Determining Whether Genetic Change Is a Pathogenic Mutation
If a patient is to be considered for a gene-based therapy, it is important for the clinician to understand how bioinformatics weights the likelihood that a genetic change is a pathogenic mutation. With the huge amount of genetic information provided by whole-exome sequencing, whole-genome sequencing, and genome arrays used in GWAS, many variants of unknown significance have been identified. Numerous types of evidence are used to distinguish a benign polymorphism from a pathogenic mutation. These include population data on the frequency of a variant in cases and controls; segregation data in pedigrees; computational and predictive data, which include SIFT (sorting intolerant from tolerant) and PolyPhen (polymorphism phenotyping); and functional data from cell and animal models (Table 5-1).
Stone EM, Andorf JL, Whitmore SS, et al. Clinically focused molecular investigation of 1000 consecutive families with inherited retinal disease. Ophthalmology. 2017;124(9):1314–1331.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.