Integrating non-mammalian model organisms in the diagnosis of rare genetic diseases in humans

Next-generation sequencing technology has rapidly accelerated the discovery of genetic variants of interest in individuals with rare diseases. However, showing that these variants are causative of the disease in question is complex and may require functional studies. Use of non-mammalian model organisms — mainly fruitflies (Drosophila melanogaster), nematode worms (Caenorhabditis elegans) and zebrafish (Danio rerio) — enables the rapid and cost-effective assessment of the effects of gene variants, which can then be validated in mammalian model organisms such as mice and in human cells. By probing mechanisms of gene action and identifying interacting genes and proteins in vivo, recent studies in these non-mammalian model organisms have facilitated the diagnosis of numerous genetic diseases and have enabled the screening and identification of therapeutic options for patients. Studies in non-mammalian model organisms have also shown that the biological processes underlying rare diseases can provide insight into more common mechanisms of disease and the biological functions of genes. Here, we discuss the opportunities afforded by non-mammalian model organisms, focusing on flies, worms and fish, and provide examples of their use in the diagnosis of rare genetic diseases. This Review explores the use of non-mammalian model organisms in the genetic diagnosis of rare diseases, focusing on the use of worms, flies and zebrafish. The strategies, genetic technologies and approaches to using these models are discussed, as well as how they can provide insight into more common disease mechanisms.