-1384-0151], Rosengren, Anders [0000-0002-6682-1288], Hurles, Matthew E [0000-0002-2333-7015], Geschwind, Daniel H [0000-0003-2896-3450], Børglum, Anders D [0000-0001-8627-7219], Grove, Jakob [0000-0003-2284-5744], Martin, Hilary C [0000-0002-4454-9084], Bourgeron, Thomas [0000-0001-8164-9220], Baron-Cohen, Simon [0000-0001-9217-2544], Apollo - University of Cambridge Repository, University of Pennsylvania, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), University of California (UC), Harvard University-Massachusetts Institute of Technology (MIT), and S.B.-C. received funding from the Wellcome Trust (214322\Z\18\Z). For the purpose of open access, we have applied a CC BY public copyright licence to any author accepted manuscript version arising from this submission. S.B.-C. also received funding from the Autism Centre of Excellence, the SFARI, the Templeton World Charitable Fund, the MRC and the National Institute for Health Research Cambridge Biomedical Research Centre. The research was supported by the National Institute for Health Research Applied Research Collaboration East of England. Any views expressed are those of the author(s) and not necessarily those of the funder. Some of the results leading to this publication have received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 777394 for the project AIMS-2-TRIALS. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation program and the EFPIA and Autism Speaks, Autistica and the SFARI. V.W. is funded by St. Catharine’s College, Cambridge. T.B. has received funding from the Institut Pasteur, the CNRS, the Bettencourt–Schueller and the Cognacq–Jay Foundations, the APHP and the Université de Paris Cité. We acknowledge with gratitude the generous support of D. and M. Gillings in strengthening the collaboration between S.B.-C. and T.B. and between Cambridge University and the Institut Pasteur. The iPSYCH team was supported by grants from the Lundbeck Foundation (R102-A9118, R155-2014-1724 and R248-2017-2003), the NIMH (1U01MH109514-01 to A.D.B.) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. High-performance computer capacity for handling and statistical analysis of iPSYCH data on the GenomeDK HPC facility was provided by the Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing, iSEQ, Aarhus University, Denmark (grant to A.D.B.). We thank J. Sebat for sharing the de novo variant calls in the SPARK and SSC datasets. We are grateful to all families at the participating SSC sites as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren and E. Wijsman). We are grateful to all families in the SPARK study, the SPARK clinical sites and SPARK staff.

Subjects
Male, Autism Spectrum Disorder, CHILDREN, behavioral disciplines and activities, Developmental psychology, Correlation, 03 medical and health sciences, Nonverbal communication, AGE, Cognition, 0302 clinical medicine, Intellectual Disability, mental disorders, Genetics, medicine, Humans, Limited evidence, GENOME-WIDE ASSOCIATION, Autistic Disorder, Association (psychology), COMMON, SPECTRUM DISORDER, 030304 developmental biology, RISK, ARCHITECTURE, 0303 health sciences, IDENTIFICATION, [SCCO.NEUR]Cognitive science/Neuroscience, medicine.disease, Educational attainment, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Adaptive behaviour, Schizophrenia, Autism, Female, SIMONS SIMPLEX COLLECTION, Psychology, 030217 neurology & neurosurgery
Abstract

Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440, Funder: Templeton World Charity Foundation (Templeton World Charity Foundation, Inc.); doi: https://doi.org/10.13039/501100011730, The substantial phenotypic heterogeneity in autism limits our understanding of its genetic etiology. To address this gap, here we investigated genetic differences between autistic individuals (nmax = 12,893) based on core and associated features of autism, co-occurring developmental disabilities and sex. We conducted a comprehensive factor analysis of core autism features in autistic individuals and identified six factors. Common genetic variants were associated with the core factors, but de novo variants were not. We found that higher autism polygenic scores (PGS) were associated with lower likelihood of co-occurring developmental disabilities in autistic individuals. Furthermore, in autistic individuals without co-occurring intellectual disability (ID), autism PGS are overinherited by autistic females compared to males. Finally, we observed higher SNP heritability for autistic males and for autistic individuals without ID. Deeper phenotypic characterization will be critical in determining how the complex underlying genetics shape cognition, behavior and co-occurring conditions in autism.

Published
2020

33. SMPD1 mutations, activity, and α‐synuclein accumulation in Parkinson's disease

Author

Alcalay, Roy N., primary, Mallett, Victoria, additional, Vanderperre, Benoît, additional, Tavassoly, Omid, additional, Dauvilliers, Yves, additional, Wu, Richard Y.J., additional, Ruskey, Jennifer A., additional, Leblond, Claire S., additional, Ambalavanan, Amirthagowri, additional, Laurent, Sandra B., additional, Spiegelman, Dan, additional, Dionne‐Laporte, Alexandre, additional, Liong, Christopher, additional, Levy, Oren A., additional, Fahn, Stanley, additional, Waters, Cheryl, additional, Kuo, Sheng‐Han, additional, Chung, Wendy K., additional, Ford, Blair, additional, Marder, Karen S., additional, Kang, Un Jung, additional, Hassin‐Baer, Sharon, additional, Greenbaum, Lior, additional, Trempe, Jean‐Francois, additional, Wolf, Pavlina, additional, Oliva, Petra, additional, Zhang, Xiaokui Kate, additional, Clark, Lorraine N., additional, Langlois, Melanie, additional, Dion, Patrick A., additional, Fon, Edward A., additional, Dupre, Nicolas, additional, Rouleau, Guy A., additional, and Gan‐Or, Ziv, additional

Published
2019
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34. Absence of Mutation Enrichment for Genes Phylogenetically Conserved in the Olivocerebellar Motor Circuitry in a Cohort of Canadian Essential Tremor Cases

Author

Schmouth, Jean-François, primary, Houle, Gabrielle, additional, Ambalavanan, Amirthagowri, additional, Leblond, Claire S., additional, Spiegelman, Dan, additional, Laurent, Sandra B., additional, Bourassa, Cynthia V., additional, Panisset, Michel, additional, Chouinard, Sylvain, additional, Dupré, Nicolas, additional, Vilariño-Güell, Carles, additional, Rajput, Alex, additional, Dion, Patrick A., additional, and Rouleau, Guy A., additional

Published
2018
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35. Homozygous 2p11.2 deletion supports the implication of ELMOD3 in hearing loss and reveals the potential association of CAPG with ASD/ID etiology

Author

Lahbib, Saida, primary, Leblond, Claire S., additional, Hamza, Mariem, additional, Regnault, Béatrice, additional, Lemée, Laure, additional, Mathieu, Alexandre, additional, Jaouadi, Hager, additional, Mkaouar, Rahma, additional, Youssef-Turki, Ilhem Ben, additional, Belhadj, Ahlem, additional, Kraoua, Ichraf, additional, Bourgeron, Thomas, additional, and Abdelhak, Sonia, additional

Published
2018
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36. Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations

Author

Gouder, Laura, Vitrac, Aline, Goubran-Botros, Hany, Danckaert, Anne, Tinevez, Jean-Yves, ANDRE-LEROUX, Gwenaelle, Atanasova, Ekatarina, Lemière, Nathalie, Leblond, Claire S, Poulet, Aurélie, Benchoua, Alexandra, Delorme, Richard, Bourgeron, Thomas, Cloëz-Tayarani, Isabelle, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS), Human Genetics and Cognitive Functions, Université Paris Diderot - Paris 7 (UPD7), Imagopole (CITECH), Institut Pasteur [Paris], Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de la Recherche Agronomique (INRA), CECS - I-STEM, Association française contre les myopathies (AFM-Téléthon), Department of Child and Adolescent Psychiatry, University Hospitals Leuven [Leuven], and auto-saisine

Subjects
nervous system, [SDV]Life Sciences [q-bio], mental disorders, behavioral disciplines and activities
Abstract

Altered spinogenesis in iPSC-derived cortical neurons from patients with autism carrying de novo SHANK3 mutations

Published
2017

37. The dementia-associated APOE ε4 allele is not associated with REM sleep behavior disorder

Author

Gan-Or, Ziv, Montplaisir, Jacques-Yves, Ross, Jay P., Poirier, Judes, Warby, Simon, Arnulf, Isabelle, Strong, Stephanie, Dauvilliers, Yves, Leblond, Claire S., Hu, Michele T. M., Högl, Birgit, Stefani, Ambra, Monaca, Christelle, Cochen De Cock, Valérie, Boivin, Michel, Ferini-Strambi, Luigi, Plazzi, Giuseppe, Antelmi, Elena, Young, Peter, Heidbreder, Anna, Barber, Thomas R, Evetts, Samuel G., Rolinski, Michal, Dion, Patrick A., Desautels, Alex, Gagnon, Jean-François, Dupré, Nicolas, Postuma, Ronald B., Rouleau, Guy, and Université de Montréal. Faculté de médecine. Département de psychiatrie et d'addictologie

Subjects
Parkinson's disease, REM sleep behavior disorder, Dementia with Lewy bodies, Genetics, APOE
Abstract

The present study aimed to examine whether the APOE ε4 allele, associated with dementia with Lewy bodies (DLB), and possibly with dementia in Parkinson's disease (PD), is also associated with idiopathic rapid eye movement sleep behavior disorder (RBD). Two single nucleotide polymorphisms, rs429358 and rs7412, were genotyped in RBD patients (n = 480) and in controls (n = 823). APOE ε4 allele frequency was 0.14 among RBD patients and 0.13 among controls (OR = 1.11, 95% CI: 0.88–1.40, p = 0.41). APOE ε4 allele frequencies were similar in those who converted to DLB (0.14) and those who converted to Parkinson's disease (0.12) or multiple system atrophy (0.14, p = 1.0). The APOE ε4 allele is neither a risk factor for RBD nor it is associated with conversion from RBD to DLB or other synucleinopathies.

Published
2016

38. Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder

Author

Li, Jiao, primary, Ruskey, Jennifer A., additional, Arnulf, Isabelle, additional, Dauvilliers, Yves, additional, Hu, Michele T.M., additional, Högl, Birgit, additional, Leblond, Claire S., additional, Zhou, Sirui, additional, Ambalavanan, Amirthagowri, additional, Ross, Jay P., additional, Bourassa, Cynthia V., additional, Spiegelman, Dan, additional, Laurent, Sandra B, additional, Stefani, Ambra, additional, Charley Monaca, Christelle, additional, Cochen De Cock, Valérie, additional, Boivin, Michel, additional, Ferini‐Strambi, Luigi, additional, Plazzi, Giuseppe, additional, Antelmi, Elena, additional, Young, Peter, additional, Heidbreder, Anna, additional, Labbe, Catherine, additional, Ferman, Tanis J., additional, Dion, Patrick A., additional, Fan, Dongsheng, additional, Desautels, Alex, additional, Gagnon, Jean‐François, additional, Dupré, Nicolas, additional, Fon, Edward A., additional, Montplaisir, Jacques Y., additional, Boeve, Bradley F., additional, Postuma, Ronald B., additional, Rouleau, Guy A., additional, Ross, Owen A., additional, and Gan‐Or, Ziv, additional

Published
2018
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40. A framework to identify contributing genes in patients with Phelan-McDermid syndrome

Author

Tabet, Anne-Claude, primary, Rolland, Thomas, additional, Ducloy, Marie, additional, Lévy, Jonathan, additional, Buratti, Julien, additional, Mathieu, Alexandre, additional, Haye, Damien, additional, Perrin, Laurence, additional, Dupont, Céline, additional, Passemard, Sandrine, additional, Capri, Yline, additional, Verloes, Alain, additional, Drunat, Séverine, additional, Keren, Boris, additional, Mignot, Cyril, additional, Marey, Isabelle, additional, Jacquette, Aurélia, additional, Whalen, Sandra, additional, Pipiras, Eva, additional, Benzacken, Brigitte, additional, Chantot-Bastaraud, Sandra, additional, Afenjar, Alexandra, additional, Héron, Delphine, additional, Le Caignec, Cédric, additional, Beneteau, Claire, additional, Pichon, Olivier, additional, Isidor, Bertrand, additional, David, Albert, additional, El Khattabi, Laila, additional, Kemeny, Stephan, additional, Gouas, Laetitia, additional, Vago, Philippe, additional, Mosca-Boidron, Anne-Laure, additional, Faivre, Laurence, additional, Missirian, Chantal, additional, Philip, Nicole, additional, Sanlaville, Damien, additional, Edery, Patrick, additional, Satre, Véronique, additional, Coutton, Charles, additional, Devillard, Françoise, additional, Dieterich, Klaus, additional, Vuillaume, Marie-Laure, additional, Rooryck, Caroline, additional, Lacombe, Didier, additional, Pinson, Lucile, additional, Gatinois, Vincent, additional, Puechberty, Jacques, additional, Chiesa, Jean, additional, Lespinasse, James, additional, Dubourg, Christèle, additional, Quelin, Chloé, additional, Fradin, Mélanie, additional, Journel, Hubert, additional, Toutain, Annick, additional, Martin, Dominique, additional, Benmansour, Abdelamdjid, additional, Leblond, Claire S., additional, Toro, Roberto, additional, Amsellem, Frédérique, additional, Delorme, Richard, additional, and Bourgeron, Thomas, additional

Published
2017
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41. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis

Author

Kenna, Kevin P, van Doormaal, Perry T C, Dekker, Annelot M, Ticozzi, Nicola, Kenna, Brendan J, Diekstra, Frank P, van Rheenen, Wouter, van Eijk, Kristel R, Jones, Ashley R, Keagle, Pamela, Shatunov, Aleksey, Sproviero, William, Smith, Bradley N, van Es, Michael A, Topp, Simon D, Kenna, Aoife, Miller, Jack W, Fallini, Claudia, Tiloca, Cinzia, McLaughlin, Russell L, Vance, Caroline, Troakes, Claire, Colombrita, Claudia, Mora, Gabriele, Calvo, Andrea, Verde, Federico, Al-Sarraj, Safa, King, Andrew, Calini, Daniela, de Belleroche, Jacqueline, Baas, Frank, van der Kooi, Anneke J, de Visser, Marianne, Ten Asbroek, Anneloor L M A, Sapp, Peter C, McKenna-Yasek, Diane, Polak, Meraida, Asress, Seneshaw, Muñoz-Blanco, José Luis, Strom, Tim M, Meitinger, Thomas, Morrison, Karen E, Lauria, Giuseppe, Williams, Kelly L, Leigh, P Nigel, Nicholson, Garth A, Blair, Ian P, Leblond, Claire S, van den Berg, Leonard H, Veldink, Jan H, and SLAGEN Consortium

Subjects
Journal Article, Comparative Study
Abstract

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.

Published
2016

42. Retention of hexanucleotide repeat-containing intron in C9orf72 mRNA:implications for the pathogenesis of ALS/FTD

Author

Niblock, Michael, Smith, Bradley N., Lee, Youn-Bok, Sardone, Valentina, Topp, Simon, Troakes, Claire, Al-Sarraj, Safa, Leblond, Claire S., Dion, Patrick A., Rouleau, Guy A., Shaw, Christopher E., and Gallo, Jean-Marc

Subjects
Models, Molecular, DNA Repeat Expansion, C9orf72 Protein, Research, Amyotrophic Lateral Sclerosis, Brain, Proteins, Repeats, Splicing, Introns, Frontotemporal Dementia, C9orf72, RNA, Humans, RNA, Messenger
Abstract

Introduction The most common forms of amyotrophic lateral sclerosis and frontotemporal dementia are caused by a large GGGGCC repeat expansion in the first intron of the C9orf72 gene. The repeat-containing intron should be degraded after being spliced out, however GGGGCC repeat-containing RNA species either accumulate in nuclear foci or are exported to the cytoplasm where they are translated into potentially toxic dipeptide repeat proteins by repeat-associated non-AUG-initiated (RAN) translation. Results In order to determine the mechanisms of repeat-containing intron misprocessing, we have analyzed C9orf72 transcripts in lymphoblasts from C9orf72 expansion carriers (n = 15) and control individuals (n = 15). We have identified polyadenylated C9orf72 RNA species retaining the repeat-containing intron and in which downstream exons are spliced correctly resulting in a C9orf72 mRNA with an enlarged 5’-UTR containing the GGGGCC repeats. Intron-retaining transcripts are produced from both wild-type and mutant alleles. Intron-retaining C9orf72 transcripts were also detected in brain with a 2.7 fold increase measured in the frontal cortex from heterozygous expansion carriers (n = 11) compared to controls (n = 10). The level of intron-retaining transcripts was increased 5.9 fold in a case homozygous for the expansion. We also show that a large proportion of intron 1-retaining C9orf72 transcripts accumulate in the nucleus. Conclusions Retention of the repeat-containing intron in mature C9orf72 mRNA can potentially explain nuclear foci formation as well as nuclear export of GGGGCC repeat RNA and suggests that the misprocessing of C9orf72 transcripts initiates the pathogenic process caused by C9orf72 hexanucleotide repeat expansions as well as provides the basis for novel therapeutic strategies. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0289-4) contains supplementary material, which is available to authorized users.

Published
2016

43. The dementia-associated APOE ε4 allele is not associated with rapid eye movement sleep behavior disorder

Author

Gan-Or, Ziv, primary, Montplaisir, Jacques Y., additional, Ross, Jay P., additional, Poirier, Judes, additional, Warby, Simon C., additional, Arnulf, Isabelle, additional, Strong, Stephanie, additional, Dauvilliers, Yves, additional, Leblond, Claire S., additional, Hu, Michele T.M., additional, Högl, Birgit, additional, Stefani, Ambra, additional, Monaca, Christelle Charley, additional, De Cock, Valérie Cochen, additional, Boivin, Michel, additional, Ferini-Strambi, Luigi, additional, Plazzi, Giuseppe, additional, Antelmi, Elena, additional, Young, Peter, additional, Heidbreder, Anna, additional, Barber, Thomas R., additional, Evetts, Samuel G., additional, Rolinski, Michal, additional, Dion, Patrick A., additional, Desautels, Alex, additional, Gagnon, Jean-François, additional, Dupré, Nicolas, additional, Postuma, Ronald B., additional, and Rouleau, Guy A., additional

Published
2017
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44. Meta-analysis of SHANK mutations in autism spectrum disorders: a gradient of severity in cognitive impairments

Author

Barsh, Gregory S., Leblond, Claire S., Nava, Caroline, Polge, Anne, Gauthier, Julie, Huguet, Guillaume, Lumbroso, Serge, Giuliano, Fabienne, Stordeur, Coline, Depienne, Christel, Mouzat, Kevin, Pinto, Dalila, Howe, Jennifer, Lemière, Nathalie, Durand, Christelle M., Guibert, Jessica, Ey, Elodie, Toro, Roberto, Peyre, Hugo, Mathieu, Alexandre, Amsellem, Frédérique, Rastam, Maria, Gillberg, I. Carina, Rappold, Gudrun A., Holt, Richard, Monaco, Anthony P., Maestrini, Elena, Galan, Pilar, Heron, Delphine, Jacquette, Aurélia, Afenjar, Alexandra, Rastetter, Agnès, Brice, Alexis, Devillard, Françoise, Assouline, Brigitte, Laffargue, Fanny, Lespinasse, James, Chiesa, Jean, Rivier, François, Bonneau, Dominique, Regnault, Beatrice, Zelenika, Diana, Delepine, Marc, Lathrop, Mark, Sanlaville, Damien, Schluth-Bolard, Caroline, Edery, Patrick, Perrin, Laurence, Tabet, Anne Claude, Schmeisser, Michael J., Boeckers, Tobias M., Coleman, Mary, Sato, Daisuke, Szatmari, Peter, Scherer, Stephen W., Rouleau, Guy A., Betancur, Catalina, Leboyer, Marion, Gillberg, Christopher, Delorme, Richard, and Bourgeron, Thomas

Subjects
mental disorders
Abstract

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

Published
2014

45. Analysis of DNAJC13 mutations in French-Canadian/French cohort of Parkinson's disease

Author

Ross, Jay P., primary, Dupre, Nicolas, additional, Dauvilliers, Yves, additional, Strong, Stephanie, additional, Ambalavanan, Amirthagowri, additional, Spiegelman, Dan, additional, Dionne-Laporte, Alexandre, additional, Pourcher, Emanuelle, additional, Langlois, Melanie, additional, Boivin, Michel, additional, Leblond, Claire S., additional, Dion, Patrick A., additional, Rouleau, Guy A., additional, and Gan-Or, Ziv, additional

Published
2016
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46. CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia

Author

Williams, Kelly L., primary, Topp, Simon, additional, Yang, Shu, additional, Smith, Bradley, additional, Fifita, Jennifer A., additional, Warraich, Sadaf T., additional, Zhang, Katharine Y., additional, Farrawell, Natalie, additional, Vance, Caroline, additional, Hu, Xun, additional, Chesi, Alessandra, additional, Leblond, Claire S., additional, Lee, Albert, additional, Rayner, Stephanie L., additional, Sundaramoorthy, Vinod, additional, Dobson-Stone, Carol, additional, Molloy, Mark P., additional, van Blitterswijk, Marka, additional, Dickson, Dennis W., additional, Petersen, Ronald C., additional, Graff-Radford, Neill R., additional, Boeve, Bradley F., additional, Murray, Melissa E., additional, Pottier, Cyril, additional, Don, Emily, additional, Winnick, Claire, additional, McCann, Emily P., additional, Hogan, Alison, additional, Daoud, Hussein, additional, Levert, Annie, additional, Dion, Patrick A., additional, Mitsui, Jun, additional, Ishiura, Hiroyuki, additional, Takahashi, Yuji, additional, Goto, Jun, additional, Kost, Jason, additional, Gellera, Cinzia, additional, Gkazi, Athina Soragia, additional, Miller, Jack, additional, Stockton, Joanne, additional, Brooks, William S., additional, Boundy, Karyn, additional, Polak, Meraida, additional, Muñoz-Blanco, José Luis, additional, Esteban-Pérez, Jesús, additional, Rábano, Alberto, additional, Hardiman, Orla, additional, Morrison, Karen E., additional, Ticozzi, Nicola, additional, Silani, Vincenzo, additional, de Belleroche, Jacqueline, additional, Glass, Jonathan D., additional, Kwok, John B. J., additional, Guillemin, Gilles J., additional, Chung, Roger S., additional, Tsuji, Shoji, additional, Brown, Robert H., additional, García-Redondo, Alberto, additional, Rademakers, Rosa, additional, Landers, John E., additional, Gitler, Aaron D., additional, Rouleau, Guy A., additional, Cole, Nicholas J., additional, Yerbury, Justin J., additional, Atkin, Julie D., additional, Shaw, Christopher E., additional, Nicholson, Garth A., additional, and Blair, Ian P., additional

Published
2016
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48. Retention of hexanucleotide repeat-containing intron in C9orf72 mRNA: implications for the pathogenesis of ALS/FTD

Author

Niblock, Michael, primary, Smith, Bradley N., additional, Lee, Youn-Bok, additional, Sardone, Valentina, additional, Topp, Simon, additional, Troakes, Claire, additional, Al-Sarraj, Safa, additional, Leblond, Claire S., additional, Dion, Patrick A., additional, Rouleau, Guy A., additional, Shaw, Christopher E., additional, and Gallo, Jean-Marc, additional

Published
2016
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49. Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis

Author

Leblond, Claire S., primary, Gan-Or, Ziv, additional, Spiegelman, Dan, additional, Laurent, Sandra B., additional, Szuto, Anna, additional, Hodgkinson, Alan, additional, Dionne-Laporte, Alexandre, additional, Provencher, Pierre, additional, de Carvalho, Mamede, additional, Orrù, Sandro, additional, Brunet, Denis, additional, Bouchard, Jean-Pierre, additional, Awadalla, Philip, additional, Dupré, Nicolas, additional, Dion, Patrick A., additional, and Rouleau, Guy A., additional

Published
2016
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50. 11q24.2‐25 micro‐rearrangements in autism spectrum disorders: Relation to brain structures

Author

Maruani, Anna, primary, Huguet, Guillaume, additional, Beggiato, Anita, additional, ElMaleh, Monique, additional, Toro, Roberto, additional, Leblond, Claire S., additional, Mathieu, Alexandre, additional, Amsellem, Frederique, additional, Lemière, Nathalie, additional, Verloes, Alain, additional, Leboyer, Marion, additional, Gillberg, Christopher, additional, Bourgeron, Thomas, additional, and Delorme, Richard, additional

Published
2015
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