Clinical exome sequencing (cES) has become the primary approach in high-throughput DNA sequencing as a means of detecting pathogenic variations in the part of the human genome that encodes proteins. However, for 50 to 70% of patients, a molecular diagnosis is still not identified after a cES test, and this pleads the case for developing genetic testing outside of the exome and for deploying other cutting-edge technologies for mapping other regions of the genome. Unfortunately, the advantage of information acquired through these technologies is only weighed against lack of knowledge of the clinical significance, for proteins, of the sequence variations identified in the non-coding regions.
The aim of the FHU TRANSLAD GAD is to shed light on (ultra-)rare diseases with as yet unidentified genetic causes. By using a multi-stage approach involving cES, RNA sequencing (RNA-seq), third-generation (long-read) DNA sequencing, epigenomic sequencing and/or proteomic sequencing, we are aiming to identify genetic variations and understand the molecular mechanisms that are the basis of their etiological involvement. By using samples and cell lines from the patient, involving as necessary the differentiation of induced pluripotent stem cells (iPSCs), we are attempting to create an in vitro model of the molecular mechanisms responsible for unknown or unidentified rare genetic diseases. Special emphasis is placed on introducing RNA-seq into diagnostics and research, so as to measure the impact detected genomic variations have on regulation, splicing and degradation in RNA transcription.
- Our group is focusing on three main areas of interest :
- The discovery of new genes responsible for diseases and of new phenotypes linked to known genes
- High-resolution identification and characterisation of pathogenic structural variations (SV)
- Functional reclassification of candidate variations of unknown significance (VUS) in ultra-rare diseases