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Start Over Author "Sarah von Spiczak" Journal american journal of human genetics
2 results on '"Sarah von Spiczak"'

1. Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies

Author

Gemma L. Carvill, Krysta L. Engel, Aishwarya Ramamurthy, J. Nicholas Cochran, Jolien Roovers, Hannah Stamberger, Nicholas Lim, Amy L. Schneider, Georgie Hollingsworth, Dylan H. Holder, Brigid M. Regan, James Lawlor, Lieven Lagae, Berten Ceulemans, E. Martina Bebin, John Nguyen, Gregory S. Barsh, Sarah Weckhuysen, Miriam Meisler, Samuel F. Berkovic, Peter De Jonghe, Ingrid E. Scheffer, Richard M. Myers, Gregory M. Cooper, Heather C. Mefford, Pasquale Striano, Federico Zara, Ingo Helbig, Rikke S. Møller, Sarah von Spiczak, Hiltrud Muhle, Hande Caglayan, Katalin Sterbova, Dana Craiu, Dorota Hoffman, Anna-Elina Lehesjoki, Kaja Selmer, Christel Depienne, Johannes Lemke, Carla Marini, Renzo Guerrini, Bernd Neubauer, Tiina Talvik, Eric Leguern, Peter de Jonghe, and EuroEPINOMICS Rare Epilepsy Syndro

Subjects
0301 basic medicine, Male, SPLICE VARIANTS, PROTEIN, Epilepsies, Myoclonic, Sodium Channels, Transcriptome, Epilepsy, Exon, poison exon, 0302 clinical medicine, SCN1A, NEURONAL SODIUM-CHANNEL, BRAIN, Child, Genetics (clinical), Exome sequencing, Genetics, Genetics & Heredity, noncoding, Exons, Middle Aged, genome sequencing, Female, REGULATOR, Life Sciences & Biomedicine, Adult, Biology, 03 medical and health sciences, alternative splicing, Dravet syndrome, Report, medicine, Humans, Gene, Science & Technology, variant interpretation, Alternative splicing, epilepsy, Genetic Variation, medicine.disease, NAV1.1 Voltage-Gated Sodium Channel, 030104 developmental biology, DE-NOVO MUTATIONS, Neurodevelopmental Disorders, Human genome, Human medicine, 030217 neurology & neurosurgery
Abstract

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs.1-3 This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a "poison" exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons,4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly.6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:103 issue:6 pages:1022-1029 ispartof: location:United States status: published

Published
2018

2. De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies

Author

Silke Appenzeller, Rudi Balling, Nina Barisic, Stéphanie Baulac, Hande Caglayan, Dana Craiu, Peter De Jonghe, Christel Depienne, Petia Dimova, Tania Djémié, Padhraig Gormley, Renzo Guerrini, Ingo Helbig, Helle Hjalgrim, Dorota Hoffman-Zacharska, Johanna Jähn, Karl Martin Klein, Bobby Koeleman, Vladimir Komarek, Roland Krause, Gregor Kuhlenbäumer, Eric Leguern, Anna-Elina Lehesjoki, Johannes R. Lemke, Holger Lerche, Tarja Linnankivi, Carla Marini, Patrick May, Rikke S. Møller, Hiltrud Muhle, Deb Pal, Aarno Palotie, Manuela Pendziwiat, Angela Robbiano, Filip Roelens, Felix Rosenow, Kaja Selmer, Jose M. Serratosa, Sanjay Sisodiya, Ulrich Stephani, Katalin Sterbova, Pasquale Striano, Arvid Suls, Tiina Talvik, Sarah von Spiczak, Yvonne Weber, Sarah Weckhuysen, Federico Zara, Bassel Abou-Khalil, Brian K. Alldredge, Eva Andermann, Frederick Andermann, Dina Amrom, Jocelyn F. Bautista, Samuel F. Berkovic, Judith Bluvstein, Alex Boro, Gregory Cascino, Damian Consalvo, Patricia Crumrine, Orrin Devinsky, Dennis Dlugos, Michael P. Epstein, Miguel Fiol, Nathan B. Fountain, Jacqueline French, Daniel Friedman, Eric B. Geller, Tracy Glauser, Simon Glynn, Kevin Haas, Sheryl R. Haut, Jean Hayward, Sandra L. Helmers, Sucheta Joshi, Andres Kanner, Heidi E. Kirsch, Robert C. Knowlton, Eric H. Kossoff, Rachel Kuperman, Ruben Kuzniecky, Daniel H. Lowenstein, Shannon M. McGuire, Paul V. Motika, Edward J. Novotny, Ruth Ottman, Juliann M. Paolicchi, Jack Parent, Kristen Park, Annapurna Poduri, Lynette Sadleir, Ingrid E. Scheffer, Renée A. Shellhaas, Elliott Sherr, Jerry J. Shih, Rani Singh, Joseph Sirven, Michael C. Smith, Joe Sullivan, Liu Lin Thio, Anu Venkat, Eileen P.G. Vining, Gretchen K. Von Allmen, Judith L. Weisenberg, Peter Widdess-Walsh, Melodie R. Winawer, Andrew S. Allen, Patrick Cossette, Norman Delanty, Evan E. Eichler, David B. Goldstein, Yujun Han, Erin L. Heinzen, Michael R. Johnson, Anthony G. Marson, Heather C. Mefford, Sahar Esmaeeli Nieh, Terence J. O’Brien, Stephen Petrou, Slavé Petrovski, Elizabeth K. Ruzzo, Neuroscience Center, Research Programs Unit, Department of Medical and Clinical Genetics, Research Programme for Molecular Neurology, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, EuroEPINOMICS-RES Consortium, Epilepsy Phenome Genome Project, and Epi4K Consortium

Subjects
0301 basic medicine, Male, Proband, INTELLECTUAL DISABILITY, Type I, Bioinformatics, medicine.disease_cause, Infantile, Synaptic Transmission, Spasms, Cohort Studies, Epilepsy, 0302 clinical medicine, Receptors, SCHIZOPHRENIA, STXBP1, Exome, Gene Regulatory Networks, Protein Interaction Maps, Dynamin I, Genetics (clinical), Genetics, 0303 health sciences, Mutation, education.field_of_study, Medicine (all), Genome project, Fatty Acid Synthase, Type I, Fatty Acid Synthase, Female, APHASIA, Spasms, Infantile, DYNAMIN-1, EPILEPSIES, ENDOCYTOSIS, Population, SPECTRUM DISORDERS, Phenome, Neurotransmission, Biology, GNAO1, Article, 03 medical and health sciences, GRIN2A MUTATIONS, medicine, Humans, AUTISM, Infant, Newborn, Lennox Gastaut Syndrome, Receptors, GABA-B, Ryanodine Receptor Calcium Release Channel, education, Gene, De novo mutations, 030304 developmental biology, GABA-B, 3112 Neurosciences, Infant, Correction, Newborn, medicine.disease, Human genetics, 030104 developmental biology, DNM1, PATTERNS, Human medicine, 030217 neurology & neurosurgery, Lennox–Gastaut syndrome
Abstract

Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de nova mutations, including de novo mutations in DNM1 in five individuals and de nova mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de nova mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 x 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de nova mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.

Published
2017

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