Exome Sequencing as a Discovery and Diagnostic Tool - Next Generation Sequencing Technologies in Medical Genetics - page 78

One source of errors can be attributed to the ambiguousness of the underlying
sequence such as regions with high degree of similarity. Another reason for error
calling is the incompleteness of the human reference sequence and the uncertainty
degree of novel sequences. The ambiguity of the human reference sequence poses
challenges for variant interpretations. A proper interpretation of sequence changes
should be complemented by matched case-control testing. Novel associations
require specialized knowledge of the disease mechanism and understanding of the
proteins involved in the pathway. A heuristic approach to interpreting changes pro-
vides the means for personalized accurate interpretation.

8.5 Summary

Clinical WES has been shown to improve molecular diagnoses and alter patient
management, as well as, provide identifi cation of genes related to specifi c pheno-
types to enhance functional research efforts (Yu et al. 2012 ; Coonrod et al. 2013 ).
With the advent of enrichment methods and parallelized sequencing the cost of
WES has recently decreased. More importantly, data management and interpreta-
tion tools have become more effi cient in handling large amounts of data. Clinical
WES also can improve diagnosis by determination of genetic causality and health
care delivery for patients/families. We foresee the diagnostic use of WES to increase
overtime and such information will enrich the SNP and mutation databases, thus,
providing a step forward towards an improved description of the exome. The para-
digm is shifting from single gene to WES in pediatrics, and medicine in general, and
is the central theme of genomic medicine.

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