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Title: | Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes. | Austin Authors: | Courage, Carolina;Oliver, Karen L;Park, Eon Joo;Cameron, Jillian M ;Grabińska, Kariona A;Muona, Mikko;Canafoglia, Laura;Gambardella, Antonio;Said, Edith;Afawi, Zaid;Baykan, Betul;Brandt, Christian;di Bonaventura, Carlo;Chew, Hui Bein;Criscuolo, Chiara;Dibbens, Leanne M;Castellotti, Barbara;Riguzzi, Patrizia;Labate, Angelo;Filla, Alessandro;Giallonardo, Anna T;Berecki, Geza;Jackson, Christopher B;Joensuu, Tarja;Damiano, John A;Kivity, Sara;Korczyn, Amos;Palotie, Aarno;Striano, Pasquale;Uccellini, Davide;Giuliano, Loretta;Andermann, Eva;Scheffer, Ingrid E ;Michelucci, Roberto;Bahlo, Melanie;Franceschetti, Silvana;Sessa, William C;Berkovic, Samuel F ;Lehesjoki, Anna-Elina | Affiliation: | Neurogenetics Unit and Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, QC H3A 2B4, Canada; Departments of Neurology & Neurosurgery and Human Genetics, McGill University, Montreal, QC H3A 0G4, Canada Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry Massachusetts General Hospital, Boston, MA 02114, USA Section of Medical Genetics, Mater dei Hospital, Msida MSD2090, Malta Department of Anatomy and Cell Biology, University of Malta, Msida MSD2090, Malta Center for Neuroscience, Ben-Gurion University of the Negev, Be'er Sheva 8410402, Israel Epilepsy Research Centre Ion Channels and Disease Group, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia Epilepsy Research Group, Australian Centre for Precision Health, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia Population Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia Department of Medical Biology, the University of Melbourne, Melbourne, VIC 3010, Australia Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia Department of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australia The Florey Institute, Parkville, VIC 3052, Australia Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA Epilepsy Center Bethel, Bielefeld 33617, Germany The Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Boston, MA 02142, USA Institute of Neurology, University Magna Græcia, Catanzaro 88100, Italy Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università, 30, 00185 Rome, Italy Folkhälsan Research Center, Helsinki 00290, Finland Blueprint Genetics, Espoo 02150, Finland Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00290, Finland IRCCS Istituto delle Scienze Neurologiche di Bologna, Unit of Neurology, Bellaria Hospital, Bologna 40139, Italy Unit of Genetics of Neurodegenerative and Metabolic Diseases, IRCCS Istituto Neurologico Carlo Besta Milan 20133, Italy Dipartimento "G.F. Ingrassia," Università degli Studi di Catania, Catania 95131, Italy Neurology - Neurophysiology Unit, ASST dei Sette Laghi, Galmarini Tradate Hospital, Tradate 21049, Italy Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "G. Gaslini," Genova 16147, Italy Neurology Unit, Human Neurosciences Department, Sapienza University, Rome 00185, Italy Department of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples 80138, Italy Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00290, Finland. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 60198, Israel Epilepsy Unit, Schneider Children's Medical Center of Israel, Petah Tiqvah 4922297, Israel Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland Departments of Neurology and Clinical Neurophysiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey Genetics Department, Kuala Lumpur Hospital, Ministry of Health Malaysia, Jalan Pahang, 50586 Kuala Lumpur, Malaysia |
Issue Date: | 1-Apr-2021 | Date: | 2021-04-01 | Publication information: | American Journal of Human Genetics 2021; 108(4): 722-738 | Abstract: | Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/26165 | DOI: | 10.1016/j.ajhg.2021.03.013 | Journal: | American Journal of Human Genetics | PubMed URL: | 33798445 | Type: | Journal Article | Subjects: | dolichol-dependent glycosylation epilepsy genetics progressive myoclonus epilepsy whole-exome sequencing |
Appears in Collections: | Journal articles |
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