Abstract
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.
Highlights
A clinical phenotype is a set of observable signs, symptoms, and behavioral features associated with a human disorder
The phenotype includes multiple features or traits and it may be categorical or quantitative. These observable variations in the phenotype of a disorder is known in Mendelian genetics as expressivity and it may range from mild to severe [1,2] Phenotypic variation in quantitative traits can be represented by a bell-shaped graph where mild and severe phenotypes are located at the tails of the distribution
The objective of this systematic review is to assess the evidence supporting the design of genetic studies using extreme phenotype strategies to find rare or novel variants or genes involved in complex disorders
Summary
A clinical phenotype is a set of observable signs, symptoms, and behavioral features associated with a human disorder. There are several factors that limit the power of the genetic contribution to complex conditions is still largely unknown, since the gene discovery approaches, such as phenotypic variance [9], the overlap observed contribution of rare variations to heritability is still undetermined. The EP strategy aims to identify design includes the selection individuals phenotypes areThe at the ends includes of a disease rare genetic variants causing aoflarge effect onwhose disease risk [11,12]. Thissmall strategy may size identify genetic by sequencing a since raresmall variants thatsize contribute totarget a particular trait are enriched at the extremes of a disease relatively sample and it can novel candidate genes, since raretwo variants that contribute to [10].are. The aim of this systematic review is to critically analyze the contribution of strategies based on EPs to uncover rare or novel variants or candidate genes in genetic studies of complex disorders
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