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

C Courage; KL Oliver; EJ Park; JM Cameron; KA Grabińska; M Muona; L Canafoglia; A Gambardella; E Said; Z Afawi; B Baykan; C Brandt; C di Bonaventura; HB Chew; C Criscuolo; LM Dibbens; B Castellotti; P Riguzzi; A Labate; A Filla; AT Giallonardo; G Berecki; CB Jackson; T Joensuu; JA Damiano; S Kivity; A Korczyn; A Palotie; P Striano; D Uccellini; L Giuliano; E Andermann; IE Scheffer; R Michelucci; M Bahlo; S Franceschetti; WC Sessa; SF Berkovic; AE Lehesjoki

Journal article

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

C Courage, KL Oliver, EJ Park, JM Cameron, KA Grabińska, M Muona, L Canafoglia, A Gambardella, E Said, Z Afawi, B Baykan, C Brandt, C di Bonaventura, HB Chew, C Criscuolo, LM Dibbens, B Castellotti, P Riguzzi, A Labate, A Filla Show all

American Journal of Human Genetics | CELL PRESS | Published : 2021

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 val..

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University of Melbourne Researchers

Karen L Oliver Author

Geza Berecki Author

Ingrid Scheffer Author

Melanie Bahlo Author

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Grants

Awarded by National Institutes of Health

Funding Acknowledgements

The authors are indebted to the families participating in this study. We thank Paula Hakala, Katri Aksentjeff, Saara Tegelberg, Simona Allievi, and Marta Bayly for technical support and Michael Hildebrand for molecular analysis. The following funding bodies are acknowledged: Swiss National Foundation (Early Postdoc Mobility Grant [to C. Courage]), Folkhalsan Research Foundation (to A.-E.L.), NIH grant R35 HL139945 (toW.C.S.), Australian National Health and Medical Research Council (NHMRC) Program Grants GNT1054618 (to M.B.) and GNT1091593 (to S.F.B. and I.E.S.), NHMRC Senior Research Fellowship (GNT1102971) and Independent Research Institute Infrastructure Support Scheme (IRIISS) (to M.B.), Victorian Government's Operational Infrastructure Support Program (to M.B.), Istanbul University Scientific Research Fund-BAP-2019K12-149071 (to B.B.), NHMRC Senior Research Fellowship (GNT1104718) (to L.M.D.); and NHMRC Practitioner Fellowship (GNT1104831) (to I.E.S.). A.-E.L. is a HiLIFE Fellow at the University of Helsinki.