Studying the genetics of rare congenital disorders disrupting cognitive function has led to the identification of multiple disease genes that helped us better understand the mechanisms underlying prenatal and postnatal development. While genetic studies have revealed great heterogeneity, the advent of next-generation sequencing genetic studies has greatly increased the pace of discovery.

Our research focuses on a group of genetically heterogeneous neuromuscular disorders, termed dystroglycanopathies. In these disorders loss or reduction of glycosylation of the transmembrane glycoprotein alpha-dystroglycan cause muscular dystrophy, associated with severe brain and ocular malformations and intellectual disability. The study of the genetics of dystroglycanopathies has been instrumental in defining that dystroglycan’s interactions with the extracellular matrix (ECM) are a key regulator of cell differentiation in the brain and retina. Twenty different genes can be mutated in dystroglycanopathies and most of these genes have a direct role in controlling assembly of glycans on the dystroglycan protein. These glycans mediate interactions with laminin and other ECM components, and different glycosylation patterns instruct protein-protein interactions. However, to date only half of dystroglycanopathy cases can be explained by mutations in the known genes and it is still unclear how most of these genes affect glycosylation processes involved in ECM function in the brain.

This presentation will focus on our recent work on gene identification in dystroglycanopathies and related neuromuscular disorders using a combination of next-generation sequencing and functional validation in the zebrafish to study how the mutated genes affect brain development.