Analysis of Regions of Homozygosity: Revisited Through New Bioinformatic Approaches

Runs of homozygosity (ROH) are contiguous homozygous segments occurring throughout the genome. ROH's number and size heavily depend upon shared parental ancestry, particularly relevant in the context of parental consanguinity. Homozygosity mapping, a valuable technique for the identification of genes associated with human genetic diseases, is based on the presence of ROH. Next-generation sequencing (NGS) improved this process by allowing simultaneous homozygosity mapping and detection of disease-causing variants. In this work, we present the methodology to automate the creation of personalized multigene panels based on whole-exome sequencing (WES) data using ROH (identified by combining two different algorithms: ROHMMCLI and HomozygosityMapper) and/or Human Phenotype Ontology (HPO) terms, and its integration in a Django Web application. The new resources’ applicability and impact on diagnostics are demonstrated through the genetic characterization of two siblings affected by a recessive disease. Resorting to a sample of 3,941 patients generated in this work, we provide an extensive analysis of ROH at a genomic scale for the first time in the Portuguese population. This work also describes the development of a new classification approach based on ROH features. In summary, this research advances ROH analysis from WES data, emphasizing its diagnostic potential and significance in population genetics’ characterization.