Our research focus has recently transitioned from genetic variant discovery to the assessment of the functional significance of variants. We are applying the high throughput method of Deep Mutational Scanning to simultaneously and quantitatively assess the effects of hundreds to thousands of variants in our gene of choice, GLI2. In addition, in collaboration with the Geisinger Health System, we are leveraging exome sequence data for >90,000 patients with linked electronic health record data to validate our results. One direct outcome of these experiments is the improved classification of variants of uncertain significance (VUS) in patients with suspected Mendelian disorders.
Our work also supports the Washington University Undiagnosed Disease Network (UDN) Model Organism Screen Center (MOSC). We provide in-depth variant-level analyses to help determine which model organism (worms, flies, or zebrafish) is most suitable to help diagnose UDN participants with novel genetic disorders. We also contributed to a Children’s Discovery Institute Large-Scale Interdisciplinary Research Initiative, focused on assessing variants in the cancer-related genes TP53 and SMAD4. Other ongoing work includes management of the Undiagnosed Mendelian Disorders (UMD) Research Repository, which includes more than 1,000 families that have consented to make genotype and phenotype information broadly available to translational science investigators, and implementation of an electronic interface between a genetic testing laboratory (GeneDx) and the patient’s electronic health record.
With generous support from:
National Human Genome Research Institute
Undiagnosed Diseases Network
Children’s Discovery Institute
Institute of Clinical and Translational Sciences
Intellectual and Developmental Disabilities Research Center