Background: Prioritization of genomic data has become a useful tool for uncovering the phenotypic effect of genetic variations (e.g. copy number variations or CNV) and disease mechanisms. Due to the complexity, brain disorders represent a major focus of genomic research aimed at revealing pathologic significance of genomic changes leading to brain dysfunction. Here, we propose a "CNV data laundering" algorithm based on filtering and prioritizing of genomic pathways retrieved from available databases for uncovering altered molecular pathways in brain disorders. The algorithm comprises seven consecutive steps of processing individual CNV data sets. First, the data are compared to in-house and web databases to discriminate recurrent non-pathogenic variants. Second, the CNV pool is confined to the genes predominantly expressed in the brain. Third, intergenic interactions are used for filtering causative CNV. Fourth, a network of interconnected elements specific for an individual genome variation set is created. Fifth, ontologic data (pathways/functions) are attributed to clusters of network elements. Sixth, the pathways are prioritized according to the significance of elements affected by CNV. Seventh, prioritized pathways are clustered according to the ontologies.
Results: The algorithm was applied to 191 CNV data sets obtained from children with brain disorders (intellectual disability and autism spectrum disorders) by SNP array molecular karyotyping. "CNV data laundering" has identified 13 pathway clusters (39 processes/475 genes) implicated in the phenotypic manifestations.
Conclusions: Elucidating altered molecular pathways in brain disorders, the algorithm may be used for uncovering disease mechanisms and genotype-phenotype correlations. These opportunities are strongly required for developing therapeutic strategies in devastating neuropsychiatric diseases.
Keywords: Autism; Bioinformatics; Brain; CNV; Intellectual disability; Pathways.
© The Author(s). 2019.