Approved Research

A functional genomics approach to investigate the molecular bases of rare genetic diseases

Lay summary

The rising of the post-genomic era opened new perspectives for treatment opportunities for many diseases, by allowing researchers and clinicians to focus on the molecular bases of such diseases in an easier fashion. Unfortunately, for most of the genetic disorders, this process is hampered by the limited cohort of patients that limits the knowledge about the driver molecular functions altered by such mutations. This, in turn, leads to an inadequate treatment of patients and to an inefficient healthcare system. In the last years, many researchers tried to build comprehensive tools that have the advantage to lead to a high number of information about the mechanisms of diseases. On the other side, it is very difficult to find a good balance between the cost of the screening and the amount of generated data. In our laboratory, we developed a method to efficiently screen thousands of protein variants in a single multiplexed experiment and with a moderate cost. As a proof of principle, we applied it to P63, a transcription factor that plays a key role in skin development and whose mutations are causative of genetic disorders. To validate the method we aim to identify patients with novel variants that we identified with our screening and "sane" patients that carry potentially pathogenic mutations. To solve this task, UKBiobank will be fundamental, by allowing us to access the genetic data of thousands of individuals with no hard disease-related phenotypes. If confirmed, our screening method could represent a milestone in the field of genetic disorder, by providing the clinicians a key weapon to fasten a specific diagnosis for a disease and, in turn, to adequately take care of the patient with a specific treatment