Exome sequencing is helping to change lives and bring understanding to families enduring genetic diseases in their loved ones.
In 2009 we sequenced a pair of fraternal twins with dopa-responsive dystonia (Read about it in The Houston Chronicle and Nature). As they entered their teenage years the responsiveness of their symptoms to Dopa began to wane. Sequencing the children identified two variants in the SPR gene, a gene already known to cause DRD. Even more amazingly, the variants themselves were already known to be deleterious, but discovering that information involved laborious searches through multiple specialized databases as well as complicated and detailed literature review. Doing this for hundreds of samples at a commercial level is impossible, so we immediately began to collect variant data from many specialized databases in a centralized location so that we could quickly identify known mutations.
Read the paper and listen to the Beery's story here:
In 2011 we sequenced a child with severe psycho-motor retardation and identified a de novo mutation in the gene ASXL3. Although no disease was associated with this gene, another gene from the same family, ASXL1, is associated with severe congenital disease. We contacted our colleagues who had discovered the association with ASXL1, to find that they had also been contacted by other researchers who had, in parallel, found de novo mutations in ASXL3. Searching our internal database of previously sequenced patients we found 2 more individuals with mutations in this gene, which were subsequently found to be de novo too! In a few short months we went from dealing with a previously undescribed disease to having identified 4 patients based not on phenotype, but on genotype alone. This case demonstrates the importance of having access to all the variants that have ever been called in every patient and ready access to their phenotypic information. Further, the association of genes with disease can be enhanced with an understanding of evolutionary biology, allowing us to connect related genes with related phenotypes.