Mendelian Diseases, Recessive
Diseases inherited in a recessive pattern have traditionally been highly amenable to genetic analysis, due to the fact that homozygous variants are easily detectable. Previously, if a large family with many affected members was available for pedigree analysis, one would perform linkage analysis by genotyping family members in order to identify relatively short genomic intervals that presumably contained the disease-associated variant. Direct interrogation of entire genomes for homozygous variants is now possible with NGS technologies, and public datasets can be used to exclude common variants that are less probable to be disease-causing. Identifying recessive variants is especially straightforward if the proband is a product of a consanguineous marriage-sequencing the entire exome of the patient would likely yield a manageable number of rare homozygous variants, and further studies could be performed to investigate the functional relevance of these variants.
In one of the earliest reports of the application of WES technology, Bilgüvar et al. [4] identified recessive mutations in WDR62 in multiple Turkish consanguineous patients with severe developmental brain defects. Very little was known about WDR62 at that time, but subsequent genetic and functional studies have since validated the importance of this gene in proper brain development. More recently, a large cohort of patients of similar genetic status and clinical manifestation were analyzed using homozygosity mapping from WES data [5]. The authors uncovered 22 genes not previously identified as disease-causing, further demonstrating the power of WES as an ideal tool for gene discovery.