Rare variation in neurological disease genes and its role in multiple sclerosis mimicry and phenotype

Nicholas B Blackburn; Bennet J McComish; Allan Motyer; James C Slimmer; Stephen J Leslie; Simon A Broadley; Vilija G Jokubaitis; Anneke Van Der Walt; Allan G Kermode; Jeannette Lechner-Scott; Grant P Parnell; Marzena J Fabis-Pedrini; Rodney J Scott; Stacey Jackson; Vicki E Maltby; Jac C Charlesworth; Kathryn P Burdon; Bruce V Taylor; Trevor J Kilpatrick; Justin P Rubio

doi:10.1186/s13073-025-01582-x

Back

Rare variation in neurological disease genes and its role in multiple sclerosis mimicry and phenotype

Journal article

Open access

Peer reviewed

Rare variation in neurological disease genes and its role in multiple sclerosis mimicry and phenotype

Nicholas B Blackburn, Bennet J McComish, Allan Motyer, James C Slimmer, Stephen J Leslie, Simon A Broadley, Vilija G Jokubaitis, Anneke Van Der Walt, Allan G Kermode, Jeannette Lechner-Scott, …

Genome medicine, Vol.17(1), 149

2025

DOI: https://doi.org/10.1186/s13073-025-01582-x

PMID: 41372986

Files and links (1)

pdf

Published 1.41 MBDownload View

Published (Version of Record)CC BY V4.0, Open Access

Abstract

Misdiagnosis

Multiple sclerosis

Genetic factors

Exome sequencing

Multimorbidity

Background Multiple sclerosis (MS) diagnosis relies on identifying disease episodes disseminated in space and time, and excluding other disease explanations. MS is a genetically complex autoimmune and neurodegenerative disorder that shares features with some monogenic progressive neurological conditions. The extent to which people diagnosed with MS have an alternate diagnosis (MS mimic), or genetic multimorbidity is unknown. Additionally, the burden of rare variation associated with MS risk and severity in monogenic neurological disease genes has not been evaluated. We investigated the prevalence of disease-causing variants in progressive neurological disease genes, and their contribution to MS risk and severity, in 4,340 MS cases diagnosed in sub-speciality clinics in Australia and New Zealand, and in 2,861 local controls. Methods Exome sequencing and array-based genotyping data were analysed for 1,680 genes with pathogenic or likely pathogenic variants reported in ClinVar. Clinical history reviews of MS cases with putative disease-causing variants were conducted. We specifically examined the contribution of rare, likely deleterious variants in a subset of 30 hereditary spastic paraplegia (HSP) genes in 421 individuals with progressive onset MS (POMS). Gene-based association tests with MS risk and severity were performed for all genes in the cohort. Results We identified 166 MS cases (3.82%) with variants prompting clinical history reviews, and of 75 cases reviewed, four (0.13% of all cases) had either genetic multimorbidity in addition to MS or a potential misdiagnosis. In contrast to previous findings we observed no enrichment of likely deleterious variants in HSP genes in POMS, nor did we find significant associations between neurological disease genes and MS risk or severity. Conclusions Our findings suggest that rare deleterious genetic variation in progressive neurological disease genes does not play a substantive role in MS risk or severity, and that misdiagnosis is exceedingly rare in this cohort. Consequently, among individuals diagnosed with MS by a specialist, a very small proportion may benefit from clinical genomic testing to inform MS diagnosis or an alternate diagnosis, which could have implications for healthcare management.

Details

Title: Rare variation in neurological disease genes and its role in multiple sclerosis mimicry and phenotype
Authors/Creators: Nicholas B Blackburn - University of Tasmania
Bennet J McComish - University of Tasmania
Allan Motyer - Melbourne Genomics Health Alliance
James C Slimmer - University of Tasmania
Stephen J Leslie - Melbourne Genomics Health Alliance
Simon A Broadley - Griffith University
Vilija G Jokubaitis - Monash University
Anneke Van Der Walt - Monash University
Allan G Kermode - Murdoch University
Jeannette Lechner-Scott - John Hunter Hospital
Grant P Parnell - The University of Sydney
Marzena J Fabis-Pedrini - Murdoch University, Personalised Medicine Centre
Rodney J Scott - John Hunter Hospital
Stacey Jackson - Florey Institute of Neuroscience and Mental Health
Vicki E Maltby - John Hunter Hospital
Jac C Charlesworth - University of Tasmania
Kathryn P Burdon - University of Tasmania
Bruce V Taylor - University of Tasmania
Trevor J Kilpatrick - Florey Institute of Neuroscience and Mental Health
Justin P Rubio - Florey Institute of Neuroscience and Mental Health
Publication Details: Genome medicine, Vol.17(1), 149
Publisher: BioMed Central Ltd unless otherwise stated. Part of Springer Nature.
Number of pages: 11
Grant note: 22-4-097 / Multiple Sclerosis Australia EPCD00008 / Medical Research Future Fund 23-SF-0034 / Multiple Sclerosis Australia 1175775 / National Health and Medical Research Council 2025360 / National Health and Medical Research Council 2009389 / National Health and Medical Research Council
Identifiers: 991005838793307891
Murdoch Affiliation: Institute for Immunology and Infectious Diseases; Personalised Medicine Centre
Language: English
Resource Type: Journal article

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Metrics

2 File views/ downloads

5 Record Views

1 Times Cited - Web of Science

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.257 Birth defects; 1.257.2442 Conjoined Twins & CADASIL
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics