Our team works on deciphering the genetics and physiopathology of holoprosencephaly (HPE). It is a rare disease (1/250 conceptuses, 1/10000 newborns) due to defects taking place during early brain development. HPE is caused by a failure to form the midline of the forebrain and face. Since 1997, we have set up a large collection of 2000 HPE patients and relatives. Genetic defects in 15 genes have already been implicated in 30% of the HPE cases. A major common effect of these mutations is the impairment of Sonic Hedgehog (SHH) activity leading to disruption of the rostroventral region of the embryo.
It has become clear that HPE has a complex basis where clinical phenotypes result from multiple interconnections between various gene networks.
To address this genetically complex developmental disorder human geneticists work with bioinformatics and developmental biologists in order to prioritize and identify candidate HPE genes.
Next Generation Sequencing (NGS) is used to collect genome wide data from HPE cohorts (patients and relatives). Genomic variants are interpreted by computational and functional analyses. With the appropriate animal models, we examine the effect of identified mutated genes in brain developmental processes.
Our goal is to identify new genetic factors involved in the variation of penetrance and expressivity of HPE. In a context of a multigenic pathology, it will allow the design of a gene network dedicated to HPE that will represent an essential tool for diagnosis.
Beyond the identification of new candidate genes for HPE, we also contribute to further understanding the broad mechanisms coordinating all aspects of normal forebrain patterning.