Exome sequencing has been commonly used to characterize rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) and searching for rare variants in coding regions. The EP strategy covers both extreme ends of a disease spectrum and it has been also used to investigate the contribution of rare variants to the heritability of complex clinical traits. We conducted a systematic review to find evidence supporting the use of EP strategies in the search for rare variants in genetic studies of complex diseases and highlight the contribution of rare variations to the genetic structure of polygenic conditions. After assessing the quality of the retrieved records, we selected 19 genetic studies considering EPs to demonstrate genetic association. All studies successfully identified several rare or de novo variants, and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach for patients with an early onset of a disease can contribute to the identification of rare variants in candidate genes or pathways involved in complex diseases. EP patients may contribute to a better understanding of the underlying genetic architecture of common heterogeneous disorders such as tinnitus or age-related hearing loss.
Keywords: exome sequencing; extreme phenotype; genetic association studies; genetic epidemiology; tinnitus.