Deciphering oligo- to polygenic genetic architecture in brain developmental disorders

Time frame: 
January 6, 2015 to January 6, 2018
Funding: 
ARC FNRS

Even when a single causative gene mutation is involved, a few (oligogenic) to many (polygenic) additional genetic variants contribute to disease outcome. Innovative bioinformatics tools are needed to tackle this complex genetic architecture within whole genome sequencing data. Here, the (IB)² bioinformatics institute, the ULB Experimental Neurology and Medical Genetics labs, will join forces to detect oligo- to polygenic inheritance in brain developmental disorders, including familial focal epilepsy, early infantile epileptic encephalopathies, and primary microcephaly, three phenotypes for which we have large collections of sequencing data. Using these different neurological datasets, (IB)² bioinformaticians will first develop statistical approaches and algorithms that will target digenic inheritance, the simplest model of oligogenic inheritance. We will validate detected (novel) gene interactions in zebrafish, as well as in iPS cells from patients and in mouse ES cells, using genome-editing technology when necessary. The bioinformatics predictor tools will then be expanded to multigenic inheritance. Our choice of pathologies in this project should allow innovative bioinformatics tools to be generally applicable and not limited (ie, overfitted) to one disease in particular. Studying different but related diseases (here all brain developmental) will foster a shared clinical expertise while gaining sufficient pathogenic “width” to be of general interest in the bioinformatics approach of complex disease.