A Comparison Study of Whole Genome Sequencing (WGS) in Clinical

Setting

Background

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?

The study

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?

1. 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.

2. 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.
 3. 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.