A frog is helping doctors diagnose rare genetic diseases that DNA sequencing alone cannot explain. Around half of patients with suspected rare genetic diseases have a "variant of uncertain significance"—a gene change whose link to illness is unknown. This project uses the frog *Xenopus tropicalis* to test those variants directly. So far, 16 out of 30 tested variants have been definitively linked to disease, and over 100 new variants from clinical geneticists are waiting to be assessed. Most of these involve neurodevelopmental disorders. The team has even adapted a working memory test from mice and zebrafish to measure behavioural changes in tadpoles, confirming two previously unknown disease-causing genes. If this research succeeds, it will turn a frog into a routine diagnostic tool—cutting the time patients spend in diagnostic limbo and directly improving their care and welfare. This is applied science with an immediate clinical payoff: faster, more certain diagnoses for people whose conditions currently have no molecular explanation.
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Improvements in DNA sequencing and sequence analysis have greatly enhanced the prospects for molecular diagnoses of the 1 in 17 UK residents who have a rare genetic disease (RGD). Nonetheless, this has created a new diagnosis bottleneck for around half of patients when there is no established link between the suspect gene variant and the disease it is believed to cause. Our ongoing MRC-funded project shows that Xenopus tropicalis, a frog, can be a powerful tool in which to re-create RGDs and to test the resulting phenotypes. Sixty-one gene variants suspected to cause disease but currently unproven (called Variants of Uncertain Significance or VUS) have been analysed, 48 (78.7%) could be made in X. tropicalis, 30 have been tested, and the link between the disease and variant definitively shown in 16; we are still testing the link for all but 1 of the others. Since these tests have been published and presented the broad recognition that these are powerful assays has led to >100 new variants from clinical geneticists and genome scientists awaiting initial assessment. 74% of these are neurodevelopmental disorders, the largest proportion. To test the VUS-disease link in two neurdevelopmental disorders we have successfully adapted a phenotyping method from mouse and zebrafish to measure working memory in tadpoles. This has been used to establish variants in two previously unknown RGD-causing genes as causes of neurodevelopmental disorders. This project is to increase the range of RGDs that can be produced in Xenopus for diagnosis and to develop the phenotype analysis of neurodevelopmental disorders at the behavioural level and by focused imaging techniques. We are focusing on neurodevelopmental disorder phenotype development because of the preponderance of these among the rare genetic disease patients. This project is important because diagnosis will directly impact the care and welfare of RGD patients; it will extend the types of VUS that can be re-created in tadpoles and the phenotypes that can be measured in them, thus enhancing their usefulness as tools for diagnosis of RGDs.
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