Biomedical Engineering Reference
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confi rm diagnosis. However, there are certain limitations to this approach.
Deleterious mutations located deep within the introns of the OTC gene are typically
not scanned by Sanger sequencing in clinical laboratories. In addition, larger genes
are also involved making diagnosis time-consuming, and, sometimes, biochemi-
cally it is diffi cult to distinguish between NAGS and CPS1 defi ciencies. Ambiguous
results can also be seen in late-onset forms of OTC defi ciency. NGS was shown to
play an important role in screening for multiple genes and improves diagnostic effi -
ciency (Amstutz et al. 2011 ). In a study of UCD, a custom array and a 454 sequencer
were used to examine variants in three genes of four patients (Amstutz et al. 2011 ).
Heterozygous and homozygous disease-associated mutations were correctly
detected in all samples.
As NGS technologies develop, we will have the ability to generate large amounts of
sequence data at lower cost and with less effort. This will eventually lead to
improved diagnosis of heterogeneous disorders. In the past few years, the transla-
tion of NGS to the clinical realm has been steadily increasing. NGS technologies
have been applied to the examination of a large number of genes in numerous genet-
ically heterogeneous disorders, as well as genes from one common pathway. We
expect the applications of NGS to continue to expand and to encompass other areas
of medicine as focused panel tests, a whole exome test, and, in the near future, a
whole genome test.
Amstutz U, Andrey-Zürcher G, Suciu D et al (2011) Sequence capture and next-generation
resequencing of multiple tagged nucleic acid samples for mutation screening of urea cycle
disorders. Clin Chem 57:102-111. doi: 10.1373/clinchem.2010.150706
Audo I, Bujakowska KM, Léveillard T et al (2012) Development and application of a next-
generation-sequencing (NGS) approach to detect known and novel gene defects underlying
retinal diseases. Orphanet J Rare Dis 7:8. doi : 10.1186/1750-1172-7-8
Berg JS, Evans JP, Leigh MW et al (2011) Next generation massively parallel sequencing of tar-
geted exomes to identify genetic mutations in primary ciliary dyskinesia: implications for
application to clinical testing. Genet Med 13:218-229. doi: 10.1097/GIM.0b013e318203cff2
Calvo SE, Compton AG, Hershman SG et al (2012) Molecular diagnosis of infantile mitochondrial
disease with targeted next-generation sequencing. Sci Transl Med 4:118ra10. doi: 10.1126/
Chan M, Ji SM, Yeo ZX et al (2012) Development of a next-generation sequencing method for
BRCA mutation screening: a comparison between a high-throughput and a benchtop platform.
J Mol Diagn 14:602-612. doi: 10.1016/j.jmoldx.2012.06.003
Chiu RWK, Chan KCA, Gao Y et al (2008) Noninvasive prenatal diagnosis of fetal chromosomal
aneuploidy by massively parallel genomic sequencing of DNA in maternal plasma. Proc Natl
Acad Sci U S A 105:20458-20463. doi: 10.1073/pnas.0810641105
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