Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/26165
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dc.contributor.authorCourage, Carolina-
dc.contributor.authorOliver, Karen L-
dc.contributor.authorPark, Eon Joo-
dc.contributor.authorCameron, Jillian M-
dc.contributor.authorGrabińska, Kariona A-
dc.contributor.authorMuona, Mikko-
dc.contributor.authorCanafoglia, Laura-
dc.contributor.authorGambardella, Antonio-
dc.contributor.authorSaid, Edith-
dc.contributor.authorAfawi, Zaid-
dc.contributor.authorBaykan, Betul-
dc.contributor.authorBrandt, Christian-
dc.contributor.authordi Bonaventura, Carlo-
dc.contributor.authorChew, Hui Bein-
dc.contributor.authorCriscuolo, Chiara-
dc.contributor.authorDibbens, Leanne M-
dc.contributor.authorCastellotti, Barbara-
dc.contributor.authorRiguzzi, Patrizia-
dc.contributor.authorLabate, Angelo-
dc.contributor.authorFilla, Alessandro-
dc.contributor.authorGiallonardo, Anna T-
dc.contributor.authorBerecki, Geza-
dc.contributor.authorJackson, Christopher B-
dc.contributor.authorJoensuu, Tarja-
dc.contributor.authorDamiano, John A-
dc.contributor.authorKivity, Sara-
dc.contributor.authorKorczyn, Amos-
dc.contributor.authorPalotie, Aarno-
dc.contributor.authorStriano, Pasquale-
dc.contributor.authorUccellini, Davide-
dc.contributor.authorGiuliano, Loretta-
dc.contributor.authorAndermann, Eva-
dc.contributor.authorScheffer, Ingrid E-
dc.contributor.authorMichelucci, Roberto-
dc.contributor.authorBahlo, Melanie-
dc.contributor.authorFranceschetti, Silvana-
dc.contributor.authorSessa, William C-
dc.contributor.authorBerkovic, Samuel F-
dc.contributor.authorLehesjoki, Anna-Elina-
dc.date2021-04-01-
dc.date.accessioned2021-04-08T02:43:44Z-
dc.date.available2021-04-08T02:43:44Z-
dc.date.issued2021-04-01-
dc.identifier.citationAmerican Journal of Human Genetics 2021; 108(4): 722-738en
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/26165-
dc.description.abstractProgressive 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.en
dc.language.isoeng-
dc.subjectdolichol-dependent glycosylationen
dc.subjectepilepsy geneticsen
dc.subjectprogressive myoclonus epilepsyen
dc.subjectwhole-exome sequencingen
dc.titleProgressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes.en
dc.typeJournal Articleen
dc.identifier.journaltitleAmerican Journal of Human Geneticsen
dc.identifier.affiliationNeurogenetics 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, Canadaen
dc.identifier.affiliationAnalytic and Translational Genetics Unit, Department of Medicine, Department of Neurology and Department of Psychiatry Massachusetts General Hospital, Boston, MA 02114, USAen
dc.identifier.affiliationSection of Medical Genetics, Mater dei Hospital, Msida MSD2090, Maltaen
dc.identifier.affiliationDepartment of Anatomy and Cell Biology, University of Malta, Msida MSD2090, Maltaen
dc.identifier.affiliationCenter for Neuroscience, Ben-Gurion University of the Negev, Be'er Sheva 8410402, Israelen
dc.identifier.affiliationEpilepsy Research Centreen
dc.identifier.affiliationIon Channels and Disease Group, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationEpilepsy Research Group, Australian Centre for Precision Health, UniSA Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australiaen
dc.identifier.affiliationPopulation Health and Immunity Division, the Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationDepartment of Medical Biology, the University of Melbourne, Melbourne, VIC 3010, Australiaen
dc.identifier.affiliationMurdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationDepartment of Paediatrics, The University of Melbourne, Royal Children's Hospital, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationThe Florey Institute, Parkville, VIC 3052, Australiaen
dc.identifier.affiliationDepartment of Pharmacology and Vascular Biology and Therapeutics Program, Yale University School of Medicine, 10 Amistad Street, New Haven, CT 06520, USAen
dc.identifier.affiliationEpilepsy Center Bethel, Bielefeld 33617, Germanyen
dc.identifier.affiliationThe Stanley Center for Psychiatric Research and Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, Boston, MA 02142, USAen
dc.identifier.affiliationInstitute of Neurology, University Magna Græcia, Catanzaro 88100, Italyen
dc.identifier.affiliationNeurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan 20133, Italyen
dc.identifier.affiliationDepartment of Human Neurosciences, Sapienza University of Rome, Viale dell'Università, 30, 00185 Rome, Italyen
dc.identifier.affiliationFolkhälsan Research Center, Helsinki 00290, Finlanden
dc.identifier.affiliationBlueprint Genetics, Espoo 02150, Finlanden
dc.identifier.affiliationDepartment of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00290, Finlanden
dc.identifier.affiliationIRCCS Istituto delle Scienze Neurologiche di Bologna, Unit of Neurology, Bellaria Hospital, Bologna 40139, Italyen
dc.identifier.affiliationUnit of Genetics of Neurodegenerative and Metabolic Diseases, IRCCS Istituto Neurologico Carlo Besta Milan 20133, Italyen
dc.identifier.affiliationDipartimento "G.F. Ingrassia," Università degli Studi di Catania, Catania 95131, Italyen
dc.identifier.affiliationNeurology - Neurophysiology Unit, ASST dei Sette Laghi, Galmarini Tradate Hospital, Tradate 21049, Italyen
dc.identifier.affiliationPediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "G. Gaslini," Genova 16147, Italyen
dc.identifier.affiliationNeurology Unit, Human Neurosciences Department, Sapienza University, Rome 00185, Italyen
dc.identifier.affiliationDepartment of Neuroscience, Reproductive, and Odontostomatological Sciences, University of Naples Federico II, Naples 80138, Italyen
dc.identifier.affiliationStem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finlanden
dc.identifier.affiliationDepartment of Medical and Clinical Genetics, Medicum, University of Helsinki, Helsinki 00290, Finland.en
dc.identifier.affiliationSackler Faculty of Medicine, Tel Aviv University, Tel Aviv 60198, Israelen
dc.identifier.affiliationEpilepsy Unit, Schneider Children's Medical Center of Israel, Petah Tiqvah 4922297, Israelen
dc.identifier.affiliationInstitute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki 00290, Finlanden
dc.identifier.affiliationDepartments of Neurology and Clinical Neurophysiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul 34452, Turkeyen
dc.identifier.affiliationGenetics Department, Kuala Lumpur Hospital, Ministry of Health Malaysia, Jalan Pahang, 50586 Kuala Lumpur, Malaysiaen
dc.identifier.doi10.1016/j.ajhg.2021.03.013en
dc.type.contentTexten
dc.identifier.pubmedid33798445-
local.name.researcherBerkovic, Samuel F
item.openairetypeJournal Article-
item.cerifentitytypePublications-
item.grantfulltextnone-
item.fulltextNo Fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.languageiso639-1en-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptNeurology-
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