Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

A Systematic Review on Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders

Version 1 : Received: 23 July 2020 / Approved: 24 July 2020 / Online: 24 July 2020 (13:43:00 CEST)

A peer-reviewed article of this Preprint also exists.

Amanat, S.; Requena, T.; Lopez-Escamez, J.A. A Systematic Review of Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders. Genes 2020, 11, 987. Amanat, S.; Requena, T.; Lopez-Escamez, J.A. A Systematic Review of Extreme Phenotype Strategies to Search for Rare Variants in Genetic Studies of Complex Disorders. Genes 2020, 11, 987.

Journal reference: Genes 2020, 11, 987
DOI: 10.3390/genes11090987

Abstract

Exome sequencing has been commonly used in rare diseases by selecting multiplex families or singletons with an extreme phenotype (EP) to search 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 heritability in complex clinical traits. We have conducted a systematic review to find evidence supporting the use of EP strategies to search for rare variants in genetic studies of complex diseases, to highlight the contribution of rare variation to the genetic structure of multiallelic conditions. After performing the quality assessment of the retrieved records, we selected 19 genetic studies considering EP to demonstrate genetic association. All the studies successfully identified several rare variants, de novo mutations and many novel candidate genes were also identified by selecting an EP. There is enough evidence to support that the EP approach in patients with an early onset of the 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.

Subject Areas

genetic association studies; extreme phenotype; genetic epidemiology; tinnitus

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