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Expanding the genetic landscape of Congenital Disorders of Glycosylation using genomic techniques - RNA-Seq

Over the last ten years, significant strides have been made in the genetic diagnosis of rare diseases. This has been enabled by the development of next generation sequencing (NGS) technologies, able to provide a wider view of a patient’s genome and transcriptome, revealing rare disease-causing mutations. One of the categories of rare disease to benefit from these advances are Congenital Disorders of Glycosylation (CDG). Glycosylation is the modification of proteins, this affects their stability and function, and is the most common protein modification. In humans, thousands of proteins are ‘glycoproteins’. Therefore, CDG cause a wide range of mostly severe diseases. The application of NGS to the field of CDG has led to the discovery of a large number of genetic defects that lead to disorders of glycosylation. Indeed, over 100 genetically distinct forms of CDG have been identified, most within the last decade. However, until very recently, our technology and understanding of the human genome has not been complete enough for us to fully exploit NGS. Despite our ability to collect information across the entire genome and transcriptome, the diagnosis of patients with single-gene disorders was mostly limited to mutations in ‘exonic’ regions of the genome (i.e. regions directly encoding proteins). The success rate of this type of genetic diagnosis is at most 50%.However, using recently developed techniques we are now able to effectively and affordably interpret the whole genomes of patients and, in combination with expression analysis, take a deeper dive into the genetics of patients with hereditary diseases. In multiple other subtypes of rare disease, these new techniques have been effective in enabling and enhancing the diagnosis of patients. By bringing together the expertise of our two centers in Leuven and Prague, we want to bring these state-of-the-art technologies to CDG, and go beyond this to expand our knowledge of diseases caused by dysfunctional glycosylation. Indeed, this project can already begin with the characterization of a novel CDG, caused by pathogenic variants in an uncharacterized gene, recently identified using whole genome sequencing.
Date:1 Oct 2021 →  Today
Keywords:Congenital Disorders of Glycosylation, Genomics, Molecular diagnostics, Transcriptomics, Pathophysiological mechanisms of abnorma
Disciplines:Molecular diagnostics, Metabolic diseases