Genome sequencing reanalysis increases the diagnostic yield in dystonia.

Diagnostic yield Dystonia Genome sequencing Reanalysis

Journal

Parkinsonism & related disorders
ISSN: 1873-5126
Titre abrégé: Parkinsonism Relat Disord
Pays: England
ID NLM: 9513583

Informations de publication

Date de publication:
14 May 2024
Historique:
received: 14 01 2024
revised: 15 03 2024
accepted: 12 05 2024
medline: 22 5 2024
pubmed: 22 5 2024
entrez: 21 5 2024
Statut: aheadofprint

Résumé

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

Identifiants

DOI: 10.1016/j.parkreldis.2024.107010 PMID: 38772265
pubmed: 38772265
pii: S1353-8020(24)01022-8
doi: 10.1016/j.parkreldis.2024.107010
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

107010

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.

Déclaration de conflit d'intérêts

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.

Auteurs

Avi Fellner (A)

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.

Gurusidheshwar M Wali (GM)

Neurospecialities Centre, Belgaum, India.

Neil Mahant (N)

Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia.

Bianca R Grosz (BR)

Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia.

Melina Ellis (M)

Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia.

Ramesh K Narayanan (RK)

Northcott Neuroscience Laboratory, ANZAC Research Institute SLHD, Concord, NSW, Australia.

Karl Ng (K)

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.

Ryan L Davis (RL)

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.

Michel C Tchan (MC)

Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Genetic Medicine, Westmead Hospital, Westmead, NSW, Australia.

Katya Kotschet (K)

Clinical Neurosciences, St. Vincent's Hospital, Melbourne, Australia.

Dennis Yeow (D)

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.

Laura I Rudaks (LI)

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.

Sue-Faye Siow (SF)

Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Clinical Genetics, Royal North Shore Hospital, St. Leonards, NSW, Australia.

Gautam Wali (G)

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.

Con Yiannikas (C)

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.

Matthew Hobbs (M)

Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

Joseph Copty (J)

Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

Michael Geaghan (M)

Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

Paul Darveniza (P)

Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW, Australia.

Christina Liang (C)

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.

Laura J Williams (LJ)

Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia.

Florence C F Chang (FCF)

Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Hugo Morales-Briceño (H)

Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Stephen Tisch (S)

Department of Neurology, St. Vincent's Hospital, Darlinghurst, NSW, Australia; School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia.

Michael Hayes (M)

Department of Neurology, Concord Repatriation General Hospital, Sydney, NSW, Australia.

Scott Whyte (S)

Department of Neurology, Gosford Hospital, Gosford, Australia.

Sarah Kummerfeld (S)

Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.

Marina L Kennerson (ML)

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.

Mark J Cowley (MJ)

School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia; Children's Cancer Institute, University of New South Wales, Sydney, Australia.

Victor S C Fung (VSC)

Movement Disorders Unit, Neurology Department, Westmead Hospital, Westmead, NSW, Australia; Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.

Carolyn M Sue (CM)

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.

Kishore R Kumar (KR)

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.

Classifications MeSH