Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes.,Parkinsonism & Related Disorders

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Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes.
Parkinsonism & Related Disorders ( IF 3.1 ) Pub Date : 2019-11-07 , DOI: 10.1016/j.parkreldis.2019.11.004
Kishore R Kumar ₁ , Ryan L Davis ₂ , Michel C Tchan ₃ , G M Wali ₄ , Neil Mahant ₅ , Karl Ng ₆ , Katya Kotschet ₇ , Sue-Faye Siow ₈ , Jason Gu ₉ , Zachary Walls ₁₀ , Ce Kang ₁₁ , Gautam Wali ₁₂ , Stan Levy ₁₃ , Chung Sen Phua ₁₃ , Con Yiannikas ₁₄ , Paul Darveniza ₁₅ , Florence C F Chang ₅ , Hugo Morales-Briceño ₅ , Dominic B Rowe ₁₆ , Alex Drew ₁₇ , Velimir Gayevskiy ₁₇ , Mark J Cowley ₁₈ , Andre E Minoche ₁₇ , Stephen Tisch ₁₅ , Michael Hayes ₁₉ , Sarah Kummerfeld ₁₇ , Victor S C Fung ₅ , Carolyn M Sue ₂₀

Affiliation

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.
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.
Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia.
Neurospecialities Centre, Jawaharlal Nehru Medical College, Belgaum, India.
Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney Medical School, University of Sydney, Sydney, 2145, Australia.
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.
Florey Neuroscience Institute, University of Melbourne, Parkville, 3052, Australia; Department of Neurology, St Vincent's Hospital, Fitzroy, 3065, 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 Genetic Medicine, Westmead Hospital, Westmead, NSW, 2145, Australia.
Department of Neurology, Wollongong Hospital, Wollongong, New South Wales, 2500, Australia.
Faculty of Engineering and Information Technologies, University of Sydney, Darlington, 2008, Australia.
Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Camperdown, 2050, 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.
Campbelltown Hospital, Campbelltown, 2560, Australia.
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.
School of Medicine, University of New South Wales, Sydney, Australia; Department of Neurology, St Vincent's Hospital, Darlinghurst, 2010, Australia.
Department of Clinical Medicine, Faculty of Medicine and Health Sciences, Macquarie University, Macquarie Park, New South Wales, 2109, Australia.
Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.
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.
Department of Neurology, Concord Hospital, 2139, Australia.
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.

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.

中文翻译：

用于异源性肌张力障碍表型遗传诊断的全基因组测序。

引言肌张力障碍是一种临床和遗传上的异质性疾病，遗传原因通常难以阐明。这是第一项使用全基因组测序（WGS）调查大量受影响个体样本中的肌张力障碍的研究。方法对111名具有异质性肌张力障碍表型的先证者进行WGS。我们对编码和非编码变体，拷贝数变体（CNV）和结构变体（SV）进行了分析。我们评估了肌张力障碍与10种已知的肌张力障碍风险变异之间的关联。结果获得了11.7％（13/111）个体的遗传诊断。我们发现，对于那些发病年龄较早，测试年龄较小以及合并肌张力障碍表型的患者，进行基因诊断的可能性更高。我们在ADCY5（n = 1），ATM（n = 1），GNAL（n = 2），GLB1（n = 1），KMT2B（n = 2），PRKN（n = 2），PRRT2（n = 1），SGCE（n = 2）和THAP1（n = 1）。在3个人中检测到CNV。我们发现已知风险变量ARSG rs11655081与肌张力障碍之间存在关联（p = 0.003）。结论在肌张力障碍患者中发现遗传学诊断的比例为11.7％。发病年龄较早，测试年龄较小且合并肌张力障碍表型的患者的诊断率较高。WGS可以检测到CNV，这在肌张力障碍中可能特别重要，它占遗传诊断病例的23％。结论在肌张力障碍患者中发现遗传学诊断的比例为11.7％。发病年龄较早，测试年龄较小且合并肌张力障碍表型的患者的诊断率较高。WGS可以检测到CNV，这在肌张力障碍中可能特别重要，它占遗传诊断病例的23％。结论在肌张力障碍患者中发现遗传学诊断的比例为11.7％。发病年龄较早，测试年龄较小且合并肌张力障碍表型的患者的诊断率较高。WGS可以检测到CNV，这在肌张力障碍中可能特别重要，它占遗传诊断病例的23％。

更新日期：2019-11-07

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