Characterization of apparently balanced chromosomal rearrangements and its association with the phenotype of carriers: breakpoint mapping by mate pair sequencing

Abstract

The majority of carriers of apparently balanced chromosomal rearrangements are phenotypically normal, but about 7% of these rearrangements are associated with birth defects. In our ongoing PhD project (FAPESP 2011/14293-4), we aim at contributing to the understanding of the causative mechanisms of phenotypic abnormalities in carriers of balanced chromosomal rearrangements. Disclosing the mechanism of formation of these chromosomal rearrangements is another objective of the study. Apparently balanced de novo rearrangements and balanced rearrangements inherited from phenotypically normal parents in patients with developmental disorders of unknown etiology are under study. In the first year of our PhD project,we investigated 12 de novo rearrangements. Cryptic genomic imbalances in the rearranged chromosomes were identified in four of them, and two other rearrangements were associated with additional breakpoints. While FISH and a-CGH revealed the complexity of some of the rearrangements we have studied, precise determination of breakpoints at the base-pair level is crucial for accurate genotype-phenotype correlations, which are dependent on the extent of genes or regulatory regions altered by the rearrangements. In addition, precise determination of breakpoints gives insights into the mechanisms underlying the rearrangement formation. The aim of our visit to the laboratory of Professor Niels Tommerup, at the University of Copenhagen, Denmark, will be to use next generation mate-pair sequencing to characterizethe breakpoints and junction fragments in balanced chromosome rearrangements, to the base-pair resolution. The research group of Professor Niels Tommerup established the method aiming at the systematic mapping of apparently balanced rearrangements ascertained worldwide, as a resource for large scale genotype-phenotype delineation in man. This project includes the engagement of PhD students from the participant laboratories, and transfer of technology. Dr. Angela Morgante was invited to join this effort and to coordinate the participation of other Brazilian laboratories. (AU)