Gene variant discovery is becoming routine, but it remains frustratingly difficult to interpret the disease relevance of most identified rare variants. Experimental assays capable of interpreting variant function with clinical predictive value are helping to fill this interpretation gap. We take advantage of Drosophila’s molecular genetic tractability to perform inexpensive, reproducible, in vivo testing for hundreds of variants. Our strategies include overexpressing human gene variants in specific tissues or testing the ability of variants to replace the function of the Drosophila orthologous gene. Overlapping these with genetic interaction analysis allows us to selectively test variant function in disease-relevant pathways. Following the ClinGen Sequence Variant Interpretation (SVI) Working Group guidelines for clinical interpretation of variant function in experimental assays, our assessments of variant function have clinical predictive value - even though the assays are performed in Drosophila.

These strategies are effective at identifying the variants that alter protein function and therefore represent a potential disease risk factors.

Using Drosophila allows us to overcome challenges in the variant testing field with assay reproducibility, genetic stability and in vivo analysis, scalability to hundreds of variants, and relevance to the pertinent disease mechanism.