Genome sequencing reanalysis increases the diagnostic yield in dystonia

Avi Fellner; Gurusidheshwar M Wali; Neil Mahant; Bianca R Grosz; Melina Ellis; Ramesh K Narayanan; Karl Ng; Ryan L Davis; Michel C Tchan; Katya Kotschet; Dennis Yeow; Laura I Rudaks; Sue-Faye Siow; Gautam Wali; Con Yiannikas; Matthew Hobbs; Joseph Copty; Michael Geaghan; Paul Darveniza; Christina Liang; Laura J Williams; Florence C F Chang; Hugo Morales-Briceño; Stephen Tisch; Michael Hayes; Scott Whyte; Sarah Kummerfeld; Marina L Kennerson; Mark J Cowley; Victor S C Fung; Carolyn M Sue; Kishore R Kumar

doi:10.1016/j.parkreldis.2024.107010

Genome sequencing reanalysis increases the diagnostic yield in dystonia

Parkinsonism Relat Disord. 2024 May 14:124:107010. doi: 10.1016/j.parkreldis.2024.107010. Online ahead of print.

Authors

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

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.