Identifying Highly Penetrant Disease Causal Mutations Using Next Generation Sequencing: Guide to Whole Process

Figure 3

Finding “the one” in Mendelian disorders. Searching for the causal variant (using a WES example). After potentially causal variants are identified, one must put into practice what past literature suggests about the disorder and make certain decisions about which path to follow in Figure 3. Familial (very rare) disorders are more likely to be following a recessive mode of inheritance; thus family data is crucial (to rule out the possibility of de novo mutations). Also it is crucial to include as many family members as possible. For common Mendelian disorders, if the disorder is following a recessive inheritance model, the possibility of the existence of compound heterozygotes should be taken into account when fitting the data into a recessive model. Finally, functional postanalysis of candidate variant(s), especially in mouse knockouts, can be crucial. This figure is here to serve as an example and by no means reflects an exhaustive model; there are alternative routes that researchers can take to identify Mendelian causal variants. If a consanguineous family, identifies regions where there are long runs of homozygosity (LRoH) for each individual, and amongst these regions, the ones which are shared by the affected and not by the unaffected.