Identification and Prioritization of Causal Variants of Human Genetic Disorders from Exome or Whole Genome Sequencing Data

Abstract

Background: With genome sequencing entering clinics as a diagnostic tool to detect genetic disorders, there is an increasing need for bioinformatics-based solutions that enable precise causal variant identification in a timely manner. Workflows for the identification of candidate disease-causing variants usually perform the following tasks: i) identification of variants; ii) filtering of variants to remove polymorphisms and technical artifacts; and iii) prioritization of remaining variants to provide a small set of candidates for further analysis. Methods: Here, we present a pipeline designed to identify variants and genes from trio sequencing or pedigree-based sequencing data that prioritizes them into distinct hierarchical tiers. Results: We applied this pipeline to a study of patients with neurodevelopmental disorders of unknown cause and identified causal variants in more than 35% of cases. Conclusions: Classification and prioritization of large numbers of variants into different tiers can help to obtain a smaller set of candidates to facilitate downstream analysis for identification of causal variants of genetic diseases.