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

especially early-onset severe neurodevelopmental disorders (Wang et al., 2019;
Boonsimma et al., 2020a; Boonsimma et al., 2020b). This strategy has been
considered a useful approach to identify de novo mutations in known genes

and discover novel disease genes.
Molecular diagnosis in some neurological phenotypes has a diagnostic yield

of less than 40-60%. Several factors have been found to contribute to this finding.
There can be some technical limitations of WES including incomplete sequencing
coverage especially in the genomic regions that are difficult to sequence, such as
GC-rich regions, repetitive elements, and pseudogenes. In addition, identification
of some variant types including repeat expansions, copy number variants, and
structural abnormalities in the genome is technically challenging when using
WES. Mutations occurring in the noncoding sequences and somatic or germline
mosaicism will not be routinely detected. Considering these limitations, precise
clinical information remains essential for interpretation of the results obtained
by WES. Insufficient clinical data may hinder molecular diagnosis. Some disease
phenotypes such as Alzheimer’s disease and cerebrovascular diseases are caused
by the complex interaction between genetic and environmental factors and the
clinical utility of WES is still unproven (Strafella et al., 2018; Wright et al., 2018).

Targeted next-generation sequencing panels

Next-generation sequencing can be targeted to analyze genes that are
specific to some key phenotypes. This approach can improve cost-effectiveness.
A pathogenic mutation could be rapidly identified in known or previously reported
genes, reducing the analysis of irrelevant genes and incidental findings (Lindy
et al., 2018). However, this approach might report more variants of uncertain
significance in the tested genes and can lead to confirmation bias. Another

challenge is the gene list for analysis. There is no clear consensus regarding which
genes should be included in a targeted gene panel. The targeted capture of the
genes of interest has limitations in the expansion of gene analysis. The approach
in which WES data is used for targeted analysis allows for the rapid expansion
of the gene list. If the pathogenic variant is not found in the first set of targeted
genes, other genes beyond initial hypothesis can also be analyzed. This method
has increasingly been used in both clinical and research contexts.

Ponghatai Boonsimma
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