Studies of Structural Chromosome Rearrangements to Identify Genes Involved in Congenital Brain Disorders

The project is focused on the detailed study of structural genomic variants (SVs). Such genetic mutations are in fact alterations in the DNA molecule structure and include copy number variants, inversions and translocations. A single event may affect many genes as well as regulatory regions and the specific phenotypic consequences will depend on the location, genetic content and type of SV. Many times, the specific disease-causing mechanism is not known. Here, the plan is to study the molecular genetic behavior of structural variants as well as the underlying mutational mechanisms involved.

First, genome sequencing will be done to pinpoint the chromosomal breakpoints at the nucleotide level, characterize the genomic architecture at the breakpoints and study the relationship between structural variants and SNVs. Second, the aim is to study how structural variants impact gene expression. Finally, disease mechanisms will be functionally explored in vivo using zebrafish and in vitro using primary patient cells and induced pluripotent stem cells.

The studies will focus on the origin, structure and impact of structural variation on human disease. The results will directly lead to a higher mutation detection rate in genetic diagnostics. Through a better understanding of disease mechanisms the findings will also assist in the development of novel biomarkers and therapeutic strategies for patients with rare genetic disorders.