Solving the Unsolved Exomes

Understanding the genotype–phenotype relationship is the essence of Precision Medicine, yet the phenotypic effects of defects in most human genes are still unknown.

Elucidating the genetic basis of rare Mendelian diseases has provided critical insights into gene function and into general pathophysiological pathways often applicable to common diseases. However, in ~30% of families with a likely single gene defect, clinical WES does not identify a known genetic cause. In these cases, we are using new technologies, segregation non-coding variants and a new tool based on phylogenetic profiling to identify the genetic basis of disease.

We are using Nanopore, long read sequencing to search for missed structural variants and promoter methylation, along with comparison of expression data when we have access to the appropriate tissue. This method allowed us to identify a large pathogenic deletion in the AGL gene in a family with GSD3, and is being used in high-risk BrCa families.

Next, we are studying WGS data from large families in fine detail, particularly in regions surrounding known genes. When only a small set of genes is suspected, we are able to look at segregation of all variants in and around these candidates.

We are also developing a new comparative genomics method of phylogenetic profiling to identify novel genes involved in disease pathways. Our method detects co-evolution of genes in different parts of the phylogenetic tree and integrates with data on protein-protein interactions and co-expression. We are presently using functional assays with patient fibroblasts to validate our findings.