Exome Pool-Seq and systems biology approach to identify and characterize genes and networks in neurodevelopmental disorders

点击翻译按钮获取中文摘要

Neurodevelopmental disorders (NDD) are clinically and genetically extremely heterogeneous with more than 1000 underlying genes identified, so far. High throughput sequencing by Next-Generation sequencing (NGS) technologies has greatly advanced the identification and confirmation of novel disease genes. Despite these advances and despite falling costs, the current gold standard of trio-based exome or genome sequencing remains prohibitively expensive and time-consuming for large cohorts. To identify further known and novel genetics causes of NDDs on a larger scale we developed Exome Pool-Seq, an approach combining pooling of DNA samples and standard capture-based exome sequencing. This method greatly reduces sequencing costs albeit maintaining a high detection rate. We now plan to improve the method computationally and screen a larger cohort of >500 individuals with NDDs to systematically identify known and new NDD causing variants. The successful application of Exome Pool-Seq results from the synergy between the two applicants’ core skills: computational data analysis and clinical/genetic expert knowledge. We want to extend this interaction to computationally and functionally characterize genes and pathways involved in NDDs. This work will be based on the further development and improvement of our established SysID database, which contains an expert-curated list of NDD associated genes and related phenotypic and molecular information. Additionally, we will functionally characterize newly identified candidate genes by e.g. Drosophila melanogaster as a model. These integrated efforts will increase the knowledge on specific candidate genes but also common processes deregulated in NDDs. In summary, our study will provide new insights into the clinical and molecular landscape of NDDs and enable researchers and clinicians to score the validity of genotype-phenotype relationships in NDDs.