| Summary: | Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication/interaction and by unusual repetitive and restricted behaviors and interests. ASD often co-occurs in the same families with other neuropsychiatric diseases (NPD), such as intellectual disability, schizophrenia, depression and attention deficit hyperactivity disorder. Genetic factors have an important role in ASD etiology. Multiple copy number variants (CNVs) and single nucleotide variants (SNVs) in candidate genes have been associated with an increased risk to develop ASD [8-10]. Nevertheless, recent heritability estimates and the high genotypic and phenotypic heterogeneity characteristic of ASD indicate a role of environmental and epigenetic factors, such as long noncoding RNA (lncRNA) and microRNA (miRNA), as modulators of genetic expression and clinical presentation. The aim of this project is to understand the role of lncRNA, miRNA and other epigenetic factors in ASD. For this purpose we are, in a first approach, screening for CNVs and SNVs encompassing lncRNA and miRNA loci in two large datasets: the Autism Genome Project (AGP), with CNV data from 2611 autism trios and the ARRA Autism Sequencing Collaboration, with whole exome sequencing data (WES) from 3056 autism trios. These datasets include data from Portuguese ASD probands recruited by our team. Thus far we have explored the variant call format files that contain all WES variants called by GATK. We started by testing different annotation tools and databases to obtain the best subset of variants that will be filtered according to their genomic coordinates and their pathogenic status. We are also selecting the CNVs from the AGP file that contain lncRNA and miRNA loci. The goal is to identify individuals with potential mutations in lncRNA and miRNA loci that may be disrupting their function upon target genes. Experimental validation will be carried out by measuring gene expression in these patients. A second approach will involve exploring available multiplex families in which ASD co-occurs with other NPDs. Segregation analysis will allow us to define patterns of NPD transmission, identify common gene variants and explore the role of modulating epigenetic factors that lead to differential disease expression.
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