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The International Journal of the Royal Society of Thailand
Volume XI - 2019

Whole genome sequencing (WGS)

This technique sequences all 3 billion nucleotides in the human genome.
Approximately 4–5 million genetic variations are identified per sample (Wrigh
et al., 2018). The analysis of these genetic variations can be complex and time-
consuming. In current clinical practice, most interpretation of WGS data is still

in the coding regions. Targeted next-generation sequencing or WES is still more
cost-effective in clinical practice. However, the increase in WGS data in both
healthy individuals (gnomAD; https://gnomad.broadinstitute.org/) and patients
is leading towards the expansion of molecular diagnosis. The pipeline for analysis
of noncoding regions is becoming more solidified. As the sequencing cost declines,
it is very likely that WGS will be widely used in the near future.
The advantages of WGS compared with WES include the identification

of structural variants, copy number variations with higher sensitivity and better
coverage. This method also detects DNA repeat expansions which are common
causes of neurodegenerative disorders such as Huntington’s disease, amyotrophic
lateral sclerosis and hereditary ataxia. WGS can unravel repeat expansions as the
molecular pathomechanism in both known and novel genes (Cortese et al., 2019;
Yeetong et al., 2019.

Despite the advantages of WGS, the majority of the rare variants detected
are mostly in the untranslated regions or introns. The effect of the variant on gene
expression is difficult to assess. Alterations of gene function could be evaluated
using RNA sequencing or transcriptome analysis to detect changes in RNA splicing
or differential expression. This complementary data could greatly improve the
diagnostic value of WGS. Previous studies have shown that synonymous variants
and deep intronic variants can result in splicing and other RNA processing defects.
As the number of individuals whose genomes have been sequenced increases and
functional studies of candidate variants obtained by WGS analysis continue to
advance; the utility of WGS in clinical practice will also improve. Different genetic
techniques which have been used in the diagnosis of neurological disorders are
shown in Table 1. (Klein and Foroud, 2017; Wright et al., 2018).

80 Precision Medicine in Hereditary Neurological Disorders:
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