Biomedical Engineering Reference
In-Depth Information
Exome Sequencing Diagnostic Applications
The cost-effectiveness and usefulness of NGS-targeted panel designs for the diagno-
sis of genetic diseases, namely, hearing loss, muscular dystrophy, neuromuscular
diseases, monogenic disease, cardiovascular diseases, retinitis pigmentosa, and
mitochondrial disorders, have been shown numerous times and this diagnostic appli-
cation of NGS is being extended to the analysis of exomes in clinical laboratories
(Neveling et al. 2012 ; Vasli et al. 2012 ; Faita et al. 2012 ; Rehm 2013 ; Sivakumaran
et al. 2013 ; Valencia et al. 2013 ; Wong 2013a ; Treff et al. 2013 ). The genetic diag-
nosis of congenital chloride diarrhea in a patient was made through WES revealing
a homozygous missense variant in SLC26A3 (Choi et al. 2009 ). However, other
studies have adopted whole genome sequencing (WGS) as a diagnostic application.
For example, it was applied to an 11-month-old patient with severe hypercholester-
olemia who was found to have mutations in ABCG5 (Rios et al. 2010 ). Although
WGS has been utilized for diagnostic applications, WES would have been suffi cient
to identify the causal variants and genes for severe hypercholesterolemia and the
cost of a diagnostic test is an important consideration. WES is increasingly being
utilized in molecular diagnosis (Bonnefond et al. 2010 ; Worthey et al. 2011 ).
Tiered Clinical Exome Analysis
In addition to performing primary, secondary, and tertiary analyses (Sect. )
similar to research exomes, clinical exome analysis is a tiered approach to facilitate
clinical interpretation of variants. The fi rst step is to focus on genes (~5,000) with
known disease associations and reported mutations. Genes found in the databases
OMIM and HGMD are prioritized. Then, variants in genes (~15,000) with unknown
phenotype or disease associations are screened as a second step. Unfortunately, this
comprises a larger fraction of the exome. In some instances, the mode of inheritance
may not be clear and all possible inheritance models must be processed. This
increases the complexity of the test and may affect the turnaround time.
Clinical Exome Analysis Guided by Clinical Features
While there are over 20,000 known genes which are targeted by various capture kits,
only about 5,000 genes have been associated with disease (OMIM and HGMD).
Since functional interpretation of genes with unknown disease association is
challenging, the clinical features of a case can be used to focus the search of caus-
ative variant(s) to genes with previously described associations. Various databases,
such as the OMIM, provide gene lists and corresponding clinical features and dis-
ease associations. This focused approach may be another fi lter that can be used in
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