engleski

Sequencing in patients with familial and sporadic multiple sclerosis reveals the possible etiological role of rare and highly penetrant genetic variation.

Multiple sclerosis (MS) is a chronic autoimmune neurological disorder with complex genetic architecture. Despite efforts, even large genome-wide association studies (GWAS) failed to completely explain heritability of MS based on common genetic variation. To characterize the possible role of rare, highly penetrant genetic variants in MS, we performed whole exome sequencing in 48 patients with familial MS, 40 patients with sporadic MS and 92 population-matched controls. We have focused the analysis to rare (<5%) and predicted pathogenic variants (truncating or predicted pathogenic missense variants) in 102 genes associated with MS in the most recent GWAS performed to date. In the subset of patients with familial MS, we identified two novel truncating variants of high impact in MMEL1 and ALPK2 genes. Truncating variants in two further GWAS genes - IL7R and AHI1 were also identified in sporadic MS cases. Several predicted pathogenic missense variants were also identified in MS associated genes: 18 variants in familial MS cases and 27 in sporadic cases. Finally, we could also demonstrate an increased burden of rare predicted pathogenic variants in GWAS genes in both familial (OR=1.77, p=0.048) and sporadic MS cases (OR=2.5, p=0.0003), when comparing this load to the population of healthy controls. Our results suggest the possible role of rare pathogenic variants in genes previously associated with MS in association studies. Furthermore, we report an increased overall burden of pathogenic variants within these genes in familial and sporadic cases with MS.

Multiple sclerosis ; Exome sequencing ; Rare variation

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