Over 70% of children suffering from rare diseases remain undiagnosed. A common approach to identify the causative mutation(s) is to sequence a number of genes or the whole set of genes of a patients(whole exome sequencing). While this approach is cost effective and provides answers to many families, genes only represent 1-2% of our genome. We have started a project utilising whole genome sequencing of undiagnosed children living in WA to provide a definitive diagnosis. A major challenge here is that the role and functions of the inter-genic regions of our genome (the remaining 98%) are relatively poorly understood. Consequently it is hard to judge the impact of a mutation in these regionson the health of a child.
We hypothesise that a variant will likely have an effect in cell types expressing the gene harbouring the variant. In turn affected cell types and tissues will give rise to the observed disease phenotype(s). Similarely, a variant in a regulatory region is likely to have a deleterious effect in cells using that region. We developed computational algorithms to essentially do the reverse: starting from the disease phenotype and using whole body maps of expression data we focus our investigation to regions likely to harbour the causative variant(s).
Our findings are reported back to the clinical genetics team lead by Gareth Baynam for critical assessment.
A second arm of the project is focussed on the functional validation of variants of unknown significance (VUS). Our approach is to use patient derived induced pluripotent stem cells combined with CRISPR/Cas-9 based gene editing to either a) ‘repair’ the variant or b) insert the variant into normal cells and see if the disease phenotype can be replicated. Technically this approach is extremely challenging but has the potential to definitively prove new disease – variant associations.
This research is funded by TPCHRF, Téa Lake and the Rare Disease Association Inc., Office of Public Health Genomics, WA Health, Stan Perron Precision Medicine Award and the McCusker Foundation.