C6orf10 Low-Frequency and Rare Variants in Italian Multiple Sclerosis Patients

摘要: In light of the complex nature multiple sclerosis (MS) and recently estimated contribution low-frequency variants into disease, decoding its genetic risk components requires novel variant prioritization strategies. We selected, by reviewing MS Genome Wide Association Studies (GWAS), 107 candidate loci marked intragenic single nucleotide polymorphisms (SNPs) with a remarkable association (p-value ≤ 5 × 10-6). A whole exome sequencing (WES)-based pilot study SNPs minor allele frequency (MAF) 0.04, conducted in three Italian families, revealed 15 exonic affected parent-child transmission. These were detected 65/120 unrelated patients, also combination (22 patients). Compared databases (controls gnomAD, dbSNP150, ExAC, Tuscany-1000 Genome), allelic frequencies C6orf10 rs16870005 IL2RA rs12722600 significantly higher (i.e., controls p = 9.89 10-7 < 1 10-20). TET2 rs61744960 TRAF3 rs138943371 higher, except Genome. Interestingly, (Ala431Thr) did not depend on linkage disequilibrium HLA-DRB1 locus. Sequencing cohort 3' region 14 rare mutations (10 previously reported). Four null, more frequent than databases. Further, observed combinations, both intra-locus other SNPs. The Ser389Xfr was found homozygous patient early onset MS. Taking account potentially functional impact identified variants, their expression at protein level could provide insights heterogeneous pathogenetic mechanisms contributing to