Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Kishore R Kumar; Ryan L Davis; Michel C Tchan; G M Wali; Neil Mahant; Karl Ng; Katya Kotschet; Sue-Faye Siow; Jason Gu; Zachary Walls; Ce Kang; Gautam Wali; Stan Levy; Chung Sen Phua; Con Yiannikas; Paul Darveniza; Florence C F Chang; Hugo Morales-Briceño; Dominic B Rowe; Alex Drew; Velimir Gayevskiy; Mark J Cowley; Andre E Minoche; Stephen Tisch; Michael Hayes; Sarah Kummerfeld; Victor S C Fung; Carolyn M Sue

doi:10.1016/j.parkreldis.2019.11.004

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes

Parkinsonism Relat Disord. 2019 Dec:69:111-118. doi: 10.1016/j.parkreldis.2019.11.004. Epub 2019 Nov 7.

Authors

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

Affiliations

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.

PMID: 31731261
DOI: 10.1016/j.parkreldis.2019.11.004

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.

Keywords: Dystonia; GNAL; Genetic diagnosis; KMT2B; Whole genome sequencing.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Aged, 80 and over
Child
DNA Copy Number Variations
Dystonic Disorders / diagnosis*
Dystonic Disorders / genetics*
Female
Humans
Male
Middle Aged
Phenotype
Whole Genome Sequencing / methods*
Young Adult