Abstract
Background: As a complex disease, multiple sclerosis (MS) shares features and symptoms with other progressive neurological conditions. Some of these conditions are caused by rare genetic variants in specific genes. The extent to which people diagnosed with MS have an alternate genetic diagnosis (MS mimic), or genetic multimorbidity, is unknown.
Objective: We sought to identify 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 from the Australia and New Zealand MS Genetics Consortium (ANZgene) and 2,861 population-based 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. Prior findings of an increased burden of variation in hereditary spastic paraplegia genes in primary progressive MS were tested in this cohort. Gene-based association tests with MS risk and severity were performed for all genes in the cohort.
Results: We identified 166 MS cases with variants prompting clinical history reviews, and of 93 cases reviewed, four had either a genetic multimorbidity in addition to MS or a potential genetic misdiagnosis. In contrast to previous findings, we observed no enrichment of likely deleterious variants in HSP genes in primary progressive MS, nor gene-based associations with neurological disease genes and MS risk or severity.
Conclusion: 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.