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101. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Author

Aref-Eshghi, Erfan, primary, Kerkhof, Jennifer, additional, Pedro, Victor P., additional, Barat-Houari, Mouna, additional, Ruiz-Pallares, Nathalie, additional, Andrau, Jean-Christophe, additional, Lacombe, Didier, additional, Van-Gils, Julien, additional, Fergelot, Patricia, additional, Dubourg, Christèle, additional, Cormier-Daire, Valerie, additional, Rondeau, Sophie, additional, Lecoquierre, François, additional, Saugier-Veber, Pascale, additional, Nicolas, Gaël, additional, Lesca, Gaetan, additional, Chatron, Nicolas, additional, Sanlaville, Damien, additional, Vitobello, Antonio, additional, Faivre, Laurence, additional, Thauvin-Robinet, Christel, additional, Laumonnier, Frederic, additional, Raynaud, Martine, additional, Alders, Mariëlle, additional, Mannens, Marcel, additional, Henneman, Peter, additional, Hennekam, Raoul C., additional, Velasco, Guillaume, additional, Francastel, Claire, additional, Ulveling, Damien, additional, Ciolfi, Andrea, additional, Pizzi, Simone, additional, Tartaglia, Marco, additional, Heide, Solveig, additional, Héron, Delphine, additional, Mignot, Cyril, additional, Keren, Boris, additional, Whalen, Sandra, additional, Afenjar, Alexandra, additional, Bienvenu, Thierry, additional, Campeau, Philippe M., additional, Rousseau, Justine, additional, Levy, Michael A., additional, Brick, Lauren, additional, Kozenko, Mariya, additional, Balci, Tugce B., additional, Siu, Victoria Mok, additional, Stuart, Alan, additional, Kadour, Mike, additional, Masters, Jennifer, additional, Takano, Kyoko, additional, Kleefstra, Tjitske, additional, de Leeuw, Nicole, additional, Field, Michael, additional, Shaw, Marie, additional, Gecz, Jozef, additional, Ainsworth, Peter J., additional, Lin, Hanxin, additional, Rodenhiser, David I., additional, Friez, Michael J., additional, Tedder, Matt, additional, Lee, Jennifer A., additional, DuPont, Barbara R., additional, Stevenson, Roger E., additional, Skinner, Steven A., additional, Schwartz, Charles E., additional, Genevieve, David, additional, and Sadikovic, Bekim, additional

Published
2020
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102. Identification of mobile retrocopies during genetic testing: Consequences for routine diagnosis

Author

Chatron, Nicolas, Cassinari, Kevin, Quenez, Olivier, Baert-Desurmont, Stephanie, Bardel, Claire, Buisine, Marie Pierre, Calpena, Eduardo, Capri, Yline, Corominas Galbany, Jordi, Diguet, F., EDERY, PATRICK, Isidor, Bertrand, Labalme, Audrey, Caignec, Cédric Le, Lecoquierre, Francois, Lindenbaum, Pierre, Rollat Farnier, Pierre Antoine, Simonet, F., Saugier Veber, Pascale, Tabet, Anne-Claude, Toutain, Annick, Wilkie, AOM, Lesca, Gaëtan, Sanlaville, Damien, Nicolas, Gael, Schluth-Bolard, Caroline, Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Hôpital Claude Huriez [Lille], CHU Lille, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Hospices Civils de Lyon (HCL), Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de cytogénétique constitutionnelle, Hospices Civils de Lyon (HCL)-CHU de Lyon-Centre Neuroscience et Recherche, Sarcomes osseux et remodelage des tissus calcifiés - Phy-Os [Nantes - INSERM U1238] (Phy-Os), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Bretagne Loire (UBL)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut du thorax, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biostatistiques [Lyon], IRCELYON-Microscopie (MICROSCOPIE), Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, UF de Cytogénétique, AP-HP Hôpital universitaire Robert-Debré [Paris], Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon], Laboratoire de Biologie Moléculaire de la Cellule (LBMC), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2019

103. Clinical spectrum of -related epileptic disorders

Author

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

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

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

Published
2019

104. Complex chromosal rearrangement : from precise molecular characterization to functional consequences

Author

Chatron, Nicolas, STAR, ABES, Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Damien Sanlaville, Caroline Schluth-Bolard, Centre de recherche en neurosciences de Lyon (CRNL), and Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Séquençage, Cytogenetics, Genome, Génome, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Retrocopies, Sequencing, RNA-Seq, Cytogénétique, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Chromoanagenesis, Transcriptome, Rétrocopies
Abstract

Human cytogenetics is a discipline aimed at studying the structure and function of the chromosomes of our species. In the early 2010's, genome sequencing revealed chromosomal rearrangements of as yet unknown complexity, termed chromoanagenesis. While a significant proportion of tumour genomes present such anomalies, descriptions of constitutional cases are rare and the underlying mechanisms poorly understood. We report here the genome sequencing of 20 new cases of constitutional chromoanagenesis (6 balanced and 14 unbalanced), constituting the largest cohort to date. In several patients, loci of less than one kilobase appear several times in the reshuffled chromosome in what we call a "hub". The analysis of the distribution of breakpoints of these chromoanagenesis and those in the literature showed that late chromatin replication was the main "risk factor" for chromosomal breakage. This result provides an orthogonal demonstration of the premature condensation of a chromosome hypothesis at the origin of these rearrangements and shows for the first time a common origin of constitutional and tumoral chromoanagenesis. At the same time, breakpoint distribution of simple rearrangements appears to be biased towards the center of the nucleus, opening up important avenues of research. To better understand the consequences of these complex reshuffles on the functioning of the genome, we studied the transcriptome of the 6 balanced chromoanagenesis. We have not detected any massive deregulation of the genome. Even locally, near the breakpoints, there does not appear to be any deregulation of gene expression, again raising important questions about the mechanisms of "resistance" to structural variants. The detection of chromosomal rearrangements is (almost) no longer limited by technology (short-read , long-read, linked-read sequencing, optical mapping). Understanding the mechanisms at their origin, knowledge of their pathogenicity and more generally the mastering of genome biology are the new limits to the genotype/phenotype correlation. By studying chromoanagenesis, an exceptional fusion transcript in a hemophiliac patient and describing poorly known transposable elements (retrocopies) we are bringing important new information to the field, La cytogénétique humaine est une discipline visant à l’étude de la structure et de la fonction des chromosomes de notre espèce. Au début des années 2010, le séquençage de génome a révélé des remaniements chromosomiques d’une complexité encore inconnue, dénommés chromoanagenesis. Si une importante proportion de génomes tumoraux présentent ce type d’anomalies, les descriptions de cas constitutionnels sont rares et les mécanismes sous-jacents mal compris. Nous rapportons ici le séquençage de génome de 20 nouveaux cas de chromoanagenesis constitutionnels (6 équilibrés et 14 déséquilibrés), constituant la plus large cohorte à ce jour. Chez plusieurs patients, des loci de moins d’un kilobase apparaissent plusieurs fois dans le remaniement dans ce que nous nommons un « hub ». L’étude de la distribution des points de cassure de ces chromoanagenesis et de ceux de la littérature a montré que la réplication tardive de la chromatine était le « facteur de risque » principal de cassure chromosomique. Ce résultat vient apporter une démonstration orthogonale à l’hypothèse de condensation prématurée d’un chromosome à l’origine de ces remaniements et montre pour la première fois une origine commune aux chromoanagenesis constitutionnels et tumoraux. Parallèlement, la distribution des points de cassure de remaniements simples apparaît biaisée vers le centre du noyau ouvrant d’importantes voies de recherche. Pour mieux comprendre les conséquences de ces remaniements complexes sur le fonctionnement du génome nous avons étudié le transcriptome des 6 cas de chromoanagenesis équilibrés. Nous n’avons pas mis en évidence de dérégulation massive du génome. Même localement, à proximité des points de cassure, il n’apparaît pas de dérégulation de l’expression génique posant là encore d’importantes questions sur les mécanismes de « résistance » aux remaniements. La détection de remaniements chromosomiques n’est aujourd’hui (presque) plus limitée par la technologie (séquençage short-read, long-read, linked-read, cartographie optique). La compréhension des mécanismes à leur origine, la connaissance de leur pouvoir pathogène et plus généralement la maîtrise de la biologie du génome sont les nouvelles limites à la corrélation génotype/phénotype. Par l’étude des chromoanagenesis, d’un exceptionnel transcrit de fusion chez un patient hémophile et la description d’éléments transposables méconnus (rétrocopies) nous apportons d’importants nouveaux éléments

Published
2019

105. Clinical spectrum of STX1B-related epileptic disorders

Author

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

Abstract

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

Published
2019

106. Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy

Author

Genetica Klinische Genetica, Brain, ZL Kinder Ner en Nec Medisch, Johannesen, Katrine M, Mitter, Diana, Janowski, Robert, Roth, Christian, Toulouse, Joseph, Poulat, Anne-Lise, Ville, Dorothee M, Chatron, Nicolas, Brilstra, Eva, Geleijns, Karin, Born, Alfred Peter, McLean, Scott, Nugent, Kimberly, Baynam, Gareth, Poulton, Cathryn, Dreyer, Lauren, Gration, Dylan, Schulz, Solveig, Dieckmann, Andrea, Helbig, Katherine L, Merkenschlager, Andreas, Jamra, Rami, Finck, Anja, Gardella, Elena, Hjalgrim, Helle, Mirzaa, Ghayda, Brancati, Francesco, Bierhals, Tatjana, Denecke, Jonas, Hempel, Maja, Lemke, Johannes R, Rubboli, Guido, Muschke, Petra, Guerrini, Renzo, Vetro, Annalisa, Niessing, Dierk, Lesca, Gaetan, Møller, Rikke S, Genetica Klinische Genetica, Brain, ZL Kinder Ner en Nec Medisch, Johannesen, Katrine M, Mitter, Diana, Janowski, Robert, Roth, Christian, Toulouse, Joseph, Poulat, Anne-Lise, Ville, Dorothee M, Chatron, Nicolas, Brilstra, Eva, Geleijns, Karin, Born, Alfred Peter, McLean, Scott, Nugent, Kimberly, Baynam, Gareth, Poulton, Cathryn, Dreyer, Lauren, Gration, Dylan, Schulz, Solveig, Dieckmann, Andrea, Helbig, Katherine L, Merkenschlager, Andreas, Jamra, Rami, Finck, Anja, Gardella, Elena, Hjalgrim, Helle, Mirzaa, Ghayda, Brancati, Francesco, Bierhals, Tatjana, Denecke, Jonas, Hempel, Maja, Lemke, Johannes R, Rubboli, Guido, Muschke, Petra, Guerrini, Renzo, Vetro, Annalisa, Niessing, Dierk, Lesca, Gaetan, and Møller, Rikke S

Published
2019

107. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis (vol 102, pg 995, 2018)

Author

Olson, Heather E., Jean-Marcais, Nolwenn, Yang, Edward, Heron, Delphine, Tatton-Brown, Katrina, van der Zwaag, Paul A., Bijlsma, Emilia K., Krock, Bryan L., Backer, E., Kamsteeg, Erik-Jan, Sinnema, Margje, Reijnders, Margot R. F., Bearden, David, Begtrup, Amber, Telegrafi, Aida, Lunsing, Roelineke J., Burglen, Lydie, Lesca, Gaetan, Cho, Megan T., Smith, Lacey A., Sheidley, Beth R., El Achkar, Christelle Moufawad, Pearl, Phillip L., Poduri, Annapurna, Skraban, Cara M., Tarpinian, Jennifer, Nesbitt, Addie I., van de Putte, Dietje E. Fransen, Ruivenkamp, Claudia A. L., Rump, Patrick, Chatron, Nicolas, Sabatier, Isabelle, De Bellescize, Julitta, Guibaud, Laurent, Sweetser, David A., Waxler, Jessica L., Wierenga, Klaas J., Donadieu, Jean, Narayanan, Vinodh, Ramsey, Keri M., Nava, Caroline, Riviere, Jean-Baptiste, Vitobello, Antonio, Mau-Them, Frerdric Tran, Philippe, Christophe, Bruel, Ange-Line, Duffourd, Yannis, Thomas, Laurel, Lelieveld, Stefan H., and Schuurs-Hoeijmakers, Janneke

Published
2018

108. A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants

Author

Chatron, Nicolas, primary, Cabet, Sara, additional, Alix, Eudeline, additional, Buenerd, Annie, additional, Cox, Phillip, additional, Guibaud, Laurent, additional, Labalme, Audrey, additional, Marks, Peter, additional, Osio, Deborah, additional, Putoux, Audrey, additional, Sanlaville, Damien, additional, Lesca, Gaetan, additional, and Vasiljevic, Alexandre, additional

Published
2019
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110. SOX3 duplication: A genetic cause to investigate in fetuses with neural tube defects

Author

Hureaux, Marguerite, primary, Ben Miled, Selima, additional, Chatron, Nicolas, additional, Coussement, Aurelie, additional, Bessières, Bettina, additional, Egloff, Matthieu, additional, Mechler, Charlotte, additional, Stirnemann, Julien, additional, Tsatsaris, Vassilis, additional, Barcia, Giulia, additional, Turleau, Catherine, additional, Ville, Yves, additional, Encha‐Razavi, Ferechte, additional, Attie‐Bitach, Tania, additional, and Malan, Valérie, additional

Published
2019
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111. Variants in the degron ofAFF3cause a multi-system disorder with mesomelic dysplasia, horseshoe kidney and developmental and epileptic encephalopathy

Author

Voisin, Norine, primary, Schnur, Rhonda E., additional, Douzgou, Sofia, additional, Hiatt, Susan M., additional, Rustad, Cecilie F., additional, Brown, Natasha J., additional, Earl, Dawn L., additional, Keren, Boris, additional, Levchenko, Olga, additional, Geuer, Sinje, additional, Amor, David, additional, Brusco, Alfredo, additional, Bebin, E. Martina, additional, Cappuccio, Gerarda, additional, Charrow, Joel, additional, Chatron, Nicolas, additional, Cooper, Gregory M., additional, Dadali, Elena, additional, Delafontaine, Julien, additional, Del Giudice, Ennio, additional, Douglas, Ganka, additional, Funari, Tara, additional, Giannuzzi, Giuliana, additional, Guex, Nicolas, additional, Heron, Delphine, additional, Holla, Øystein L., additional, Hurst, Anna C.E., additional, Juusola, Jane, additional, Kronn, David, additional, Lavrov, Alexander, additional, Lee, Crystle, additional, Merckoll, Else, additional, Mikhaleva, Anna, additional, Norman, Jennifer, additional, Pradervand, Sylvain, additional, Sanders, Victoria, additional, Sirchia, Fabio, additional, Takenouchi, Toshiki, additional, Tanaka, Akemi J., additional, Taska-Tench, Heidi, additional, Tønne, Elin, additional, Tveten, Kristian, additional, Vitiello, Giuseppina, additional, Uehara, Tomoko, additional, Nava, Caroline, additional, Yalcin, Binnaz, additional, Kosaki, Kenjiro, additional, Donnai, Dian, additional, Mundlos, Stefan, additional, Brunetti-Pierri, Nicola, additional, Chung, Wendy K., additional, and Reymond, Alexandre, additional

Published
2019
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113. Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders

Author

Schluth-Bolard, Caroline, primary, Diguet, Flavie, additional, Chatron, Nicolas, additional, Rollat-Farnier, Pierre-Antoine, additional, Bardel, Claire, additional, Afenjar, Alexandra, additional, Amblard, Florence, additional, Amiel, Jeanne, additional, Blesson, Sophie, additional, Callier, Patrick, additional, Capri, Yline, additional, Collignon, Patrick, additional, Cordier, Marie-Pierre, additional, Coubes, Christine, additional, Demeer, Benedicte, additional, Chaussenot, Annabelle, additional, Demurger, Florence, additional, Devillard, Françoise, additional, Doco-Fenzy, Martine, additional, Dupont, Céline, additional, Dupont, Jean-Michel, additional, Dupuis-Girod, Sophie, additional, Faivre, Laurence, additional, Gilbert-Dussardier, Brigitte, additional, Guerrot, Anne-Marie, additional, Houlier, Marine, additional, Isidor, Bertrand, additional, Jaillard, Sylvie, additional, Joly-Hélas, Géraldine, additional, Kremer, Valérie, additional, Lacombe, Didier, additional, Le Caignec, Cédric, additional, Lebbar, Aziza, additional, Lebrun, Marine, additional, Lesca, Gaetan, additional, Lespinasse, James, additional, Levy, Jonathan, additional, Malan, Valérie, additional, Mathieu-Dramard, Michele, additional, Masson, Julie, additional, Masurel-Paulet, Alice, additional, Mignot, Cyril, additional, Missirian, Chantal, additional, Morice-Picard, Fanny, additional, Moutton, Sébastien, additional, Nadeau, Gwenaël, additional, Pebrel-Richard, Céline, additional, Odent, Sylvie, additional, Paquis-Flucklinger, Véronique, additional, Pasquier, Laurent, additional, Philip, Nicole, additional, Plutino, Morgane, additional, Pons, Linda, additional, Portnoï, Marie-France, additional, Prieur, Fabienne, additional, Puechberty, Jacques, additional, Putoux, Audrey, additional, Rio, Marlène, additional, Rooryck-Thambo, Caroline, additional, Rossi, Massimiliano, additional, Sarret, Catherine, additional, Satre, Véronique, additional, Siffroi, Jean-Pierre, additional, Till, Marianne, additional, Touraine, Renaud, additional, Toutain, Annick, additional, Toutain, Jérome, additional, Valence, Stéphanie, additional, Verloes, Alain, additional, Whalen, Sandra, additional, Edery, Patrick, additional, Tabet, Anne-Claude, additional, and Sanlaville, Damien, additional

Published
2019
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114. Supravalvular Aortic Stenosis Caused by a Familial Chromosome 7 Inversion Disrupting the ELN Gene Uncovered by Whole-Genome Sequencing

Author

Pons, Linda, primary, Bouvagnet, Patrice, additional, Bakloul, Mohamed, additional, Di Filippo, Sylvie, additional, Buisson, Adrien, additional, Chatron, Nicolas, additional, Labalme, Audrey, additional, Metton, Olivier, additional, Mitchell, Julia, additional, Diguet, Flavie, additional, Rollat-Farnier, Pierre-Antoine, additional, Sanlaville, Damien, additional, and Schluth-Bolard, Caroline, additional

Published
2019
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115. The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Author

Chatron, Nicolas, Moller, R.S., Champaigne, Neena L., Schneider, A., Kuechler, Alma, Labalme, Audrey, Kamsteeg, E.J., Pfundt, R.P., Carvill, Gemma L., Lesca, Gaetan, Chatron, Nicolas, Moller, R.S., Champaigne, Neena L., Schneider, A., Kuechler, Alma, Labalme, Audrey, Kamsteeg, E.J., Pfundt, R.P., Carvill, Gemma L., and Lesca, Gaetan

Abstract

Item does not contain fulltext

Published
2018

116. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

Author

Olson, Heather E, Jean-Marçais, Nolwenn, Yang, Edward, Heron, Delphine, Tatton-Brown, Katrina, van der Zwaag, Paul A, Bijlsma, Emilia K, Krock, Bryan L, Backer, E, Kamsteeg, Erik-Jan, Sinnema, Margje, Reijnders, Margot R F, Bearden, David, Begtrup, Amber, Telegrafi, Aida, Lunsing, Roelineke J, Burglen, Lydie, Lesca, Gaetan, Cho, Megan T, Smith, Lacey A, Sheidley, Beth R, Moufawad El Achkar, Christelle, Pearl, Phillip L, Poduri, Annapurna, Skraban, Cara M, Tarpinian, Jennifer, Nesbitt, Addie I, Fransen van de Putte, Dietje E, Ruivenkamp, Claudia A L, Rump, Patrick, Chatron, Nicolas, Sabatier, Isabelle, De Bellescize, Julitta, Guibaud, Laurent, Sweetser, David A, Waxler, Jessica L, Wierenga, Klaas J, Donadieu, Jean, Narayanan, Vinodh, Ramsey, Keri M, Nava, Caroline, Rivière, Jean-Baptiste, Vitobello, Antonio, Tran Mau-Them, Frédéric, Philippe, Christophe, Bruel, Ange-Line, Duffourd, Yannis, Thomas, Laurel, Lelieveld, Stefan H, Schuurs-Hoeijmakers, Janneke, DDD Study, Olson, Heather E, Jean-Marçais, Nolwenn, Yang, Edward, Heron, Delphine, Tatton-Brown, Katrina, van der Zwaag, Paul A, Bijlsma, Emilia K, Krock, Bryan L, Backer, E, Kamsteeg, Erik-Jan, Sinnema, Margje, Reijnders, Margot R F, Bearden, David, Begtrup, Amber, Telegrafi, Aida, Lunsing, Roelineke J, Burglen, Lydie, Lesca, Gaetan, Cho, Megan T, Smith, Lacey A, Sheidley, Beth R, Moufawad El Achkar, Christelle, Pearl, Phillip L, Poduri, Annapurna, Skraban, Cara M, Tarpinian, Jennifer, Nesbitt, Addie I, Fransen van de Putte, Dietje E, Ruivenkamp, Claudia A L, Rump, Patrick, Chatron, Nicolas, Sabatier, Isabelle, De Bellescize, Julitta, Guibaud, Laurent, Sweetser, David A, Waxler, Jessica L, Wierenga, Klaas J, Donadieu, Jean, Narayanan, Vinodh, Ramsey, Keri M, Nava, Caroline, Rivière, Jean-Baptiste, Vitobello, Antonio, Tran Mau-Them, Frédéric, Philippe, Christophe, Bruel, Ange-Line, Duffourd, Yannis, Thomas, Laurel, Lelieveld, Stefan H, Schuurs-Hoeijmakers, Janneke, and DDD Study

Published
2018

117. A Recurrent De Novo PACS2 Heterozygous Missense Variant Causes Neonatal-Onset Developmental Epileptic Encephalopathy, Facial Dysmorphism, and Cerebellar Dysgenesis

Author

Genetica Klinische Genetica, Cancer, Olson, Heather E, Jean-Marçais, Nolwenn, Yang, Edward, Heron, Delphine, Tatton-Brown, Katrina, van der Zwaag, Paul A, Bijlsma, Emilia K, Krock, Bryan L, Backer, E, Kamsteeg, Erik-Jan, Sinnema, Margje, Reijnders, Margot R F, Bearden, David, Begtrup, Amber, Telegrafi, Aida, Lunsing, Roelineke J, Burglen, Lydie, Lesca, Gaetan, Cho, Megan T, Smith, Lacey A, Sheidley, Beth R, Moufawad El Achkar, Christelle, Pearl, Phillip L, Poduri, Annapurna, Skraban, Cara M, Tarpinian, Jennifer, Nesbitt, Addie I, Fransen van de Putte, Dietje E, Ruivenkamp, Claudia A L, Rump, Patrick, Chatron, Nicolas, Sabatier, Isabelle, De Bellescize, Julitta, Guibaud, Laurent, Sweetser, David A, Waxler, Jessica L, Wierenga, Klaas J, Donadieu, Jean, Narayanan, Vinodh, Ramsey, Keri M, Nava, Caroline, Rivière, Jean-Baptiste, Vitobello, Antonio, Tran Mau-Them, Frédéric, Philippe, Christophe, Bruel, Ange-Line, Duffourd, Yannis, Thomas, Laurel, Lelieveld, Stefan H, Schuurs-Hoeijmakers, Janneke, DDD Study, Genetica Klinische Genetica, Cancer, Olson, Heather E, Jean-Marçais, Nolwenn, Yang, Edward, Heron, Delphine, Tatton-Brown, Katrina, van der Zwaag, Paul A, Bijlsma, Emilia K, Krock, Bryan L, Backer, E, Kamsteeg, Erik-Jan, Sinnema, Margje, Reijnders, Margot R F, Bearden, David, Begtrup, Amber, Telegrafi, Aida, Lunsing, Roelineke J, Burglen, Lydie, Lesca, Gaetan, Cho, Megan T, Smith, Lacey A, Sheidley, Beth R, Moufawad El Achkar, Christelle, Pearl, Phillip L, Poduri, Annapurna, Skraban, Cara M, Tarpinian, Jennifer, Nesbitt, Addie I, Fransen van de Putte, Dietje E, Ruivenkamp, Claudia A L, Rump, Patrick, Chatron, Nicolas, Sabatier, Isabelle, De Bellescize, Julitta, Guibaud, Laurent, Sweetser, David A, Waxler, Jessica L, Wierenga, Klaas J, Donadieu, Jean, Narayanan, Vinodh, Ramsey, Keri M, Nava, Caroline, Rivière, Jean-Baptiste, Vitobello, Antonio, Tran Mau-Them, Frédéric, Philippe, Christophe, Bruel, Ange-Line, Duffourd, Yannis, Thomas, Laurel, Lelieveld, Stefan H, Schuurs-Hoeijmakers, Janneke, and DDD Study

Published
2018

118. Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS.

Author

Mazzola, Laure, Oliver, Karen L., Labalme, Audrey, Baykan, Betül, Muona, Mikko, Joensuu, Tarja H., Courage, Carolina, Chatron, Nicolas, Borsani, Giuseppe, Alix, Eudeline, Ramond, Francis, Touraine, Renaud, Bahlo, Melanie, Bebek, Nerses, Berkovic, Samuel F., Lehesjoki, Anna‐Elina, and Lesca, Gaetan

Subjects
REVERSE transcriptase polymerase chain reaction, MYOCLONUS, EPILEPSY
Abstract

Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected individuals from both families shared a rare, homozygous c.191A > G variant affecting a splice site in SLC7A6OS. Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A > G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss‐of‐function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021;89:402–407 [ABSTRACT FROM AUTHOR]

Published
2021
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120. The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Author

Chatron, Nicolas, primary, Møller, Rikke S., additional, Champaigne, Neena L., additional, Schneider, Amy L., additional, Kuechler, Alma, additional, Labalme, Audrey, additional, Simonet, Thomas, additional, Baggett, Lauren, additional, Bardel, Claire, additional, Kamsteeg, Erik‐Jan, additional, Pfundt, Rolph, additional, Romano, Corrado, additional, Aronsson, Johan, additional, Alberti, Antonino, additional, Vinci, Mirella, additional, Miranda, Maria J., additional, Lacroix, Amy, additional, Marjanovic, Dragan, additional, des Portes, Vincent, additional, Edery, Patrick, additional, Wieczorek, Dagmar, additional, Gardella, Elena, additional, Scheffer, Ingrid E., additional, Mefford, Heather, additional, Sanlaville, Damien, additional, Carvill, Gemma L., additional, and Lesca, Gaetan, additional

Published
2018
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121. Inhibition of G-protein signalling in cardiac dysfunction of intellectual developmental disorder with cardiac arrhythmia (IDDCA) syndrome

Author

De Nittis, Pasquelena, Efthymiou, Stephanie, Sarre, Alexandre, Guex, Nicolas, Chrast, Jacqueline, Putoux, Audrey, Sultan, Tipu, Raza Alvi, Javeria, ur Rahman, Zia, Zafar, Faisal, Rana, Nuzhat, Rahman, Fatima, Anwar, Najwa, Maqbool, Shazia, Zaki, Maha S, Gleeson, Joseph G, Murphy, David, Galehdari, Hamid, Shariati, Gholamreza, Mazaheri, Neda, Sedaghat, Alireza, Lesca, Gaetan, Chatron, Nicolas, Salpietro, Vincenzo, Christoforou, Marilena, Houlden, Henry, Simonds, William F, Pedrazzini, Thierry, Maroofian, Reza, and Reymond, Alexandre

Abstract

BackgroundPathogenic variants of GNB5encoding the β5subunit of the guanine nucleotide-binding protein cause IDDCA syndrome, an autosomal recessive neurodevelopmental disorder associated with cognitive disability and cardiac arrhythmia, particularly severe bradycardia.MethodsWe used echocardiography and telemetric ECG recordings to investigate consequences of Gnb5loss in mouse.ResultsWe delineated a key role of Gnb5in heart sinus conduction and showed that Gnb5-inhibitory signalling is essential for parasympathetic control of heart rate (HR) and maintenance of the sympathovagal balance. Gnb5−/−mice were smaller and had a smaller heart than Gnb5+/+and Gnb5+/−, but exhibited better cardiac function. Lower autonomic nervous system modulation through diminished parasympathetic control and greater sympathetic regulation resulted in a higher baseline HR in Gnb5−/−mice. In contrast, Gnb5−/−mice exhibited profound bradycardia on treatment with carbachol, while sympathetic modulation of the cardiac stimulation was not altered. Concordantly, transcriptome study pinpointed altered expression of genes involved in cardiac muscle contractility in atria and ventricles of knocked-out mice. Homozygous Gnb5loss resulted in significantly higher frequencies of sinus arrhythmias. Moreover, we described 13 affected individuals, increasing the IDDCA cohort to 44 patients.ConclusionsOur data demonstrate that loss of negative regulation of the inhibitory G-protein signalling causes HR perturbations in Gnb5−/−mice, an effect mainly driven by impaired parasympathetic activity. We anticipate that unravelling the mechanism of Gnb5signalling in the autonomic control of the heart will pave the way for future drug screening.

Published
2021
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123. SETD5 haploinsufficiency phenotypic refinement: Expanding the range of chromatin disorders

Author

Chatron, Nicolas, primary, Lesca, Gaetan, additional, Till, Marianne, additional, Hurst, Anna C., additional, Boogaerts, Anneleen, additional, Journel, Hubert, additional, Tabet, Anne Claude, additional, Thevenon, Julien, additional, Isidor, Bertrand, additional, Vincent, Marie, additional, Amiel, Jeanne, additional, Rio, Marlène, additional, Moutton, Sébastien, additional, Naudion, Sophie, additional, Lasseaux, Eulalie, additional, Morin, Gilles, additional, Olivier-Faivre, Laurence, additional, Sanlaville, Damien, additional, Malan, Valerie, additional, and Genevieve, David, additional

Published
2017
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124. Mosaic variegated aneuploidy syndrome: Case report of two brothers

Author

Dery, Tania, primary, Chatron, Nicolas, additional, Alqahtani, Amerh, additional, Pugeat, Michel, additional, Nicolino, Marc, additional, Till, Marianne, additional, Lesca, Gaetan, additional, Edery, Patrick, additional, Sanlaville, Damien, additional, Schluth-Bolard, Caroline, additional, and Putoux, Audrey, additional

Published
2017
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127. Mutations in GABRB3

Author

Møller, Rikke S., primary, Wuttke, Thomas V., additional, Helbig, Ingo, additional, Marini, Carla, additional, Johannesen, Katrine M., additional, Brilstra, Eva H., additional, Vaher, Ulvi, additional, Borggraefe, Ingo, additional, Talvik, Inga, additional, Talvik, Tiina, additional, Kluger, Gerhard, additional, Francois, Laurence L., additional, Lesca, Gaetan, additional, de Bellescize, Julitta, additional, Blichfeldt, Susanne, additional, Chatron, Nicolas, additional, Holert, Nils, additional, Jacobs, Julia, additional, Swinkels, Marielle, additional, Betzler, Cornelia, additional, Syrbe, Steffen, additional, Nikanorova, Marina, additional, Myers, Candace T., additional, Larsen, Line H.G., additional, Vejzovic, Sabina, additional, Pendziwiat, Manuela, additional, von Spiczak, Sarah, additional, Hopkins, Sarah, additional, Dubbs, Holly, additional, Mang, Yuan, additional, Mukhin, Konstantin, additional, Holthausen, Hans, additional, van Gassen, Koen L., additional, Dahl, Hans A., additional, Tommerup, Niels, additional, Mefford, Heather C., additional, Rubboli, Guido, additional, Guerrini, Renzo, additional, Lemke, Johannes R., additional, Lerche, Holger, additional, Muhle, Hiltrud, additional, and Maljevic, Snezana, additional

Published
2017
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128. Genetic Counselling Pitfall: Co-Occurrence of an 11.8-Mb Xp22 Duplication and an Xp21.2 Duplication Disrupting IL1RAPL1

Author

Chatron, Nicolas, primary, Thibault, Lucie, additional, Lespinasse, James, additional, Labalme, Audrey, additional, Schluth-Bolard, Caroline, additional, Till, Marianne, additional, Edery, Patrick, additional, Touraine, Renaud, additional, des Portes, Vincent, additional, Lesca, Gaetan, additional, and Sanlaville, Damien, additional

Published
2017
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129. Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy

Author

Assoum, Mirna, primary, Philippe, Christophe, additional, Isidor, Bertrand, additional, Perrin, Laurence, additional, Makrythanasis, Periklis, additional, Sondheimer, Neal, additional, Paris, Caroline, additional, Douglas, Jessica, additional, Lesca, Gaetan, additional, Antonarakis, Stylianos, additional, Hamamy, Hanan, additional, Jouan, Thibaud, additional, Duffourd, Yannis, additional, Auvin, Stéphane, additional, Saunier, Aline, additional, Begtrup, Amber, additional, Nowak, Catherine, additional, Chatron, Nicolas, additional, Ville, Dorothée, additional, Mireskandari, Kamiar, additional, Milani, Paolo, additional, Jonveaux, Philippe, additional, Lemeur, Guylène, additional, Milh, Mathieu, additional, Amamoto, Masano, additional, Kato, Mitsuhiro, additional, Nakashima, Mitsuko, additional, Miyake, Noriko, additional, Matsumoto, Naomichi, additional, Masri, Amira, additional, Thauvin-Robinet, Christel, additional, Rivière, Jean-Baptiste, additional, Faivre, Laurence, additional, and Thevenon, Julien, additional

Published
2016
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130. Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders

Author

Cali, Elisa, Quirin, Tania, Rocca, Clarissa, Efthymiou, Stephanie, Riva, Antonella, Marafi, Dana, Zaki, Maha S., Suri, Mohnish, Dominguez, Roberto, Elbendary, Hasnaa M., Alavi, Shahryar, Abdel-Hamid, Mohamed S., Morsy, Heba, Mau-Them, Frederic Tran, Nizon, Mathilde, Tesner, Pavel, Ryba, Lukáš, Zafar, Faisal, Rana, Nuzhat, Saadi, Nebal W., Firoozfar, Zahra, Gencpinar, Pinar, Unay, Bulent, Ustun, Canan, Bruel, Ange-Line, Coubes, Christine, Stefanich, Jennifer, Sezer, Ozlem, Agolini, Emanuele, Novelli, Antonio, Vasco, Gessica, Lettori, Donatella, Milh, Mathieu, Villard, Laurent, Zeidler, Shimriet, Opperman, Henry, Strehlow, Vincent, Issa, Mahmoud Y., El Khassab, Hebatallah, Chand, Prem, Ibrahim, Shahnaz, Nejad-Rashidi, Ali, Miryounesi, Mohammad, Larki, Pegah, Morrison, Jennifer, Cristian, Ingrid, Thiffault, Isabelle, Bertsch, Nicole L., Noh, Grace J., Pappas, John, Moran, Ellen, Marinakis, Nikolaos M., Traeger-Synodinos, Joanne, Hosseini, Susan, Abbaszadegan, Mohammad Reza, Caumes, Roseline, Vissers, Lisenka E.L.M., Neshatdoust, Maedeh, Montazer, Mostafa Zohour, El Fahime, Elmostafa, Canavati, Christin, Kamal, Lara, Kanaan, Moien, Askander, Omar, Voinova, Victoria, Levchenko, Olga, Haider, Shahzhad, Halbach, Sara S., Maia, Elias Rayana, Mansoor, Salehi, Vivek, Jain, Tawde, Sanjukta, Challa, Viveka Santhosh R., Gowda, Vykuntaraju K., Srinivasan, Varunvenkat M., Victor, Lucas Alves, Pinero-Banos, Benito, Hague, Jennifer, Ei-Awady, Heba Ahmed, Maria de Miranda Henriques-Souza, Adelia, Cheema, Huma Arshad, Anjum, Muhammad Nadeem, Idkaidak, Sara, Alqarajeh, Firas, Atawneh, Osama, Mor-Shaked, Hagar, Harel, Tamar, Zifarelli, Giovanni, Bauer, Peter, Kok, Fernando, Kitajima, Joao Paulo, Monteiro, Fabiola, Josahkian, Juliana, Lesca, Gaetan, Chatron, Nicolas, Ville, Dorothe, Murphy, David, Neul, Jeffrey L., Mullegama, Sureni V., Begtrup, Amber, Herman, Isabella, Mitani, Tadahiro, Posey, Jennifer E., Tay, Chee Geap, Javed, Iram, Carr, Lucinda, Kanani, Farah, Beecroft, Fiona, Hane, Lee, Abdelkreem, Elsayed, Macek, Milan, Bispo, Luciana, Elmaksoud, Marwa Abd, Hashemi-Gorji, Farzad, Pehlivan, Davut, Amor, David J., Jamra, Rami Abou, Chung, Wendy K., Ghayoor, Eshan Karimiani, Campeau, Philippe, Alkuraya, Fowzan S., Pagnamenta, Alistair T., Gleeson, Joseph, Lupski, James R., Striano, Pasquale, Moreno-De-Luca, Andres, Lafontaine, Denis L.J., Houlden, Henry, and Maroofian, Reza

Abstract

This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear.

Published
2024
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131. Comparison of two next-generation sequencing kits for diagnosis of epileptic disorders with a user-friendly tool for displaying gene coverage, DeCovA

Author

Dimassi, Sarra, primary, Simonet, Thomas, additional, Labalme, Audrey, additional, Boutry-Kryza, Nadia, additional, Campan-Fournier, Amandine, additional, Lamy, Raphaelle, additional, Bardel, Claire, additional, Elsensohn, Mad-Hélénie, additional, Roucher-Boulez, Florence, additional, Chatron, Nicolas, additional, Putoux, Audrey, additional, de Bellescize, Julitta, additional, Ville, Dorothée, additional, Schaeffer, Laurent, additional, Roy, Pascal, additional, Mougou-Zerelli, Soumaya, additional, Saad, Ali, additional, Calender, Alain, additional, Sanlaville, Damien, additional, and Lesca, Gaetan, additional

Published
2015
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132. Supravalvular Aortic Stenosis Caused by a Familial Chromosome 7 Inversion Disrupting the ELNGene Uncovered by Whole-Genome Sequencing

Author

Pons, Linda, Bouvagnet, Patrice, Bakloul, Mohamed, Di Filippo, Sylvie, Buisson, Adrien, Chatron, Nicolas, Labalme, Audrey, Metton, Olivier, Mitchell, Julia, Diguet, Flavie, Rollat-Farnier, Pierre-Antoine, Sanlaville, Damien, and Schluth-Bolard, Caroline

Abstract

Apparently, balanced chromosomal rearrangements usually have no phenotypic consequences for the carrier. However, in some cases, they may be associated with an abnormal phenotype. We report herein the case of a 4-year-old boy presenting with clinically isolated supravalvular aortic stenosis (SVAS). No chromosomal imbalance was detected by array CGH. The karyotype showed a balanced paracentric chromosome 7 inversion. Breakpoint characterization using paired-end whole-genome sequencing (WGS) revealed an ELN gene disruption in intron 1, accounting for the phenotype. Family study showed that the inversion was inherited, with incomplete penetrance. To our knowledge, this is the first case of a disruption of the ELNgene characterized by WGS. It contributes to refine the genotype-phenotype correlation in ELNdisruption. Although this disruption is a rare etiology of SVAS, it cannot be detected by the diagnostic tests usually performed, such as array CGH or sequencing methods (Sanger, panel, or exome sequencing). With the future perspective of WGS as a diagnostic tool, it will be important to include a structural variation analysis in order to detect balanced rearrangements and gene disruption.

Published
2019
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133. Missense variants in ANKRD11cause KBG syndrome by impairment of stability or transcriptional activity of the encoded protein

Author

de Boer, Elke, Ockeloen, Charlotte W., Kampen, Rosalie A., Hampstead, Juliet E., Dingemans, Alexander J.M., Rots, Dmitrijs, Lütje, Lukas, Ashraf, Tazeen, Baker, Rachel, Barat-Houari, Mouna, Angle, Brad, Chatron, Nicolas, Denommé-Pichon, Anne-Sophie, Devinsky, Orrin, Dubourg, Christèle, Elmslie, Frances, Elloumi, Houda Zghal, Faivre, Laurence, Fitzgerald-Butt, Sarah, Geneviève, David, Goos, Jacqueline A.C., Helm, Benjamin M., Kini, Usha, Lasa-Aranzasti, Amaia, Lesca, Gaetan, Lynch, Sally A., Mathijssen, Irene M.J., McGowan, Ruth, Monaghan, Kristin G., Odent, Sylvie, Pfundt, Rolph, Putoux, Audrey, van Reeuwijk, Jeroen, Santen, Gijs W.E., Sasaki, Erina, Sorlin, Arthur, van der Spek, Peter J., Stegmann, Alexander P.A., Swagemakers, Sigrid M.A., Valenzuela, Irene, Viora-Dupont, Eléonore, Vitobello, Antonio, Ware, Stephanie M., Wéber, Mathys, Gilissen, Christian, Low, Karen J., Fisher, Simon E., Vissers, Lisenka E.L.M., Wong, Maggie M.K., and Kleefstra, Tjitske

Published
2023
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134. Author Correction: Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts.

Author

Giannuzzi, Giuliana, Chatron, Nicolas, Mannik, Katrin, Auwerx, Chiara, Pradervand, Sylvain, Willemin, Gilles, Hoekzema, Kendra, Nuttle, Xander, Chrast, Jacqueline, Sadler, Marie C., Porcu, Eleonora, Männik, Katrin, Sanlaville, Damien, Schluth-Bolard, Caroline, Le Caignec, Cédric, Nizon, Mathilde, Martin, Sandra, Jacquemont, Sébastien, Bottani, Armand, and Gérard, Marion

Published
2023
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135. Neonatal tremor episodes and hyperekplexia‐like presentation at onset in a child with SCN8Adevelopmental and epileptic encephalopathy

Author

Pons, Linda, Lesca, Gaëtan, Sanlaville, Damien, Chatron, Nicolas, Labalme, Audrey, Manel, Véronique, Arzimanoglou, Alexis, de Bellescize, Julitta, and Lion‐François, Laurence

Abstract

SCN8Aencephalopathy is a newly defined epileptic encephalopathy caused by de novomutations of the SCN8Agene. We report herein a four‐year‐old boy presenting with severe non‐epileptic abnormal movements, of possibly antenatal onset, progressively associated with pharmacoresistant epilepsy and regression, associated with a de novoheterozygous missense mutation of SCN8A. This case shows that paroxysmal non‐epileptic episodes of severe tremor and hyperekplexia‐like startles and a striking vegetative component can be the first early symptoms of severe SCN8Adevelopmental and epileptic encephalopathy. Clinicians should be aware of these symptoms in order to avoid misdiagnosis and ensure early appropriate therapeutic management. [Published with video sequences onwww.epilepticdisorders.com].

Published
2018
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136. Clinical and functional heterogeneity associated with the disruption of retinoic acid receptor beta

Author

Caron, Véronique, Chassaing, Nicolas, Ragge, Nicola, Boschann, Felix, Ngu, Angelina My-Hoa, Meloche, Elisabeth, Chorfi, Sarah, Lakhani, Saquib A., Ji, Weizhen, Steiner, Laurie, Marcadier, Julien, Jansen, Philip R., van de Pol, Laura A., van Hagen, Johanna M., Russi, Alvaro Serrano, Le Guyader, Gwenaël, Nordenskjöld, Magnus, Nordgren, Ann, Anderlid, Britt-Marie, Plaisancié, Julie, Stoltenburg, Corinna, Horn, Denise, Drenckhahn, Anne, Hamdan, Fadi F., Lefebvre, Mathilde, Attie-Bitach, Tania, Forey, Peggy, Smirnov, Vasily, Ernould, Françoise, Jacquemont, Marie-Line, Grotto, Sarah, Alcantud, Alberto, Coret, Alicia, Ferrer-Avargues, Rosario, Srivastava, Siddharth, Vincent-Delorme, Catherine, Romoser, Shelby, Safina, Nicole, Saade, Dimah, Lupski, James R., Calame, Daniel G., Geneviève, David, Chatron, Nicolas, Schluth-Bolard, Caroline, Myers, Kenneth A., Dobyns, William B., Calvas, Patrick, Salmon, Caroline, Holt, Richard, Elmslie, Frances, Allaire, Marc, Prigozhin, Daniil M., Tremblay, André, and Michaud, Jacques L.

Abstract

Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12.

Published
2023
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137. Description of a novel patient with the TRPM3 recurrent p.Val837Met variant.

Author

Gauthier, Lucas W, Chatron, Nicolas, Cabet, Sara, Labalme, Audrey, Carneiro, Maryline, Poirot, Isabelle, Delvert, Céline, Gleizal, Arnaud, Lesca, Gaetan, and Putoux, Audrey

Subjects
*MISSENSE mutation, *INTELLECTUAL disabilities
Abstract

De novo heterozygous missense mutations in TRPM3 have been shown to cause developmental and epileptic encephalopathies (DEE). It is a very rare condition, as only 9 patients have been described to date. We report here a novel patient carrying the recurrent p.Val837Met variant and presenting new clinical features, such as trigonocephaly, expanding the phenotypical spectrum of the disease. [ABSTRACT FROM AUTHOR]

Published
2021
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138. Drosophilafunctional screening of de novovariants in autism uncovers damaging variants and facilitates discovery of rare neurodevelopmental diseases

Author

Marcogliese, Paul C., Deal, Samantha L., Andrews, Jonathan, Harnish, J. Michael, Bhavana, V. Hemanjani, Graves, Hillary K., Jangam, Sharayu, Luo, Xi, Liu, Ning, Bei, Danqing, Chao, Yu-Hsin, Hull, Brooke, Lee, Pei-Tseng, Pan, Hongling, Bhadane, Pradnya, Huang, Mei-Chu, Longley, Colleen M., Chao, Hsiao-Tuan, Chung, Hyung-lok, Haelterman, Nele A., Kanca, Oguz, Manivannan, Sathiya N., Rossetti, Linda Z., German, Ryan J., Gerard, Amanda, Schwaibold, Eva Maria Christina, Fehr, Sarah, Guerrini, Renzo, Vetro, Annalisa, England, Eleina, Murali, Chaya N., Barakat, Tahsin Stefan, van Dooren, Marieke F., Wilke, Martina, van Slegtenhorst, Marjon, Lesca, Gaetan, Sabatier, Isabelle, Chatron, Nicolas, Brownstein, Catherine A., Madden, Jill A., Agrawal, Pankaj B., Keren, Boris, Courtin, Thomas, Perrin, Laurence, Brugger, Melanie, Roser, Timo, Leiz, Steffen, Mau-Them, Frederic Tran, Delanne, Julian, Sukarova-Angelovska, Elena, Trajkova, Slavica, Rosenhahn, Erik, Strehlow, Vincent, Platzer, Konrad, Keller, Roberto, Pavinato, Lisa, Brusco, Alfredo, Rosenfeld, Jill A., Marom, Ronit, Wangler, Michael F., and Yamamoto, Shinya

Abstract

Individuals with autism spectrum disorder (ASD) exhibit an increased burden of de novomutations (DNMs) in a broadening range of genes. While these studies have implicated hundreds of genes in ASD pathogenesis, which DNMs cause functional consequences in vivoremains unclear. We functionally test the effects of ASD missense DNMs using Drosophilathrough “humanization” rescue and overexpression-based strategies. We examine 79 ASD variants in 74 genes identified in the Simons Simplex Collection and find 38% of them to cause functional alterations. Moreover, we identify GLRA2as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in 13 previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes points to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

Published
2022
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139. Detecting small Copy Number Variations, smaller than 400 kb, improves the diagnostic yield of CMA in intellectual disability

Author

Faoucher, Marie, Fonteneau, Eric, Chatron, Nicolas, Depienne, Christel, Labalme, Audrey, Lejeune, Elodie, Till, Marianne, Mignot, Cyril, Schluth-Bolard, Caroline, Nava, Caroline, Putoux, Audrey, Lesca, Gaetan, Mochel, Fanny, Alex, Marie-Pierre, Jacquette, Aurelia, Massimiliano Rossi, Heron, Delphine, Edery, Patrick, Brice, Alexis, Sanlaville, Damien, and Keren, Boris

140. Developmental epileptic encephalopathy in DLG4‐related synaptopathy.

Author

Kassabian, Benedetta, Levy, Amanda M., Gardella, Elena, Aledo‐Serrano, Angel, Ananth, Amitha L., Brea‐Fernández, Alejandro J., Caumes, Roseline, Chatron, Nicolas, Dainelli, Alice, De Wachter, Matthias, Denommé‐Pichon, Anne‐Sophie, Dye, Thomas J., Fazzi, Elisa, Felt, Roxanne, Fernández‐Jaén, Alberto, Fernández‐Prieto, Montse, Gantz, Emily, Gasperowicz, Piotr, Gil‐Nagel, Antonio, and Gómez‐Andrés, David

Subjects
*EPILEPSY, *SLEEP interruptions, *POSTSYNAPTIC density protein, *BRAIN diseases, *SEIZURES (Medicine), *MOVEMENT disorders
Abstract

Objective: The postsynaptic density protein of excitatory neurons PSD‐95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4‐related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4‐related synaptopathy. Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video‐polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow‐wave sleep (ESES)/developmental epileptic encephalopathy with spike–wave activation during sleep (DEE‐SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE‐SWAS, as well as some who did not. We could not identify a clear genotype–phenotype relationship even between individuals with the same DLG4 variants. Significance: Our study shows that a subgroup of individuals with DLG4‐related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE‐SWAS. Our study confirms DEE as part of the DLG4‐related phenotypic spectrum. Occurrence of ESES/DEE‐SWAS in DLG4‐related synaptopathy requires proper investigation with sleep EEG. [ABSTRACT FROM AUTHOR]

Published
2024
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141. Delineation of the adult phenotype of Coffin–Siris syndrome in 35 individuals.

Author

Schmetz, Ariane, Lüdecke, Hermann-Josef, Surowy, Harald, Sivalingam, Sugirtahn, Bruel, Ange-Line, Caumes, Roseline, Charles, Perrine, Chatron, Nicolas, Chrzanowska, Krystyna, Codina-Solà, Marta, Colson, Cindy, Cuscó, Ivon, Denommé-Pichon, Anne-Sophie, Edery, Patrick, Faivre, Laurence, Green, Andrew, Heide, Solveig, Hsieh, Tzung-Chien, Hustinx, Alexander, and Kleinendorst, Lotte

Subjects
*PHENOTYPES, *ADULTS, *SYNDROMES, *VISION disorders, *SOX transcription factors
Abstract

Coffin–Siris syndrome (CSS) is a rare multisystemic autosomal dominant disorder. Since 2012, alterations in genes of the SWI/SNF complex were identified as the molecular basis of CSS, studying largely pediatric cohorts. Therefore, there is a lack of information on the phenotype in adulthood, particularly on the clinical outcome in adulthood and associated risks. In an international collaborative effort, data from 35 individuals ≥ 18 years with a molecularly ascertained CSS diagnosis (variants in ARID1B, ARID2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, SOX11, BICRA) using a comprehensive questionnaire was collected. Our results indicate that overweight and obesity are frequent in adults with CSS. Visual impairment, scoliosis, and behavioral anomalies are more prevalent than in published pediatric or mixed cohorts. Cognitive outcomes range from profound intellectual disability (ID) to low normal IQ, with most individuals having moderate ID. The present study describes the first exclusively adult cohort of CSS individuals. We were able to delineate some features of CSS that develop over time and have therefore been underrepresented in previously reported largely pediatric cohorts, and provide recommendations for follow-up. [ABSTRACT FROM AUTHOR]

Published
2024
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142. PCSK9 post-transcriptional regulation: Role of a 3′UTR microRNA-binding site variant in linkage disequilibrium with c.1420G.

Author

Decourt, Charlotte, Janin, Alexandre, Moindrot, Marine, Chatron, Nicolas, Nony, Séverine, Muntaner, Manon, Dumont, Sabrina, Divry, Eléonore, Dauchet, Luc, Meirhaeghe, Aline, Marmontel, Oriane, Bardel, Claire, Charrière, Sybil, Cariou, Bertrand, Moulin, Philippe, and Di Filippo, Mathilde

Subjects
*LINKAGE disequilibrium, *CARDIOVASCULAR diseases, *SUBTILISINS, *MICRORNA, *ALLELES
Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis. A common variant, the G allele in position c.1420 (c.1420G), has been associated with a decrease of both plasma PCSK9 and LDL-cholesterol concentrations. However, the functional effect of this variant is currently not well understood. We hypothesized that it could be explained by functional variants in linkage disequilibrium (LD), more specifically, by variants located in the PCSK9 3′ UTR as targets for miR regulation of PCSK9 expression. Variations in LD with c.1420G were studied in 1029 patients followed for dyslipidaemia. In silico studies identified potential miRNA binding sites induced by PCSK9 3′UTR variants in LD with c.1420G. Their functionality was studied with a luciferase reporter assay in HuH-7 cells and confirmed by cotransfection of anti-miRNAs. The c.*571C and c.*234T variants located in the PCSK9 3′UTR were found in tight LD with c.1420G (D' = 0.962; LOD = 163.06). The haplotype carrying c.*571C showed a 6.7% decrease in luciferase activity (p = 0.003). Inhibition of hsa-miR-1228-3p and hsa-miR-143-5p counteracted their effect on the haplotype carrying c.*571C allele, suggesting that PCSK9 expression was decreased by the endogenous binding of hsa-miR-1228-3p and hsa-miR-143-5p on its 3′UTR. This post-transcriptional regulation might contribute towards the association between plasma PCSK9 levels and c.1420G. Such regulation of PCSK9 expression may open new perspectives for the treatment of hypercholesterolemia and atherosclerosis cardiovascular diseases. Image 1. • PCSK9 plays a crucial role in cholesterol homeostasis and cardiovascular diseases. • PCSK9 c.1420G hypocholesterolemic allele is in linkage disequilibrium with c.*571C. • PCSK9 3′UTR variant c.*571C creates an illegitimate and functional miR binding site. • 3′UTR PCSK9 post-transcriptional regulation could explain the c.1420G LoF effect. • This post-transcriptional regulation may open new therapeutic perspectives. [ABSTRACT FROM AUTHOR]

Published
2020
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143. PHGDH-related microcephalic dwarfism in two fetuses: Expanding the phenotypical spectrum of L-serine biosynthesis defect.

Author

Cuinat, Silvestre, Quélin, Chloé, Pasquier, Laurent, Loget, Philippe, Aussel, Dominique, Odent, Sylvie, Laquerrière, Annie, Proisy, Maia, Mazoyer, Sylvie, Delous, Marion, Edery, Patrick, Chatron, Nicolas, Lesca, Gaetan, and Putoux, Audrey

Subjects
*FETAL growth retardation, *DWARFISM, *BIOSYNTHESIS, *FETAL death, *CENTRAL nervous system, *FETUS
Abstract

Defects in L-serine biosynthesis are a group of autosomal recessive diseases resulting in a wide phenotypic spectrum ranging from viable to lethal presentations and caused by variants in the three genes encoding the L-serine biosynthesis enzymes, PHGDH , PSAT1, and PSPH. Neu-Laxova syndrome (NLS) is the fetal form of this group, characterized by multiple congenital anomalies including severe intrauterine growth retardation, cutaneous lesions extending from ichthyosis to severe restrictive dermopathy with ectropion and eclabion, edema, microcephaly, central nervous system abnormalities, and flexion contractures. Here we report on two unrelated fetuses with an attenuated phenotype of NLS, that initially evoked Taybi-Linder syndrome. They carry biallelic pathogenic variants in the PHGDH gene. These observations expand the phenotypic continuum of L-serine biosynthesis defects, and illustrate the phenotypic overlap between NLS and microcephalic primordial dwarfism. [ABSTRACT FROM AUTHOR]

Published
2023
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144. Defining causal variants in rare epilepsies: an essential team effort between biomedical scientists, geneticists and epileptologists.

Author

McTague, Amy, Brunklaus, Andreas, Barcia, Giulia, Varadkar, Sophia, Zuberi, Sameer M., Chatron, Nicolas, Parrini, Elena, Mei, Davide, Nabbout, Rima, and Lesca, Gaetan

Subjects
*MEDICAL scientists, *GENETICISTS, *EPILEPSY, *GENETIC counseling, *PHENOTYPIC plasticity
Abstract

In the last few years, with the advent of next generation sequencing (NGS), our knowledge of genes associated with monogenic epilepsies has significantly improved. NGS is also a powerful diagnostic tool for patients with epilepsy, through gene panels, exomes and genomes. This has improved diagnostic yield, reducing the time between the first seizure and a definitive molecular diagnosis. However, these developments have also increased the complexity of data interpretation, due to the large number of variants identified in a given patient and due to the phenotypic variability associated with many of the epilepsy-related genes. In this paper, we present examples of variant classification in "real life" clinic situations. We emphasize the importance of accurate phenotyping of the epilepsies including recognising variable/milder phenotypes and expansion of previously described phenotypes. There are some important issues specific to rare epilepsies – mosaicism and reduced penetrance - which affect genetic counselling. These challenges may be overcome through multidisciplinary meetings including epileptologists, pediatric neurologists, and clinical and molecular geneticists, in which every specialist learns from the others in a process which leads to for rapid and accurate diagnosis. This is an important milestone to achieve as targeted therapiesbased on the functional effects of pathogenic variants become available. [ABSTRACT FROM AUTHOR]

Published
2022
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145. The EPIGENE network: A French initiative to harmonize and improve the nationwide diagnosis of monogenic epilepsies.

Author

Arnaud, Lionel, Abi Warde, Marie-Thérèse, Barcia, Giulia, de Bellescize, Julitta, Chatron, Nicolas, Faoucher, Marie, de Saint Martin, Anne, Héron, Delphine, Jedraszak, Guillaume, Lacoste, Caroline, Lèbre, Anne-Sophie, Jenneson-Lyver, Mélanie, Labalme, Audrey, Leguern, Eric, Mignot, Cyril, Milh, Mathieu, Nabbout, Rima, Nava, Caroline, Panagiotakaki, Eleni, and Piton, Amélie

Subjects
*DIAGNOSIS of epilepsy, *GENETIC testing, *NUCLEOTIDE sequencing, *GENETIC disorder diagnosis, *EPILEPSY, *MULTIDRUG-resistant tuberculosis
Abstract

The EPIGENE network was created in 2014 by four multidisciplinary teams composed of geneticists, pediatric neurologists and neurologists specialized in epileptology and neurophysiology. The ambition of the network was to harmonize and improve the diagnostic strategy of Mendelian epileptic disorders using next-generation sequencing, in France. Over the years, five additional centers have joined EPIGENE and the network has been working in close collaboration, since 2018, with the French reference center for rare epilepsies (CRéER). Since 2014, biannual meetings have led to the design of four successive versions of a monogenic epilepsy gene panel (PAGEM), increasing from 68 to 144 genes. A total of 4035 index cases with epileptic disorders have been analyzed with a diagnostic yield of 31% (n = 1265/4035). The top 10 genes, S CN1A, KCNQ2, STXBP1, SCN2A, SCN8A, PRRT2 , PCDH19, KCNT1, SYNGAP1 , and GRIN2A, account for one-sixth of patients and half of the diagnoses provided by the PAGEM. These results suggest that a gene-panel approach is an efficient first-tier test for the genetic diagnosis of Mendelian epileptic disorders. In a near future, French patients with "drug-resistant epilepsies with seizure-onset in the first two-years of life" can benefit from whole-genome sequencing (WGS), as a second line genetic screening with the implementation of the 2025 French Genomic Medicine Plan. The EPIGENE network has also promoted scientific collaborations on genetic epilepsies within CRéER. [ABSTRACT FROM AUTHOR]

Published
2022
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146. Neurodevelopmental Disorder Caused by Deletion of CHASERR , a lncRNA Gene.

Author

Ganesh VS, Riquin K, Chatron N, Yoon E, Lamar KM, Aziz MC, Monin P, O'Leary MC, Goodrich JK, Garimella KV, England E, Weisburd B, Aguet F, Bacino CA, Murdock DR, Dai H, Rosenfeld JA, Emrick LT, Ketkar S, Sarusi Y, Sanlaville D, Kayani S, Broadbent B, Pengam A, Isidor B, Bezieau S, Cogné B, MacArthur DG, Ulitsky I, Carvill GL, and O'Donnell-Luria A

Subjects
Child, Preschool, Female, Humans, Infant, Male, Brain pathology, Brain diagnostic imaging, Brain metabolism, DNA-Binding Proteins analysis, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Gene Deletion, Haploinsufficiency, Phenotype, Sequence Deletion, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology, RNA, Long Noncoding genetics
Abstract

CHASERR encodes a human long noncoding RNA (lncRNA) adjacent to CHD2 , a coding gene in which de novo loss-of-function variants cause developmental and epileptic encephalopathy. Here, we report our findings in three unrelated children with a syndromic, early-onset neurodevelopmental disorder, each of whom had a de novo deletion in the CHASERR locus. The children had severe encephalopathy, shared facial dysmorphisms, cortical atrophy, and cerebral hypomyelination - a phenotype that is distinct from the phenotypes of patients with CHD2 haploinsufficiency. We found that the CHASERR deletion results in increased CHD2 protein abundance in patient-derived cell lines and increased expression of the CHD2 transcript in cis . These findings indicate that CHD2 has bidirectional dosage sensitivity in human disease, and we recommend that other lncRNA-encoding genes be evaluated, particularly those upstream of genes associated with mendelian disorders. (Funded by the National Human Genome Research Institute and others.)., (Copyright © 2024 Massachusetts Medical Society.)

Published
2024
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147. Familial severe skeletal Class II malocclusion with gingival hyperplasia caused by a complex structural rearrangement at the KCNJ2-KCNJ16 locus.

Author

Maroofian R, Pagnamenta AT, Navabazam A, Schwessinger R, Roberts HE, Lopopolo M, Dehghani M, Vahidi Mehrjardi MY, Haerian A, Soltanianzadeh M, Noori Kooshki MH, Knight SJL, Miller KA, McGowan SJ, Chatron N, Timberlake AT, Melo US, Mundlos S, Buck D, Twigg SRF, Taylor JC, Wilkie AOM, and Calpena E

Subjects
Humans, Female, Male, Phenotype, Genetic Loci, Polymorphism, Single Nucleotide, SOX9 Transcription Factor genetics, Malocclusion, Angle Class II genetics, Pedigree, Gingival Hyperplasia genetics, Gingival Hyperplasia pathology, Potassium Channels, Inwardly Rectifying genetics
Abstract

The aim of this work was to identify the underlying genetic cause in a four-generation family segregating an unusual phenotype comprising a severe form of skeletal Class II malocclusion with gingival hyperplasia. SNP array identified a copy number gain on chromosome 1 (chr1); however, this chromosomal region did not segregate correctly in the extended family. Exome sequencing also failed to identify a candidate causative variant but highlighted co-segregating genetic markers on chr17 and chr19. Short- and long-read genome sequencing allowed us to pinpoint and characterize at nucleotide-level resolution a chromothripsis-like complex rearrangement (CR) inserted into the chr17 co-segregating region at the KCNJ2-SOX9 locus. The CR involved the gain of five different regions from chr1 that are shuffled, chained, and inserted as a single block (∼828 kb) at chr17q24.3. The inserted sequences contain craniofacial enhancers that are predicted to interact with KCNJ2/KCNJ16 through neo-topologically associating domain (TAD) formation to induce ectopic activation. Our findings suggest that the CR inserted at chr17q24.3 is the cause of the severe skeletal Class II malocclusion with gingival hyperplasia in this family and expands the panoply of phenotypes linked to variation at the KCNJ2-SOX9 locus. In addition, we highlight a previously overlooked potential role for misregulation of the KCNJ2/KCNJ16 genes in the pathomechanism of gingival hyperplasia associated with deletions and other rearrangements of the 17q24.2-q24.3 region (MIM 135400)., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2024
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149. Germline mutations in a G protein identify signaling cross-talk in T cells.

Author

Ham H, Jing H, Lamborn IT, Kober MM, Koval A, Berchiche YA, Anderson DE, Druey KM, Mandl JN, Isidor B, Ferreira CR, Freeman AF, Ganesan S, Karsak M, Mustillo PJ, Teo J, Zolkipli-Cunningham Z, Chatron N, Lecoquierre F, Oler AJ, Schmid JP, Kuhns DB, Xu X, Hauck F, Al-Herz W, Wagner M, Terhal PA, Muurinen M, Barlogis V, Cruz P, Danielson J, Stewart H, Loid P, Rading S, Keren B, Pfundt R, Zarember KA, Vill K, Potocki L, Olivier KN, Lesca G, Faivre L, Wong M, Puel A, Chou J, Tusseau M, Moutsopoulos NM, Matthews HF, Simons C, Taft RJ, Soldatos A, Masle-Farquhar E, Pittaluga S, Brink R, Fink DL, Kong HH, Kabat J, Kim WS, Bierhals T, Meguro K, Hsu AP, Gu J, Stoddard J, Banos-Pinero B, Slack M, Trivellin G, Mazel B, Soomann M, Li S, Watts VJ, Stratakis CA, Rodriguez-Quevedo MF, Bruel AL, Lipsanen-Nyman M, Saultier P, Jain R, Lehalle D, Torres D, Sullivan KE, Barbarot S, Neu A, Duffourd Y, Similuk M, McWalter K, Blanc P, Bézieau S, Jin T, Geha RS, Casanova JL, Makitie OM, Kubisch C, Edery P, Christodoulou J, Germain RN, Goodnow CC, Sakmar TP, Billadeau DD, Küry S, Katanaev VL, Zhang Y, Lenardo MJ, and Su HC

Subjects
Humans, Cell Movement genetics, Cell Proliferation, Immunity genetics, MAP Kinase Signaling System, Phosphatidylinositol 3-Kinases metabolism, Phosphatidylinositol 3-Kinases genetics, Proto-Oncogene Proteins c-akt metabolism, ras Proteins metabolism, ras Proteins genetics, Signal Transduction, Pedigree, Germ-Line Mutation, GTP-Binding Protein alpha Subunit, Gi2 genetics, ras GTPase-Activating Proteins genetics, Receptors, Antigen, T-Cell metabolism, T-Lymphocytes immunology, T-Lymphocytes metabolism
Abstract

Humans with monogenic inborn errors responsible for extreme disease phenotypes can reveal essential physiological pathways. We investigated germline mutations in GNAI2 , which encodes G αi2 , a key component in heterotrimeric G protein signal transduction usually thought to regulate adenylyl cyclase-mediated cyclic adenosine monophosphate (cAMP) production. Patients with activating G αi2 mutations had clinical presentations that included impaired immunity. Mutant G αi2 impaired cell migration and augmented responses to T cell receptor (TCR) stimulation. We found that mutant G αi2 influenced TCR signaling by sequestering the guanosine triphosphatase (GTPase)-activating protein RASA2, thereby promoting RAS activation and increasing downstream extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)-AKT S6 signaling to drive cellular growth and proliferation.

Published
2024
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150. Possible incomplete penetrance of Xq28 int22h-1/int22h-2 duplication.

Author

Billes A, Pujalte M, Jedraszak G, Amsallem D, Boudry-Labis E, Boute O, Bouquillon S, Brischoux-Boucher E, Callier P, Coutton C, Denizet AA, Dieterich K, Kuentz P, Lespinasse J, Mazel B, Morin G, Amram F, Pennamen P, Rio M, Piard J, Putoux A, Rama M, Roze-Guillaumey V, Schluth-Bolard C, Till M, Trouvé C, Vieville G, Rooryck C, Sanlaville D, and Chatron N

Subjects
Humans, Male, Female, Child, Adult, Adolescent, Child, Preschool, Phenotype, Chromosome Duplication genetics, Gene Duplication, Pedigree, Young Adult, Penetrance, Chromosomes, Human, X genetics, Intellectual Disability genetics
Abstract

Xq28 int22h-1/int22h-2 duplication is the result of non-allelic homologous recombination between int22h-1/int22h-2 repeats separated by 0.5 Mb. It is responsible for a syndromic form of intellectual disability (ID), with recurrent infections and atopic diseases. Minor defects, nonspecific facial dysmorphic features, and overweight have also been described. Half of female carriers have been reported with ID, whereas all reported evaluated born males present mild to moderate ID, suggesting complete penetrance. We collected data on 15 families from eight university hospitals. Among them, 40 patients, 21 females (one fetus), and 19 males (two fetuses), were carriers of typical or atypical Xq28 int22h-1/int22h-2 duplication. Twenty-one individuals were considered asymptomatic (16 females and 5 males), without significantly higher rate of recurrent infections, atopia, overweight, or facial dysmorphism. Approximately 67% live-born males and 23% live-born female carriers of the typical duplication did not have obvious signs of intellectual disability, suggesting previously undescribed incomplete penetrance or low expression in certain carriers. The possibility of a second-hit or modifying factors to this possible susceptibility locus is yet to be studied but a possible observational bias should be considered in assessing such challenging X-chromosome copy number gains. Additional segregation studies should help to quantify this newly described incomplete penetrance., (© 2024 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

Published
2024
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