Disease gene identification strategies for exome sequencing

Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing

“…6,7 Improvements in bioinformatics and sequencing technology are likely to increase the success rate for gene discovery even more. When considered for clinical diagnostics, ES is reported to have a diagnostic yield of ~25-28%.…”

“…Depending on the type of exome enrichment set being used, the number of variants typically varies between 20,000 and 50,000 per exome. 7 Even after the application of various analysis parameters and bioinformatics filters, at least 150 to 500 private nonsynonymous or splice-site variants are Review short-listed as potential pathogenic variants in each ES case. Interpretation and reporting of these variants in the context of the patient's phenotype is an enormous task for clinical diagnostic labs.…”

Exploring the landscape of pathogenic genetic variation in the ExAC population database: insights of relevance to variant classification

“…Additionally, these databases are utilized in next-generation sequencing pipelines to exclude common variants that are less likely to be pathogenic. 3,4 If the frequency threshold is set too low or if the data set used to ascertain frequency contains affected individuals, then potentially disease-causing variants may be filtered out in the early stages of the pipeline. Therefore, the utility of large frequency databases to support classification and analysis of variants is rapidly gaining momentum.…”

Lessons learned from gene identification studies in Mendelian epilepsy disorders

“…The most frequently used strategies are further referred to as the autosomal recessive (AR) homozygous, AR compound heterozygous, autosomal dominant (AD) heterozygous, AD de novo, and candidate approach strategy. 1 Despite the importance of a good starting strategy, NGS permits to investigate different hypotheses in a single experiment.…”

“…They have enabled high-throughput gene identification studies and introduced novel strategies to unravel the genetic etiology of Mendelian inherited disorders. [1][2][3][4] Since targeted resequencing of selected genes, whole-exome and -genome sequencing (WES/WGS) have become affordable, the number of individuals that are being studied has rapidly enlarged. Henceforth, more and more researchers have been generating, analyzing, and interpreting NGS data.…”