The diagnosis of neurological diseases and particularly those of foetal development is difficult because of their complex etiology involving several genetic factors. The identification of these factors requires new strategies for interpreting pathogenic variations in the human genome. The main objective of my thesis is to specify the genetic mechanisms involved in holoprosencephaly (HPE) - an extremely severe pathology of early brain development, which affects about 3,000 children per year in France.
In a first step, I explored and described cases of HPE caused by a cumulative effect of several rare variants acting in a hypomorphic manner. This study describes for the first time cases of oligogenic EHPE, involving a dysfunction simultané́ of several genes involved in the Sonic Hedgehog (SHH) pathway - the major pathway of this disease. This work has shown the importance of considering the combined effect of several mutations in the study of SHH. Secondly, I demonstrated the pathogenic impact of mutations synonymous with the SHH gene on the stability and folding of the resulting protein, leading to protein degradation and disease development. These results indicate that synonymous mutations may have a major role in the etiology of genetic diseases.
In conclusion, this work contributes to the understanding of the complex genetic architecture of HPE. Ultimately, these results should make it possible to reduce diagnostic wandering and improve the management of patients suffering from complex genetic diseases.
The jury will be composed of
Thomas Bourgeron, Professor, UMR3571, Pasteur Institute, University of Paris
Gaël Nicolas, MCU-PH, Inserm U1079, University of Rouen
Sylvain Lehmann, Professor, UMR_S 1051, Institute of Neurosciences, Montpelier
Sandrine Lagarrigue, Professor, UMR13448, Agrocampus Ouest, Rennes
Marie de Tayrac, MCU-PH, UMR6290, University of Rennes 1, Rennes, France
Véronique David, Professor, UMR6290, University of Rennes 1, Rennes, France
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