A web-based interactive framework to assist in the prioritization of disease candidate genes in whole-exome sequencing studies

Abstract

Whole-exome sequencing has become a fundamental tool for the discovery of disease-related genes of familial diseases and the identification of somatic driver variants in cancer. However, finding the causal mutation among the enormous background of individual variability in a small number of samples is still a big challenge. Here we describe a web-based tool, BiERapp, which efficiently helps in the identification of causative variants in family and sporadic genetic diseases. The program reads lists of predicted variants (nucleotide substitutions and indels) in affected individuals or tumor samples and controls. In family studies, different modes of inheritance can easily be defined to filter out variants that do not segregate with the disease along the family. Moreover, BiERapp integrates additional information such as allelic frequencies in the general population and the most popular damaging scores to further narrow down the number of putative variants in successive filtering steps. BiERapp provides an interactive and user-friendly interface that implements the filtering strategy used in the context of a large-scale genomic project carried out by the Spanish Network for Research in Rare Diseases (CIBERER) in which more than 800 exomes have been analyzed. BiERapp is freely available at: http://bierapp.babelomics.org/

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“…Such applications are not intended to be used as stand-alone programs for the interpretation of WES data, as their output, a list of tens of thousands of annotated variants, does not attempt to pinpoint likely candidate genes or mutations. A number of applications combine annotation, filtering by allelic frequency and predicted pathogenicity, and segregation analysis or intersection of multiple unrelated affected individuals 59–63 .…”

Single Nucleotide Variants in A Family of Monozygotic Twins Discordant for the Phenotype Congenital Megaureter: A Genomic Analysis

“…For this reason, WES still poses challenges regarding the establishement of a standard method for data analysis and for the interpretation of the results [52]. Consequently, the combination of other bioinformatics techniques [53,54], including data from prior GWAS studies, may still be needed for identifying causative mutations.…”

Understanding the pathogenesis of hip fracture in the elderly, osteoporotic theory is not reflected in the outcome of prevention programmes

“…Whole exome sequencing (WES) using NGS has the capacity to determine in a single assay an individual's exomic variation profile, limited to about 85% of the protein coding sequence of an individual, composed of some 20000 genes, 180000 exons, and constituting approxi mately 1% of the whole genome. A sensitivity of 98.3% for detecting previously identified mutations, as well as benign variants, has been reported by WES [70] . Furthermore, WES allows the phenotype expansion and identification of new candidate disease genes that would have been impossible to diagnose by other targeted testing methods [70] .…”

“…A sensitivity of 98.3% for detecting previously identified mutations, as well as benign variants, has been reported by WES [70] . Furthermore, WES allows the phenotype expansion and identification of new candidate disease genes that would have been impossible to diagnose by other targeted testing methods [70] . Proofofconcept examples of the identification of rare, diseasecausing variants are now available for WGS and WES strategies [7173] .…”