Whole-exome sequencing as a diagnostic tool: current challenges and future opportunities

Abstract

Whole-exome sequencing (WES) represents a significant breakthrough in the field of human genetics. This technology has largely contributed to the identification of new disease-causing genes and is now entering clinical laboratories. WES represents a powerful tool for diagnosis and could reduce the ‘diagnostic odyssey’ for many patients. In this review, we present a technical overview of WES analysis, variants annotation and interpretation in a clinical setting. We evaluate the usefulness of clinical WES in different clinical indications, such as rare diseases, cancer and complex diseases. Finally, we discuss the efficacy of WES as a diagnostic tool and the impact on patient management.

Keywords:

• cancer
• diagnostic
• rare diseases
• variants detection
• whole-exome sequencing

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Whole-exome sequencing (WES) is a cost-effective and efficient approach that has provided an unprecedented opportunity to detect disease-causing variants across virtually all coding regions of the genome.

• Apart from its immediate clinical utility, WES has offered ample insight into the genetic characteristics of many diseases, potentially paving the way for diagnostic and therapeutic applications in the near future.

• WES is likely to gain popularity and remain the genetic testing method of choice in the next few years, particularly for the cases of suspected Mendelian disorders, which are either difficult to diagnose or where many candidate genes are considered.

• Current WES pipelines are able to detect single nucleotide variants with high confidence and therefore systematic validation via a second method may not be necessary; however, INDEL and small copy number variants should be verified before reporting.

• While it is currently possible to extract clinically acceptable copy number variants information from WES data, array comparative genomic hybridization may still be considered as the method of choice in many clinical laboratories, mainly due to the ease of use and legacy issues.

• Only whole genome sequencing (WGS) has the potential to comprehensively detect all types of genomic variants.

• Advances in sequencing technology, data storage and analysis will render, in the near future, the cost of WGS comparable to (or even lower than) that of WES, leading to the transition toward WGS in genetic testing.

• Lessons learned from WES can be directly applied in WGS analysis; however, interpretation of non-coding variants will remain challenging. This limitation may also be gradually overcome with the wealth of genomic information that is increasingly being uncovered with functional genomics technologies.