Current association studies have focused on common variation across the genome, as these are the easiest to identify with our current assays. However, disease-causing variants of large effect have been found to lie within exomes in candidate gene studies, and because of negative selection, are found in much lower allele frequencies and may remain untyped in current standard genotyping assays. Whole genome sequencing is a potential method to assay novel variant across the genome. However, in complex disorders (such as autism), a large number of genes are thought to be associated with disease risk. This heterogeneity of underlying risk means that very large sample sizes are required for gene discovery, and thus whole genome sequencing is not particularly cost-effective. This sample size issue is alleviated by the development of novel advanced analytic methods, which effectively map disease genes despite the genetic mutations are rare at variant level. In addition, variants in coding regions have been much more extensively studied and their functional implications are much easier to derive, making the practical applications of variants within the targeted exome region more immediately accessible.
Exome sequencing in rare variant gene discovery remains a very active and ongoing area of research, and there is growing evidence that a significant burden of risk is observed across sets of genes. The exome sequencing has been reported rare variants in KRT82 gene in the autoimmune disorder Alopecia Areata.