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Impact of genetic variants on genomic stability and their effects on the phenotype


The investigation of cytogenomic and molecular alterations through refined and powerful research methodologies has been allowing the characterization of genetic variants at a higher resolution, enabling a better understanding of their mechanisms of formation and their impact on the phenotype. The current project proposes the use of innovative approaches, including several types of next-generation sequencing, bioinformatics tools, and other techniques that can grant better insight into genome architecture and its clinical consequences. The present research project contains three subprojects, harboring different Studies as follows: subproject 1 refers to the "Investigation of balanced and unbalanced structural rearrangements involving the X chromosome". In patients with unbalanced X-autosome translocations, both the spread of X-chromosome inactivation into autosomal sequences and the impact of autosomal silencing on the patients' phenotype will be investigated (study 1). In women carrying different X-autosome balanced translocations, and phenotypic alterations, the breakpoints will be mapped to identify gene disruptions in the derivative X whose association with a skewed inactivation of the normal X may result in the lack of functional copies of those genes with clinical consequences (study 2). In women with balanced X-autosome translocations, and premature ovarian failure, without gene disruptions associated with the phenotype, the chromatin reorganization caused by the rearrangement will be explored since the position effect is one of the main hypotheses to explain gonadal dysfunction in these patients (study 3). Subproject 2 refers to the "Investigation of rare autosomal structural rearrangements of scientific interest". Patients with intrachromosomal rearrangements will be evaluated, focusing on breakpoint sequencing to elucidate their mechanisms of formation and their impact on the phenotype (study 1). Other patients with sundry rearrangements will also be evaluated, focusing on determining the pathogenic mechanisms of the rearrangements and their relationship with the phenotype (study 2). Subproject 3, on the other hand, refers to the "Investigation of patients with 22q11.2 deletion syndrome" and harbors different approaches, with a focus on phenotypic variability that the patients present. Copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) will be analyzed to better understand the genetic modifiers that can impact the patients' phenotypes, especially cardiac malformation and scoliosis. Bioinformatics tools, including machine learning, will be employed (study 1). Through the sequencing of a panel of candidate genes, the role of genetic variants and their impact on mRNA and miRNA expressions will be evaluated (study 2). Structural variants in low copy repeats (LCRs) in the 22q11.2 region will also be investigated to identify their different genomic compositions that may predispose the region to rearrangements (study 3). In general, by investigating structural rearrangements, the subprojects proposed herein compose a single unity directed towards a better comprehension of the genome. Thus, their development will be crucial to increase our knowledge of the impact that genetic variants may cause on the phenotype as well as plasticity and stability of our genome. (AU)