Identification of genes for Aicardi syndrome by exome sequencing

Aicardi syndrome (AIS) is a rare neurodevelopmental disorder characterized by specific brain (total or partial agenesis of the corpus callosum) and ocular (chorioretinal lacunae) abnormalities and epileptic spasms. Most patients with AIS have a very poor outcome, with severe intellectual disability, intractable epilepsy, and reduced life expectancy. The lack of familial cases and affected males suggests that AIS is a X-linked dominant disorder caused by mutations arising de novo and lethal in males. So far no extensive studies have been carried out on this specific syndrome and the genetic etiology of AIS is completely unknown. The advent of novel genomic technologies has boosted the identification of disease gene for monogenic disorders. The rapid and low-cost sequencing of the coding region of individual genomes (i.e. exome) were initially applied to rare Mendelian disorders which were uninformative for classical genetic approaches. Since the first report in 2010, the comparative analysis of the variation profiles of limited cohort of unrelated individuals is being systematically utilized to identify the causative gene of several diseases. In the present project we propose to approach the genetics of AIS by exome sequencing to test different genetic models under the conservative assumption of genetic heterogeneity. The study is based on two main experimental tasks: i) exome sequecing of proband-parents trios to detect de novo mutations at the genome-wide level or recessive mutations in autosomal genes; ii) resequencing of X-linked genes at very high coverage in probands to identify low-frequency somatic mutations. The identification of the causative gene(s) for AIS may shed light into the biological processes underlying this severe disorder and provide valuable information on mechanisms involved in brain development and function.