Objective The clinical utility of routine genetic sequencing in amyotrophic lateral sclerosis (ALS) is uncertain. Our aim was to determine whether routine targeted sequencing of 44 ALS-relevant genes would have a significant impact on disease subclassification and clinical care.
Methods We performed targeted sequencing of a 44-gene panel in a prospective case series of 100 patients with ALS recruited consecutively from the Sheffield Motor Neuron Disorders Clinic, UK. All participants were diagnosed with ALS by a specialist Consultant Neurologist. 7/100 patients had familial ALS, but the majority were apparently sporadic cases.
Results 21% of patients with ALS carried a confirmed pathogenic or likely pathogenic mutation, of whom 93% had no family history of ALS. 15% met the inclusion criteria for a current ALS genetic-therapy trial. 5/21 patients with a pathogenic mutation had an additional variant of uncertain significance (VUS). An additional 21% of patients with ALS carried a VUS in an ALS-associated gene. Overall, 13% of patients carried more than one genetic variant (pathogenic or VUS). Patients with ALS carrying two variants developed disease at a significantly earlier age compared with patients with a single variant (median age of onset=56 vs 60 years, p=0.0074).
Conclusions Routine screening for ALS-associated pathogenic mutations in a specialised ALS referral clinic will impact clinical care in 21% of cases. An additional 21% of patients have variants in the ALS gene panel currently of unconfirmed significance after removing non-specific or predicted benign variants. Overall, variants within known ALS-linked genes are of potential clinical importance in 42% of patients.
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JK and PJS are joint senior authors.
SRS, MDP and JC-K contributed equally.
Collaborators The Project MinE: Ian Blair (Centre for Motor Neuron Disease Research, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia), Matthew C. Kiernan (Brain and Mind Centre, The University of Sydney, Sydney, Australia), Miguel Mitne Neto (Universidade de São Paulo, Brazil), Adriano Chio (“Rita Levi Montalcini” Department of Neuroscience, ALS Centre, University of Torino, Turin, Italy; Azienda Ospedaliera Città della Salute e della Scienza, Torino, Italy), Ruben Cauchi (Centre for Molecular Medicine & Biobanking, University of Malta, Malta; Department of Physiology & Biochemistry, Faculty of Medicine & Surgery, University of Malta, Malta), Wim Robberecht (KU Leuven - University of Leuven, Department of Neurosciences, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium), Philip van Damme (KU Leuven - University of Leuven, Department of Neurosciences, Leuven, Belgium; VIB, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium), Philippe Corcia (Centre SLA, CHRU de Tours, Tours, France; UMR 1253, iBrain, Université de Tours, Inserm, Tours, France; Federation des Centres SLA Tours and Limoges, LITORALS, Tours, France), Philippe Couratier (Centre SLA, CHU Dupuytren Limoges, France), Orla Hardiman (Academic Unit of Neurology, Trinity College Dublin, Trinity Biomedical Sciences Institute, Dublin, Republic of Ireland; Department of Neurology, Beaumont Hospital, Dublin, Republic of Ireland), Russell McLaughin (Complex Trait Genomics Laboratory, Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Republic of Ireland), Marc Gotkine (The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew,University Medical Center, Jerusalem, Israel), Vivian Drory (Department of Neurology Tel-Aviv Sourasky Medical Centre, Israel), Nicola Ticozzi (Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; Department of Pathophysiology and Tranplantation, ‘Dino Ferrari’ Center, Università degli Studi di Milano, Milano, Italy), Vincenzo Silani (Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milano, Italy; Department of Pathophysiology and Tranplantation, ‘Dino Ferrari’ Center, Università degli Studi di Milano, Milano, Italy), Jan H. Veldink (Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands), Leonard H. van den Berg (Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands), Mamede de Carvalho (Instituto de Fisiologia, Instituto de Medicina Molecular,Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal; Department of Neurosciences, Hospital de Santa Maria-CHLN, Lisbon, Portugal), Jesus S. Mora Pardina (ALS Unit, Hospital San Rafael, Madrid, Spain), Monica Povedano (la Unitat Funcional de Motoneurona, Cap de Secció de Neurofisiologia, Servei de Neurologia, Hospital Universitario de Bellvitge-IDIBELL), Peter Andersen (Department of Clinical Science, Neurosciences, Umeå University, Sweden), Markus Weber (Neuromuscular Diseases Unit/ALS Clinic, Kantonsspital St. Gallen, 9007, St. Gallen, Switzerland), Nazli A. Ba_ak (Koç University, School of Medicine, KUTTAM-NDAL, Istanbul Turkey), Ammar Al-Chalabi (Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK), Chris Shaw (Maurice Wohl Clinical Neuroscience Institute, King's College London, Department of Basic and Clinical Neuroscience, London, UK), Pamela J. Shaw (Sheffield Institute for Translational Neuroscience (SITraN), University of Sheffield, Sheffield, UK), Karen E. Morrison (School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, UK), John E. Landers (Department of Neurology, University of Massachusetts Medical School, Worcester, MA, USA), Jonathan D. Glass (Department Neurology, Emory University School of Medicine, Atlanta, GA, USA; Emory ALS Center, Emory University School of Medicine, Atlanta, GA, USA), Eran Hornsetin (Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel).
Contributors PJS and JK conceived and designed the study. JC-K, MDP, MRT, AM and PF contributed to the design, theoretical analysis and implementation of the analysis pipeline. SRS, MDP, JC-K, NSV, LT, CH, TMJ, CJM, PJS, NB, EP and ESAS were responsible for data acquisition. SRS, MDP, JC-K, NSV, JK and PJS were responsible for analysis of data. JK, PJS, MDP and JC-K were responsible for interpretation of data. PJS, JK and MDP supervised the project. The Project MinE ALS Sequencing Consortium (online supplementary table 4) was involved in data acquisition and analysis. All authors meet the four ICMJE authorship criteria, and were responsible for revising the manuscript, approving the final version for publication, and for accuracy and integrity of the work.
Funding PJS is supported as an NIHR Senior Investigator (NF-SI-0617–10077). PJS, SRS, NV, JK, PF, MRT and AM are supported by the Motor Neurone Disease Association (AMBRoSIA 972-797 and NECTAR 974-797 awards). LT is supported by the NIHR Yorkshire and Humber Clinical Research Network. This research was supported by the NIHR Sheffield Biomedical Research Centre (BRC) (IS-BRC-1215-20017) and the NIHR Sheffield Clinical Research Facility (CRF).
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information. Data are stored in the AMBRoSIA consortium repository. Anonymised raw data can be made available on reasonable request.
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