Exome Sequencing Analysis of Familial Cases of Multiple Sclerosis and a Monozygotic Discordant Twin

Abstract

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease, which leads to neurodegenerative processes that cause neuron demyelination. MS is multifactorial with uncertain etiology, where interactions between genetic makeup of an individual and environmental factors influence disease risk. More than 200 risk variants have been implicated in MS, each contributed to understanding the etiology of MS through providing meaningful clues of the functional mechanisms underlying the development of this disease. This study aimed to identify genetic variants associated with MS in the Jordanian population. We performed whole exome sequencing for eight pairs of related patients from eight different families including one pair of discordant monozygotic twins, to determine the shared genetic information and genetic variants, and their correlation to MS. We identified rare exonic missense and frame shift variants segregating in all patients in MUC6, MUC16, and MUC19 genes, which are involved in innate immunity, in addition to ZNF717 gene. Moreover, variants in two of the previously described MS genes (HLA-DRB1, HLA- DRQ1) were also segregating in most patients. These molecular genetic details require further validation and functional analysis, to be implicated in the clinical diagnosis process of MS. This is the first attempt to characterize the genetic factors associated with MS in the Jordanian population.