CCEPAS: the creation and validation of a fast and sensitive clinical whole exome analysis pipeline based on gene and variant ranking

Abstract

Aim: Whole exome sequencing technology has permitted the discovery of genes that cause Mendelian disorders and was used in clinical laboratories. However, identifying the disease causing variant(s) for a specific disorder from thousands of variants is challenging. In this study, we describe the Cincinnati Clinical Exome Pipeline Analysis Suite (CCEPAS) that utilizes a four-level framework into one analysis procedure that rapidly identify the most likely causative gene variants to establish a clinical diagnosis.

Methods: We developed and validated CCEPAS using 100 clinical exome cases. We applied this pipeline to clinical cases by first translating phenotypic information into candidate gene lists using Pheno2Gene. This list of candidate genes was given to the VarEval algorithm to guide variant filtering and prioritization. Finally, a short list of filtered variants was produced for clinical interpretation.

Results: We demonstrated the development and implementation of CCEPAS to aid in the variant prioritization and filtering to produce a short list of candidate variants for clinical diagnosis. Its unique Pheno2Gene tool utilized an extensive list of resources and provided an accurate, sensitive and specific way to obtain gene lists from clinical feature keywords. In addition, VarEval narrowed down the variants from ~150,000 to the top 20 (trios) and top 50 (singleton) for further variant curation and candidate determination.

Conclusion: Significantly, employment of CCEPAS rapidly provided causative variants in the top 20 and top 50 variants for single and trio cases, respectively, thus, ending the diagnostic odyssey in more than 30% of our clinical exome cases.

Keywords

Exome / sequencing / bioinformatics / pipeline / ranking / weighing

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