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

Alejandro Alemán,Joaquín Dopazo,Ignacio Medina,Francisco Garcia-Garcia,Francisco Salavert

doi:10.1093/nar/gku407

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/

Highlights

Recent advances in high-throughput sequencing technologies have made it possible to sequence whole genomes or exomes at unprecedented speeds and low costs
With more than 30 000 variants found per exome [1], finding disease-causing genes is a cumbersome, time-consuming task that often requires intensive human intervention [5]
Most of the available tools cover the primary analysis (QC, alignment and variant calling) [7,8,9] that ends up in a list of variants found in sequencing experiments (VCF file) that can be annotated with different programs, such as VARIANT [10], ANNOVAR [11], etc

Summary

INTRODUCTION

Recent advances in high-throughput sequencing technologies have made it possible to sequence whole genomes or exomes at unprecedented speeds and low costs. More sophisticated tools can use such information to help in the detection of diseasecausing variants segregating along family pedigrees [12,13] or somatic mutations in cancer [14]. These tools increase the precision of the calling process but lack, in some cases, userfriendliness and fail to provide other filtering steps. The tool allows for the consecutive application of filters that include segregation in familial cases (with different inheritance modes that can be defined), allelic frequencies in the general population, mutational consequences and other that narrow down the number of putative variants to a small number of promising candidate variants.

MATERIALS AND METHODS

DISCUSSION