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Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes

Courage C 1 , Oliver KL 2 , Park EJ 3 , Cameron JM 4 , Grabińska KA 3 , Muona M 5 Show all authors , Canafoglia L 6 , Gambardella A 7 , Said E 8 , Afawi Z 9 , Baykan B 10 , Brandt C 11 , di Bonaventura C 12 , Chew HB 13 , Criscuolo C 14 , Dibbens LM 15 , Castellotti B 16 , Riguzzi P 17 , Labate A 7 , Filla A 14 , Giallonardo AT 18 , Berecki G 19 , Jackson CB 20 , Joensuu T 21 , Damiano JA 4 , Kivity S 22 , Korczyn A 23 , Palotie A 24 , Striano P 25 , Uccellini D 26 , Giuliano L 27 , Andermann E 28 , Scheffer IE 29 , Michelucci R 17 , Bahlo M 30 , Franceschetti S 6 , Sessa WC 3 , Berkovic SF 31 , Lehesjoki AE 32

Affiliations 

  • 1 Folkhälsan Research Center, Helsinki 00290, Finland; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00290, Finland
  • 2 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, 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
  • 3 Department of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USA
  • 4 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia
  • 5 Folkhälsan Research Center, Helsinki 00290, Finland; Blueprint Genetics, Espoo 02150, Finland
  • 6 Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italy
  • 7 Institute of Neurology, University Magna Græcia, Catanzaro 88100, Italy
  • 8 Section of Medical Genetics, Mater dei Hospital, Msida MSD2090, Malta; Department of Anatomy and Cell Biology, University of Malta, Msida MSD2090, Malta
  • 9 Center for Neuroscience, Ben-Gurion University of the Negev, Be'er Sheva 8410402, Israel
  • 10 Departments of Neurology and Clinical Neurophysiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkey
  • 11 Epilepsy Center Bethel, Bielefeld 33617, Germany
  • 12 Department of Human Neurosciences, Sapienza University of Rome, Viale dell'Università, 30, 00185 Rome, Italy
  • 13 Genetics Department, Kuala Lumpur Hospital, Ministry of Health Malaysia, Jalan Pahang, 50586 Kuala Lumpur, Malaysia
  • 14 Department of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples 80138, Italy
  • 15 Epilepsy Research Group, Australian Centre for Precision Health, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
  • 16 Unit of Genetics of Neurodegenerative and Metabolic Diseases, IRCCS Istituto Neurologico Carlo Besta Milan 20133, Italy
  • 17 IRCCS Istituto delle Scienze Neurologiche di Bologna, Unit of Neurology, Bellaria Hospital, Bologna 40139, Italy
  • 18 Neurology Unit, Human Neurosciences Department, Sapienza University, Rome 00185, Italy
  • 19 Ion Channels and Disease Group, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia
  • 20 Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
  • 21 Folkhälsan Research Center, Helsinki 00290, Finland
  • 22 Epilepsy Unit, Schneider Children's Medical Center of Israel, Petah Tiqvah 4922297, Israel
  • 23 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 60198, Israel
  • 24 Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finland; Analytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry Massachusetts General Hospital, Boston, MA 02114, USA; 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
  • 25 Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "G. Gaslini," Genova 16147, Italy
  • 26 Neurology - Neurophysiology Unit, ASST dei Sette Laghi, Galmarini Tradate Hospital, Tradate 21049, Italy
  • 27 Dipartimento "G.F. Ingrassia," Università degli Studi di Catania, Catania 95131, Italy
  • 28 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
  • 29 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, 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
  • 30 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
  • 31 Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg 3084, Victoria, Australia. Electronic address: s.berkovic@unimelb.edu.au
  • 32 Folkhälsan Research Center, Helsinki 00290, Finland; Department of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00290, Finland. Electronic address: anna-elina.lehesjoki@helsinki.fi
Am J Hum Genet, 2021 04 01;108(4):722-738.
PMID: 33798445 DOI: 10.1016/j.ajhg.2021.03.013

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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