The Department of Medical Genetics has been focusing on a number of projects aimed at translating local research expertise into new and novel clinical diagnostic assays. In the cytogenetics domain, we have been using NIHR BRC funding in order to test the potential of high resolution arrays for detecting small copy number variants associated with congenital abnormalities.

We identified several interesting abnormalities we are now following up. Since small copy number changes are frequent in normal individuals, it remains a major challenge to be able to infer causality for such variants. In other words, when a patient present with an abnormality, such as a structural cardiac defect and a small gene deletion (or duplication), then one needs to be able to answer the question if the genetic

abnormality is likely to be causal or an epiphenomenon. In order to address this issue, we have been testing whether we can use zebrafish as a model for this purpose. In order to generate proof-of-principle data, we have been knocking down expression of genes associated with defined congenital abnormalities, and then are testing whether the resulting zebrafish phenotypes mirror those seen in patients. Ultimately, we hope to be able to provide sufficient support for this approach to be able to apply it as a diagnostic adjunct for a range of phenotypes that are amenable to analysis in zebrafish.

In the molecular genetics diagnostic domain, we are defining the potential for next generation sequencing, initially using X-linked learning disability cases as a prototype condition, and the sequencing and bioinformatics of expertise of EASIH. The X-linked LD project has to date completed the sequence of the whole-exome complement of the X chromosome, accounting for over 700 genes, in 10 patient samples. Using 'first generation' sequencing approaches would have required approximately 5 years of NHS sequencing throughput, whereas with 'next generation' approaches this has been completed in less than 6 months. We have successfully developed the performance of both the sequencing platform and the data analysis tools required to validate the assay as fit for use in the diagnostic laboratory. This project will continue to validate a number of alternative strategies to allow the selective sequencing of genes relevant to X-linked learning disability, and will offer the assay as a diagnostic service UK wide within the next 6-8 months.