An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery

Workflow overview. The workflow begins with the clinical assessment of cases, where referring physicians present cases of presumptive unknown monogenic etiology from their clinical practice for the collective development of a case solution strategy. Based on the inferred inheritance mode, the most informative family members are selected for genomic sequencing followed by analysis of the WES/WGS data using a computational pipeline designed to identify rare Mendelian variants. A final candidate gene list is prioritized using in-house bioinformatic tools, literature surveys, and crowdsourcing. The final candidate gene is confirmed by segregation analysis, matchmaking for second case hits, and by in vitro and in vivo functional studies. Both genomics and functional biology thus inform the diagnosis and clinical management of individual patients, while unique patient conditions provide insight into gene and pathway functio