Medical Research

Children's Hospital of Wisconsin

Howard Jacob, David Dimmock, Stephen Duncan, Brian Link, James Verbsky, Fyodor Urnov, Elizabeth Worthey
Milwaukee, WI
$1,000,000
December 2013

A team of basic scientists and clinical investigators at the Children’s Hospital of Wisconsin (CHW), the Medical College of Wisconsin propose to develop a novel strategy for determining the molecular basis of rare undiagnosed diseases.  CHW recently established a Genomic Medicine Clinic for rare diseases and will use whole genome sequencing (WGS) to advance a diagnostic odyssey for rare diseases.  With WGS, CHW’s diagnosis rate for genetic diseases has increased to ~27% (compared with 5–10% in a standard genetics clinic), yet ~39% of patients remain undiagnosed because they have genetic variants of uncertain significance (VUS).  The challenge that CHW’s team is taking on is to convert as many as possible of the undiagnosed cases into firm diagnoses.  In collaboration with Sangamo BioSciences, they propose to build a high throughput strategy, involving gene editing technologies, to rapidly identify the functionality of VUSs in cellular assays or a vertebrate model system.  The proposed approach for evaluating VUSs would allow the characterization of many genetic variants that have already been identified in clinical labs around the country but not yet linked to specific genetic diseases.  If successful, this project could establish a generalizable strategy for screening genetic mutations for any disease whether or not there is existing knowledge about the disease.

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