Journal article

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

Carolina Courage, Karen L Oliver, Eon Joo Park, Jillian M Cameron, Kariona A Grabinska, Mikko Muona, Laura Canafoglia, Antonio Gambardella, Edith Said, Zaid Afawi, Betul Baykan, Christian Brandt, Carlo di Bonaventura, Hui Bein Chew, Chiara Criscuolo, Leanne M Dibbens, Barbara Castellotti, Patrizia Riguzzi, Angelo Labate, Alessandro Filla Show all



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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Awarded by NIH

Awarded by Australian National Health and Medical Research Council (NHMRC)

Awarded by NHMRC Senior Research Fellowship

Awarded by Istanbul University

Awarded by NHMRC Practitioner Fellowship

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.