Disease-causing variants in the non-coding genome
Despite extensive testing involving whole genome sequencing over 50% of patients with developmental disorders remain without a genetic diagnosis. This diagnostic gap exposes the limitations of current technologies to detect and interpret disease-causing mutations. For instance, whole genome sequencing can detect mutations throughout the genome but pinpointing a disease-causing mutation among hundreds of thousands of benign variants remains a daunting task. Thus, accurate identification of disease-causing mutations, especially in non-coding regions of the genome, currently represents a major challenge in human genetics.
So far, the non-coding genome has not been the focus of human genetics and Mendelian disease research on non-coding variants is only slowly emerging. This is mainly due to a large number of variants per genome and difficulties in interpreting non-coding variants. Together, this poses major problems that partially require the use of other/new technologies as well as new concepts of thinking and data interpretation. Our lab focuses on elucidating the patho-mechanisms underlying disease-causing mutations in the non-coding genome. Since there is currently no general concept to interpret mutations in the non-coding genome for their ability to cause disease, it is the aim of our group to develop such a framework and predict the regulatory effect of structural variations (SVs) in a disease setting.
To address this challenge, we are applying state-of-the-art functional genomics technologies to identify pathogenic mutations underlying human developmental disease and dissect the molecular mechanism through which these alterations disrupt human development. Our research aims to better understand the genetic causes and mechanisms of currently unsolved developmental disorders. Ultimately, our goal is to translate results from basic research carried out at the lab bench into the clinic by improving current methods of genetic diagnosis and setting a base on which to provide better medical treatment and accurate genetic counselling to individuals affected by developmental disorders.
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