Genome sequencing reanalysis increases the diagnostic yield in dystonia

Avi Fellner¹, Gurusidheshwar M Wali², Neil Mahant³, Bianca R Grosz⁴, Melina Ellis⁴, Ramesh K Narayanan⁴, Karl Ng⁵, Ryan L Davis⁶, Michel C Tchan⁷, Katya Kotschet⁸, Dennis Yeow⁹, Laura I Rudaks¹⁰, Sue-Faye Siow¹¹, Gautam Wali¹², Con Yiannikas¹³, Matthew Hobbs¹⁴, Joseph Copty¹⁴, Michael Geaghan¹⁴, Paul Darveniza¹⁵, Christina Liang¹⁶, Laura J Williams³, Florence C F Chang¹⁷, Hugo Morales-Briceño¹⁷, Stephen Tisch¹⁸, Michael Hayes¹⁹, Scott Whyte²⁰, Sarah Kummerfeld¹⁴, Marina L Kennerson²¹, Mark J Cowley²², Victor S C Fung¹⁷, Carolyn M Sue²³, Kishore R Kumar²⁴

Affiliations

¹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Neurogenetics Clinic, Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel. Electronic address: avi.fellner@gmail.com.
² Neurospecialities Centre, Belgaum, India.
³ Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia.
⁴ Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia.
⁵ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia.
⁶ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia.
⁷ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia.
⁸ Clinical Neurosciences, St. Vincent's Hospital, Melbourne, Australia.
⁹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia.
¹⁰ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; Department of Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia.
¹¹ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia.
¹² Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia.
¹³ Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia.
¹⁴ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
¹⁵ Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW, Australia.
¹⁶ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia.
¹⁷ Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹⁸ Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁹ Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia.
²⁰ Department of Neurology, Gosford Hospital, Gosford, Australia.
²¹ Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia.
²² School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; Children's Cancer Institute, University of New South Wales, Sydney, Australia.
²³ Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
²⁴ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia. Electronic address: k.kumar@garvan.org.au.

PMID: 38772265
DOI: 10.1016/j.parkreldis.2024.107010

Free article

Genome sequencing reanalysis increases the diagnostic yield in dystonia

Avi Fellner et al. Parkinsonism Relat Disord. 2024 Jul.

Free article

. 2024 Jul:124:107010.

doi: 10.1016/j.parkreldis.2024.107010. Epub 2024 May 14.

Authors

Affiliations

¹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; The Neurogenetics Clinic, Raphael Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel. Electronic address: avi.fellner@gmail.com.
² Neurospecialities Centre, Belgaum, India.
³ Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia.
⁴ Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia.
⁵ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia.
⁶ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia.
⁷ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia.
⁸ Clinical Neurosciences, St. Vincent's Hospital, Melbourne, Australia.
⁹ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia.
¹⁰ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; Department of Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia.
¹¹ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia.
¹² Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia.
¹³ Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia.
¹⁴ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
¹⁵ Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW, Australia.
¹⁶ Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia.
¹⁷ Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
¹⁸ Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
¹⁹ Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia.
²⁰ Department of Neurology, Gosford Hospital, Gosford, Australia.
²¹ Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia.
²² School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; Children's Cancer Institute, University of New South Wales, Sydney, Australia.
²³ Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia; Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney and Northern Sydney Local Health District, St. Leonards, NSW, Australia; Neuroscience Research Australia, Sydney, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.
²⁴ Garvan Institute of Medical Research, Darlinghurst, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia; Molecular Medicine Laboratory, Concord Repatriation General Hospital, Concord, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia. Electronic address: k.kumar@garvan.org.au.

PMID: 38772265
DOI: 10.1016/j.parkreldis.2024.107010

Abstract

Purpose: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing.

Methods: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis.

Results: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants.

Conclusion: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

Keywords: Diagnostic yield; Dystonia; Genome sequencing; Reanalysis.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Kishore Raj Kumar reports financial support was provided by the Ainsworth 4 Foundation. Stephen Tisch reports a relationship with Medtronic that includes: consulting or advisory and speaking and lecture fees. Stephen Tisch reports a relationship with Boston Scientific that includes: consulting or advisory and speaking and lecture fees. Stephen Tisch reports a relationship with Seqirus Pharmaceuticals that includes: consulting or advisory and speaking and lecture fees. Carolyn M. Sue reports a relationship with Living Cell Technologies Ltd. that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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Genome sequencing reanalysis increases the diagnostic yield in dystonia

Affiliations

Genome sequencing reanalysis increases the diagnostic yield in dystonia

Authors

Affiliations

Abstract

Conflict of interest statement

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