Novel Genetic Variants Distinguishing Myelin Oligodendrocyte Glycoprotein-IgG-Positive From Myelin Oligodendrocyte Glycoprotein-IgG-Negative Pediatric Acute Disseminated Encephalomyelitis in Northern China

Background Acute disseminated encephalomyelitis (ADEM) is a common phenotype in children with myelin oligodendrocyte glycoprotein IgG (MOG-IgG)-associated disease. We aimed to identify novel genetic variants that distinguish children with MOG-IgG positive ADEM (MOG-IgG+ADEM) from children with MOG-IgG negative ADEM (MOG-IgG-ADEM) using whole exome sequencing (WES) analysis. Methods We conducted a two-stage study design. First, we performed WES on five MOG-IgG+ADEM patients and five MOG-IgG-ADEM patients. Following bioinformatics analysis, the candidate variant list was constructed. Second, 29 children with MOG-IgG+ADEM and 27 children with MOG-IgG-ADEM, together with discovery cohort, were genotyped to identify the novel variants. Results WES resulted in 33,999 variants, and 5,388 nonsynonymous variants were selected for downstream analysis. In total, 118 protein-affecting variants that were significantly different between the two groups were identified. Together with the five variants extracted from the literature, 49 variants were selected as the candidate variant list for genotyping in the replication cohort. Finally, we identified three variants: rs11171951 in NACα, rs231775 in CTLA4 and rs11171951 in GOLGA5, which were significantly different between MOG-IgG+ADEM and MOG-IgG-ADEM. Only rs12440118 in NACα remained significant after Bonferroni correction for multiple testing (Padj<0.001). Conclusions We identified strong associations between NACα, CTLA4 and GOLGA5 variants and MOG-IgG+ADEM in a Han Chinese population of Northern China, Which may present novel genetic risk factor distinguishing patients with MOG-IgG+ADEM from those with MOG-IgG-ADEM.