Risk variants investigation in patients with Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) is an early-onset neuropsychiatric genetic disorder that affects 1 in 54 children. Most cases of ASD are associated with a multifactorial inheritance pattern. In recent years, great clinical effect variants in many genes have been associated with ASD, but still a large percentage of cases remain without molecular diagnosis. Currently, there are at least two limiting factors in the analysis of genetic factors in ASD: the interpretation of the pathogenicity of non-described variants or variants in genes not yet associated with ASD and the minimum number of rare variants with medium to moderate effect per individual that can contribute with the clinical condition. Considering the great genetic heterogeneity of ASD and the challenges of categorizing variants, this study aims to: a) evaluate the proportion of individuals with ASD carrying a high impact de novo variant and b) investigate variants in two important pathways related to ASD - mTOR pathway and reelin pathway - in a cohort of 240 trios (proband with ASD, mother and father). In this last analysis, the contribution of variants per individual in these two pathways will be evaluated, corresponding to an oligogenic model. Finally, the data on the risk variants identified in the present study will be used in the making of a guide for requesting genetic tests to be used in the genetic counseling of families with affected children.