Evidence map›Paper›PMID 41372986›Full record

ArticleGenome medicine2025

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 and 10 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Genome medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed, 1 synthesis or guideline pooled it.

  1. Association between interleukin-10 gene polymorphisms and multiple sclerosis susceptibility: evidence from a meta-analysis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
    Pooled it
  2. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors.

Nicholas B Blackburn *Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia. Nicholas.Blackburn@utas.edu.au.
Bennet J McComish *Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia.
Allan Motyer *School of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, 3052, Australia.
James C SlimmerMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia.
Stephen J LeslieSchool of Mathematics and Statistics, The University of Melbourne, Parkville, VIC, 3052, Australia.
Simon A BroadleyMenzies Health Institute Queensland, Griffith University, Gold Coast, QLD, 4215, Australia.
Vilija G JokubaitisDepartment of Neuroscience, Monash University, Melbourne, VIC, 3004, Australia.
Anneke Van Der WaltDepartment of Neuroscience, Monash University, Melbourne, VIC, 3004, Australia.
Allan G KermodePerron Institute for Neurological and Translational Science, QE II Medical Centre, The University of Western Australia, Perth, 6009, Australia.
Jeannette Lechner-ScottDepartment of Neurology, John Hunter Hospital, Newcastle, NSW, 2305, Australia.
Grant P ParnellCentre for Immunology and Allergy Research, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW, 2145, Australia.
Marzena J Fabis-PedriniPerron Institute for Neurological and Translational Science, QE II Medical Centre, The University of Western Australia, Perth, 6009, Australia.
Rodney J ScottDivision of Molecular Medicine, NSW Health Pathology-North, John Hunter Hospital, New Lambton Heights, NSW, 2305, Australia.
Stacey JacksonThe Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia.
Vicki E MaltbyDepartment of Neurology, John Hunter Hospital, Newcastle, NSW, 2305, Australia.
Jac C CharlesworthMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia.
Kathryn P BurdonMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia.
Bruce V TaylorMenzies Institute for Medical Research, University of Tasmania, Hobart, TAS, 7000, Australia.
Trevor J KilpatrickThe Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia.
Justin P RubioThe Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3052, Australia. justin.rubio@florey.edu.au.

Funding

Medical Research Future Fund EPCD00008Multiple Sclerosis Australia 22-4-097Multiple Sclerosis Australia 23-SF-0034National Health and Medical Research Council 1175775National Health and Medical Research Council 2009389National Health and Medical Research Council 2025360
6 · The paper itself

Abstract

backgroundMultiple 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.

methodsExome 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.

resultsWe 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.

conclusionsOur 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.

Indexed as

Genetic VariationMultiple SclerosisNervous System DiseasesPhenotypeAdultExome SequencingFemaleGenetic Predisposition to DiseaseHumansMaleMiddle AgedExome sequencingGenetic factorsMisdiagnosisMultimorbidityMultiple sclerosis

Identifiers

PMID41372986
PMCPMC12715922

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.