Identification of rare variants in complex neurological diseases through next generation sequencing

Complex diseases are caused by a complex interaction among genetic and environmental factors. The Identified common variants occount for only a small fraction of the genetic component of these diseases. Therefore, low (1X<5%) and rare (MAR<15) frequency varlants may help fill in some of the heritability Eap. We have focused on two different neurological diseases, Multiple Sclerosis (MS) and Epilepsy. The general aim of the study was on ole side to dentify new low and fare frequency genetic variants associated to the susceptibility to MS in the Italian continental population, and, on the other side associated to Epilepsy. From the analysis of Multiplex MS families, our study allowed us to identify 10 geres harboring rare coding variants and other 11 genes herboring rare non-coding variants. The extension of these analyses to other cohorts of non-familial MS patients, MS multiple families and Controls:{HC) is ongoing to further assess the role in MS Susceptibility of the identified rare variants. From the research of rare functional variants in MS associated loci, our study allowed us to identify one gene with the most promising result especially for disruptive variants (stop-gain, stop-loss and splicing), Identifying a novel low frequency functional variant associated with MS susceptibility. Moreover, regarding a project on pediatric MS, our preliminary wGRSs analyses on already avallable pediatric MS patients suggested that pediatric MS have a higher risk score compared to adult-onset MS and HC, conferred by common non-HLA MS associated variants and more slightly by the analyzed 5 HLA markers: From the screening of epileptic patients, for diagnostic and research purposes, our study identified four rare pathogenic variants causative of the epilepsy forms in four different patients: Moreover, our analyses showed that epileptic patients can have an increased burden of rare variants in genes associated to epilepsy.