DISPHPE

Holoprosencephaly (HPE) is a common congenital brain disease; its aetiology remains too poorly understood to provide proper clinical management. Genetics is the major component of this disorder, with alterations leading to a decrease in the Sonic Hedgehog (SHH) signalling pathway. However, genetic variants are found in only 30% of patients. The complex mode of inheritance of HPE associating several variants of low penetrance and the impossibility of accessing the primarily affected tissues are two major impediments to a comprehensive knowledge on pathophysiology of HPE and the improvement of molecular diagnosis. Our DISPHPE project aims to overcome these limitations. We will conduct an extensive clinical study of a unique cohort of patients spanning the spectrum of HPE and carrying variants in the DISP1 gene that controls SHH secretion. Quantitative characterization of the level of SHH secretion by these variants will be performed. Pathological modelling of HPE using differentiated human iPSC cells will allow us to evaluate the deleterious impacts of DISP1 variants on the two embryonic tissues affected in HPE, the forebrain and notochord. The work will focus on SHH secretion, cell transcriptomic identity and differentiation. Finally, we will establish a collection of transcriptomic signatures characteristic of the variations of the SHH pathway that will serve as a molecular diagnostic tool. The relevance of this tool will then be established using iPSC lines from HPE patients without molecular diagnosis. The overall experimental design will provide a better understanding of the contribution of a DISP1 gene in HPE, the link between SHH concentrations and the phenotypic spectrum of HPE. Most importantly, we will provide proof of concept that a multi-omics approach is relevant to improve the diagnosis rate of overall neurodevelopmental disorders.