Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users' views

Abstract

Background: Whole-exome sequencing (WES) consists in the capture, sequencing and analysis of all exons in the human genome. Originally developed in the research context, this technology is now increasingly used clinically to inform patient care. The implementation of WES into healthcare poses significant organizational, regulatory, and ethical hurdles, which are widely discussed in the literature.

Methods: In order to inform future policy decisions on the integration of WES into standard clinical practice, we performed a systematic literature review to identify the most important challenges directly reported by technology users.

Results: Out of 2094 articles, we selected and analyzed 147 which reported a total of 23 different challenges linked to the production, analysis, reporting and sharing of patients' WES data. Interpretation of variants of unknown significance, incidental findings, and the cost and reimbursement of WES-based tests were the most reported challenges across all articles.

Conclusions: WES is already used in the clinical setting, and may soon be considered the standard of care for specific medical conditions. Yet, technology users are calling for certain standards and guidelines to be published before this technology replaces more focused approaches such as gene panels sequencing. In addition, a number of infrastructural adjustments will have to be made for clinics to store, process and analyze the amounts of data produced by WES.

Fig. 1

Selected articles types. Review: the authors do not report directly on the way they personally use WES, but rather review the current body of evidence about a certain aspect of the technology. Application: authors report on the application of WES on a specific patient, family, or a larger group of patients in a healthcare service. Data analysis: authors focus on challenges linked with WES data processing, analysis and interpretation. Efficiency: authors compare the efficiency of WES compared to other techniques, such as gene or gene panels sequencing. Report: authors report on the use of a technology other than WES, and explain this choice by identifying challenges with WES

Fig. 2

Number of articles per country of institution of corresponding author

Fig. 3

Number of challenges covered across articles

Fig. 4

List of unsolved challenges and proportion of articles reporting on them. We highlighted the challenges found in more than 40 % articles (58 total) in red, and challenges found in 30 to 40 % articles (44 to 58) in green

Fig. 5

Proportion of articles addressing VUS and IF per year. In parenthesis next to the year of publication of articles, we indicated the total number of selected articles published that year