Is It Worth To Study Families With Multiple Sclerosis (MS)? The Case Of A Novel Rare Variant In A Novel Unexpected Interferon-Stimulated Gene. (P6.155)

摘要: OBJECTIVE: To identify rare genetic variants contributing to MS susceptibility and explore their potential functional role. BACKGROUND: While the role of common is established from recent studies on sporadic cases, it unclear contribution in multiplex families. DESIGN/METHODS: SNP micro-array genotyping , whole-genome (WG) expression array WG sequencing have been performed 4 affected unaffected individuals an Italian consanguineous family. Linkage analysis has using Merlin software, SNPeff software used prioritize variants. RESULTS: We identified 406 with high impact, which narrowed 208 present all 53 if novel or (MAF<1%) 1 under one two LOD peaks (8p21.2 11q23.3). This variant not reported dbSNP 1000 Genomes project, co-segregates family being homozygote 3 heterozygote 1. It lies a very conserved region yeast human, causing amino acid change (S601P) GRAMD1B gene encodes membrane protein, part GRAM containing domain highly expressed CNS some specific immune cells subtypes (e.g. dendritic cells). found that this was down-regulated whole blood vs relatives (p=0.04), exception interferon(IFN)-treated case. Further experiments PBMCs isolated healthy donors showed IFN beta stimulation upregulated gene, providing link between disease treatment. The currently screened 1,000 cases sequenced probands 100 additional families. CONCLUSIONS: Sequencing successful identifying variant, unraveled implicated disease. Disclosure: Dr. Boneschi received personal compensation editorial capacity for Teva Neuroscience as scientific advisory board member speaker. Esposito nothing disclose. Osiceanu Sorosina Cittaro Lazarevic Stupka Comi activities Sanofi-Aventis Pharmaceuticals Inc., Novartis, Merck Serono, Biogen Idec, Bayer Corp., Neuroscience, Actellion.