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Improving rare disease diagnosis and prognosis with yeast functional assays

While many human disease genes are clinically actionable, i.e. knowledge of a pathogenic genotype changes medical management, currently only ~2% of germline missense variants have clinical interpretations. The remainder, so called variants of uncertain significance (VUS), are confusing to patients and families, frustrating to clinicians and genetic counselors, and offer no information to inform diagnosis or guide treatment. As the use of whole exome and genome sequencing in health care increases, the number of VUS will skyrocket. Thus, there is a critical need for methods that can aid clinical interpretation of genetic variation, particularly for highly actionable diseases, such as urea cycle disorders. In this lecture, I will explain how our laboratory is using yeast functional assays to improve the diagnosis and prognosis of rare, inherited metabolic diseases. Many of these diseases which often appear in infancy and childhood and are priority targets for gene therapies. After viewing this lecture, participants should be able to: 1. Describe what a variant of uncertain significance is and how its utility differs from variants that are classified as pathogenic or benign. 2. Explain how a functional assay, such as a yeast complementation assay, can aid in the clinical interpretation of human gene variants. 3. Describe how early diagnosis and treatment of a urea cycle disorder could improve patient outcome. Aimee Dudley, PhD Senior Investigator Pacific Northwest Research Institute 01/28/26