Proteoglycans (PGs) are critical components of the extracellular matrix of many tissues throughout the body. They are composed of glycosaminoglycan (GAG) chains that are covalently attached to a core protein. Synthesis of these GAG chains starts with formation of a tetrasaccharide linker region, that is common to chondroitin/dermatan sulfate and heparan sulfate GAGs, and that is formed by the stepwise action of specific glycosyltransferases. Deficiency of any of these enzymes, due to genetic defects, results in a group of rare, severe and multisystemic disorders, coined ‘linkeropathies’. Our understanding of the molecular mechanisms linking the causal defect to the clinical manifestations, severity and variability observed in these conditions is very limited. We propose to generate and deep-phenotype zebrafish models that closely mimic the linkeropathies by introducing specific mutations using an in-house optimized CRISPR/Cas9 genome editing technique. These models will allow us to decipher the molecular pathomechanisms linking the genetic defect to the variable disease manifestations, through an integrated omics approach. We will translate these data to the development of a simplified method for the diagnosis of these rare disorders. Understanding the factors influencing the presentation of these rare disorders will pave the way towards improved diagnosis and prognosis, and personalized treatment options, and will increase our understanding of the role of PGs in development.