Progressive myoclonus epilepsies-Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes
| Autor: | Leanne M. Dibbens, Anna-Elina Lehesjoki, Roberto Michelucci, Aarno Palotie, Barbara Castellotti, Jillian M. Cameron, Amos D. Korczyn, Loretta Giuliano, Davide Uccellini, Alessandro Filla, Edith Said, Karen Oliver, Zaid Afawi, William C. Sessa, Hui Bein Chew, Silvana Franceschetti, Carlo Di Bonaventura, Eva Andermann, Anna Teresa Giallonardo, Angelo Labate, Samuel F. Berkovic, Betül Baykan, Kariona A. Grabińska, Carolina Courage, Patrizia Riguzzi, Melanie Bahlo, Antonio Gambardella, John A. Damiano, Laura Canafoglia, Tarja Joensuu, Pasquale Striano, Christopher B. Jackson, Mikko Muona, Christian Brandt, Chiara Criscuolo, Sara Kivity, Eon Joo Park, Ingrid E. Scheffer, Géza Berecki |
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| Přispěvatelé: | HUSLAB, Medicum, Department of Medical and Clinical Genetics, University of Helsinki, Clinicum, Research Programs Unit, STEMM - Stem Cells and Metabolism Research Program, Faculty of Medicine, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, Helsinki Institute of Life Science HiLIFE, Courage, Carolina, Oliver, Karen L, Park, Eon Joo, Cameron, Jillian M, Dibbens, Leanne M, Lehesjoki, Anna Elina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Glycosylation medicine.disease_cause Whole Exome Sequencing Cohort Studies 0302 clinical medicine Dolichols whole-exome sequencing Age of Onset Child Genetics (clinical) Exome sequencing Genetics Mutation 1184 Genetics developmental biology physiology dolichol-dependent glycosylation Middle Aged 3. Good health Child Preschool ASAH1 Female medicine.symptom Adult Adolescent DNA Copy Number Variations Progressive myoclonus epilepsy Biology progressive myoclonus epilepsy Article 03 medical and health sciences Young Adult Progressive Myoclonic Epilepsies Exome Sequencing medicine Humans epilepsy genetics Preschool Gene Genetic heterogeneity Intron Introns Myoclonic Epilepsies Progressive medicine.disease 030104 developmental biology 3111 Biomedicine Myoclonus 030217 neurology & neurosurgery |
| Zdroj: | Am J Hum Genet |
| ISSN: | 1537-6605 |
| Popis: | 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. Refereed/Peer-reviewed |
| Databáze: | OpenAIRE |
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