Familial cohort
If large families with the disease of interest are available, WES should be performed on at least two affected family members. In analyzing the results, any shared variants could potentially be disease-causing; using linkage data to focus on the variants located in linked intervals would greatly reduce the number of variants to be considered. A recent example of such an approach is a WES study on familial amyotrophic lateral sclerosis (FALS) [6]. The authors recruited two large families with FALS and selected two affected members with the greatest genetic distance from each family for WES. Among the rare functional variants that were identified, they tested the shared variants for Mendelian segregation among affected family members, eventually narrowing their search down to a single common gene, PFN1.