In recent years, with the further development of high-throughput sequencing technology, the cost of sequencing has continued to decrease, and whole-exome sequencing (WES) has been increasingly applied to genetic disease detection, which has improved the diagnosis rate of diseases. However, it comes with the question: does the widely used whole-genome sequencing (WGS) currently suitable for clinical application?
On March 22nd, Genet Med. published an article online (PMID: 29565419) entitled Whole-genome sequencing offers additional but limited clinical utility compared with reanalysis of whole-exome sequencing.
There have been few previous comparisons of WGS and WES for the detection rate of genetic diseases. After screening, a total of 108 patients were enrolled in the WGS analysis. Their gene chip and WES test both showed negative results and their clinical data and previous sequencing raw data were preserved intact. After WGS test, the results showed that 10 cases (9%) of positive results, 5 cases were uncertain, and 93 cases were negative.
The authors analyzed the reasons for the positive results of 10 cases of WGS, including three aspects:
(1) The academic background of WES and WGS: Although WES also detected mutation site on the 1st, 2cd, and 3rd case, it was not reported as the pathogenic site, mainly because at the time of detection, the correlation between pathogenic gene and clinical phenotype has not been determined yet;
(2) The influence of structural variation and non-coding region variation: such as the 4th, 5th, and 6th case;
(3) Impact of sequencing platform: The 7th, 8th, 9th and 10th case belongs to this situation. The mutation sites were detected by WES on the Illumina platform.
In summary, among the 10 cases with negative WES previously, 7 cases were detected by WES reanalysis and WGS, and 3 cases were detected by WGS for structural variation and non-coding region variation.
Why Whole Genome Sequencing (WGS) Is Important for Clinical Applications?
- Whole genome sequencing (WGS) has broad spectrum of applications in clinical field, especially for diseases with unexplained clinical conditions, especially children with poor development and mental retardation. If Chromosomal Microarray Analysis (CMA), Next Generation Sequencing (NGS), and Whole Exome Sequencing (WES) unable to diagnose, WGS could be another option.
- Due to the uniformity brought by WGS, 30X coverage is generally considered to be very sufficient. Without depending on capture reagents, WGS is easier to achieve the basic unification on the wet lab, and save some cost.
For WGS price, the market completion is fierce and good for reducing cost. So, I think it is very likely that WGS will become mainstream in the near future.
Another benefit of WGS is its homogeneity of mtDNA. Theoretically it could solve the difficulty of finding large CNV and partial heterogeneity problems in mtDNA.
- Although WGS is not suitable for clinical application at present, it is tentative to start trials in some “pilot” units.
Compared with WES, WGS can find non-coding/intronic variants, CNV/SV, skip the need for capture, etc. The difficulty lies in the cost of interpretation and sequencing. As the cost of sequencing decreases, the superiority of WGS will become more apparent. Therefore, the application of WGS in the clinic is only a matter of time.
However, what is the best practice for WGS, is still a question for colleagues and experts to work together to study and explore.