An in vivo platform to identify clinically relevant pathogenic loci using Drosophila melanogaster .

Rare genetic disease discovery efforts typically lead to the identification of new disease genes. While there is inherent value in uncovering the genetic basis of disease for diagnosis, there is also significant opportunity to gain deep mechanistic or biological insights into disease pathogenesis. PreMIER ( Pre cision M edicine Integrated E xperimental R esources) is a collaborative platform among Washington University faculty designed to facilitate functional evaluation of human genetic variants in model systems. The PreMIER platform has identified seven cases could be effectively modeled in fruit flies. A survey of recent, high-impact disease-modeling studies in Drosophila identified six commonly used physiological assays that assess viability, longevity, behavior, and motor function. We knocked down each of the seven genes in neurons and in muscle throughout development and into adulthood, and assessed physiological phenotypes in adults. Tissue-specific knockdown of each gene caused significant changes in adult physiology in multiple assays, arguing that a set of six physiological assays can be used to show a candidate GUS is required for normal viability, longevity, behavior, or motor function. This study lays the foundation for our ongoing GUS screens, which may provide the first genephenotype correlations for patients with idiopathic genetic disorders.