Whole Exome Sequence and unsolved cases: Where are pathogenic mutations

The advent of whole Exome sequencing (WES) has revolutionized genomic research/diagnostics. Despite the promising WES results, unsolved cases still remain and points to the importance of technical limitations and also interpretation of WES results which will be described in this study.Current WES protocols generally capture no more than approximately 80-90% of the exons. Even assuming 99% of targeted regions are covered above 10X, it means that 0.3 Mb (0.01 x 30 Mb) or 200 genes (0.01 x 20,000 genes) will lack sufficient coverage to enable sensitive variant detection. Non-coding regions of the genome such as introns, miRNAs, lncRNAs, SnRNA are not captured and sequenced when using WES. There is increasing evidence for associations between non-coding RNAs and brain development in mice or neurodegenerative/neuropsychiatric disorders in humans. There are several reports on the involvement of lncRNAs in neurodevelopmental disorders such as Prader–Willi syndrome, Angelmann syndrome, etc. The third limitation is the inability of WES to detect pseudo-exons. Insertion of a pseudo-exon may introduce an extraneous exon within the mature mRNA that may cause either the disruption of or the insertion of a novel stretch of amino acid in translational reading frame. Associations with synonymous mutations have been reported for at least 50 diseases while these mutations are normally ignored. Interpretation of variants located in pseudogenes is another challenge. It has been shown that pseudogenes are capable of regulating tumor suppressors and oncogenes by acting as microRNA. A final limitation in interpreting WES results will be yet undiscovered causal genes.

Keywords:

whole Exome sequencing , coverage , Non-coding regions , pseudo-exons , pseudogenes , synonymous mutations