Kishore R Kumar1, Ryan L Davis2, Michel C Tchan3, G M Wali4, Neil Mahant5, Karl Ng6, Katya Kotschet7, Sue-Faye Siow8, Jason Gu9, Zachary Walls10, Ce Kang11, Gautam Wali12, Stan Levy13, Chung Sen Phua14, Con Yiannikas15, Paul Darveniza16, Florence C F Chang17, Hugo Morales-Briceño18, Dominic B Rowe19, Alex Drew20, Velimir Gayevskiy21, Mark J Cowley22, Andre E Minoche23, Stephen Tisch24, Michael Hayes25, Sarah Kummerfeld26, Victor S C Fung27, Carolyn M Sue28. 1. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia; Molecular Medicine Laboratory, Concord Hospital, 2139, Australia; Department of Neurology, Concord Hospital, 2139, Australia. Electronic address: kkum4618@uni.sydney.edu.au. 2. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia. Electronic address: ryan.davis@sydney.edu.au. 3. Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia. Electronic address: michel.tchan@health.nsw.gov.au. 4. Neurospecialities Centre, Jawaharlal Nehru Medical College, Belgaum, India. Electronic address: walidoc@hotmail.com. 5. Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney Medical School, University of Sydney, Sydney, 2145, Australia. Electronic address: nmahant@gmail.com. 6. Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia; Department of Neurology and Neurophysiology, Royal North Shore Hospital, Reserve Road, St Leonards, New South Wales, 2065, Australia. Electronic address: karl.ng@health.nsw.gov.au. 7. Florey Neuroscience Institute, University of Melbourne, Parkville, 3052, Australia; Department of Neurology, St Vincent's Hospital, Fitzroy, 3065, Australia. Electronic address: katya.kotschet@svha.org.au. 8. Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia. Electronic address: suefaye.siow@health.nsw.gov.au. 9. Department of Neurology, Wollongong Hospital, Wollongong, New South Wales, 2500, Australia. Electronic address: gujason07@gmail.com. 10. Faculty of Engineering and Information Technologies, University of Sydney, Darlington, 2008, Australia. Electronic address: zac971@hotmail.com. 11. Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia. Electronic address: kkan1041@uni.sydney.edu.au. 12. Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia. Electronic address: gautam.wali@sydney.edu.au. 13. Campbelltown Hospital, Campbelltown, 2560, Australia. Electronic address: Stanley.Levy@sswahs.nsw.gov.au. 14. Campbelltown Hospital, Campbelltown, 2560, Australia. Electronic address: chunsengphua@yahoo.com. 15. Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia; Department of Neurology, Concord Hospital, 2139, Australia; Department of Neurology, Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia. Electronic address: y.con@bigpond.com. 16. School of Medicine, University of New South Wales, Sydney, Australia; Department of Neurology, St Vincent's Hospital, Darlinghurst, 2010, Australia. Electronic address: recep702@stvincents.com.au. 17. Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney Medical School, University of Sydney, Sydney, 2145, Australia. Electronic address: Florence.Chang@health.nsw.gov.au. 18. Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney Medical School, University of Sydney, Sydney, 2145, Australia. Electronic address: Hugo.MoralesBriceno@health.nsw.gov.au. 19. Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, New South Wales, 2109, Australia. Electronic address: dominicrowe@mac.com. 20. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. Electronic address: a.drew@garvan.org.au. 21. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. Electronic address: vel@vel.nz. 22. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; Children's Cancer Institute, Kensington, 2750, Australia; St Vincent's Clinical School, UNSW Sydney, Darlinghurst, 2010, Australia. Electronic address: MCowley@ccia.org.au. 23. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. Electronic address: a.minoche@garvan.org.au. 24. School of Medicine, University of New South Wales, Sydney, Australia; Department of Neurology, St Vincent's Hospital, Darlinghurst, 2010, Australia. Electronic address: stephen.tisch@svha.org.au. 25. Department of Neurology, Concord Hospital, 2139, Australia. Electronic address: michael.hayes1@health.nsw.gov.au. 26. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia. Electronic address: s.kummerfeld@garvan.org.au. 27. Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney Medical School, University of Sydney, Sydney, 2145, Australia. Electronic address: vscfung@ozemail.com.au. 28. Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia; Department of Neurogenetics, Kolling Institute, University of Sydney and Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia; Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia; Department of Neurology, Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia. Electronic address: carolyn.sue@sydney.edu.au.
Abstract
INTRODUCTION: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. METHODS: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. RESULTS: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). CONCLUSION: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.
INTRODUCTION:Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. METHODS: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. RESULTS: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). CONCLUSION: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.
Authors: Sophie E Waller; Hugo Morales-Briceño; Laura Williams; Shekeeb S Mohammad; Avi Fellner; Kishore R Kumar; Michel Tchan; Victor S C Fung Journal: Mov Disord Clin Pract Date: 2021-12-16
Authors: Maja Rogić Vidaković; Ivana Gunjača; Josipa Bukić; Vana Košta; Joško Šoda; Ivan Konstantinović; Braco Bošković; Irena Bilić; Nikolina Režić Mužinić Journal: J Clin Med Date: 2022-06-15 Impact factor: 4.964
Authors: Michael Zech; Robert Jech; Sylvia Boesch; Matej Škorvánek; Sandrina Weber; Matias Wagner; Chen Zhao; Angela Jochim; Ján Necpál; Yasemin Dincer; Katharina Vill; Felix Distelmaier; Malgorzata Stoklosa; Martin Krenn; Stephan Grunwald; Tobias Bock-Bierbaum; Anna Fečíková; Petra Havránková; Jan Roth; Iva Příhodová; Miriam Adamovičová; Olga Ulmanová; Karel Bechyně; Pavlína Danhofer; Branislav Veselý; Vladimír Haň; Petra Pavelekova; Zuzana Gdovinová; Tobias Mantel; Tobias Meindl; Alexandra Sitzberger; Sebastian Schröder; Astrid Blaschek; Timo Roser; Michaela V Bonfert; Edda Haberlandt; Barbara Plecko; Birgit Leineweber; Steffen Berweck; Thomas Herberhold; Berthold Langguth; Jana Švantnerová; Michal Minár; Gonzalo Alonso Ramos-Rivera; Monica H Wojcik; Sander Pajusalu; Katrin Õunap; Ulrich A Schatz; Laura Pölsler; Ivan Milenkovic; Franco Laccone; Veronika Pilshofer; Roberto Colombo; Steffi Patzer; Arcangela Iuso; Julia Vera; Monica Troncoso; Fang Fang; Holger Prokisch; Friederike Wilbert; Matthias Eckenweiler; Elisabeth Graf; Dominik S Westphal; Korbinian M Riedhammer; Theresa Brunet; Bader Alhaddad; Riccardo Berutti; Tim M Strom; Martin Hecht; Matthias Baumann; Marc Wolf; Aida Telegrafi; Richard E Person; Francisca Millan Zamora; Lindsay B Henderson; David Weise; Thomas Musacchio; Jens Volkmann; Anna Szuto; Jessica Becker; Kirsten Cremer; Thomas Sycha; Fritz Zimprich; Verena Kraus; Christine Makowski; Pedro Gonzalez-Alegre; Tanya M Bardakjian; Laurie J Ozelius; Annalisa Vetro; Renzo Guerrini; Esther Maier; Ingo Borggraefe; Alice Kuster; Saskia B Wortmann; Annette Hackenberg; Robert Steinfeld; Birgit Assmann; Christian Staufner; Thomas Opladen; Evžen Růžička; Ronald D Cohn; David Dyment; Wendy K Chung; Hartmut Engels; Andres Ceballos-Baumann; Rafal Ploski; Oliver Daumke; Bernhard Haslinger; Volker Mall; Konrad Oexle; Juliane Winkelmann Journal: Lancet Neurol Date: 2020-11 Impact factor: 44.182
Authors: Maria Abel; Robert Pfister; Iman Hussein; Fahd Alsalloum; Christina Onyinzo; Simon Kappl; Michael Zech; Walter Demmel; Martin Staudt; Manfred Kudernatsch; Steffen Berweck Journal: Front Neurol Date: 2021-05-14 Impact factor: 4.003
Authors: Laura Cif; Diane Demailly; Jean-Pierre Lin; Katy E Barwick; Mario Sa; Lucia Abela; Sony Malhotra; Wui K Chong; Dora Steel; Alba Sanchis-Juan; Adeline Ngoh; Natalie Trump; Esther Meyer; Xavier Vasques; Julia Rankin; Meredith W Allain; Carolyn D Applegate; Sanaz Attaripour Isfahani; Julien Baleine; Bettina Balint; Jennifer A Bassetti; Emma L Baple; Kailash P Bhatia; Catherine Blanchet; Lydie Burglen; Gilles Cambonie; Emilie Chan Seng; Sandra Chantot Bastaraud; Fabienne Cyprien; Christine Coubes; Vincent d'Hardemare; Asif Doja; Nathalie Dorison; Diane Doummar; Marisela E Dy-Hollins; Ellyn Farrelly; David R Fitzpatrick; Conor Fearon; Elizabeth L Fieg; Brent L Fogel; Eva B Forman; Rachel G Fox; William A Gahl; Serena Galosi; Victoria Gonzalez; Tracey D Graves; Allison Gregory; Mark Hallett; Harutomo Hasegawa; Susan J Hayflick; Ada Hamosh; Marie Hully; Sandra Jansen; Suh Young Jeong; Joel B Krier; Sidney Krystal; Kishore R Kumar; Chloé Laurencin; Hane Lee; Gaetan Lesca; Laurence Lion François; Timothy Lynch; Neil Mahant; Julian A Martinez-Agosto; Christophe Milesi; Kelly A Mills; Michel Mondain; Hugo Morales-Briceno; John R Ostergaard; Swasti Pal; Juan C Pallais; Frédérique Pavillard; Pierre-Francois Perrigault; Andrea K Petersen; Gustavo Polo; Gaetan Poulen; Tuula Rinne; Thomas Roujeau; Caleb Rogers; Agathe Roubertie; Michelle Sahagian; Elise Schaefer; Laila Selim; Richard Selway; Nutan Sharma; Rebecca Signer; Ariane G Soldatos; David A Stevenson; Fiona Stewart; Michel Tchan; Ishwar C Verma; Bert B A de Vries; Jenny L Wilson; Derek A Wong; Raghda Zaitoun; Dolly Zhen; Anna Znaczko; Russell C Dale; Claudio M de Gusmão; Jennifer Friedman; Victor S C Fung; Mary D King; Shekeeb S Mohammad; Luis Rohena; Jeff L Waugh; Camilo Toro; F Lucy Raymond; Maya Topf; Philippe Coubes; Kathleen M Gorman; Manju A Kurian Journal: Brain Date: 2020-12-05 Impact factor: 13.501