Biomedical Engineering Reference
In-Depth Information
Reporting and Interpretation
Disease-related gene panel testing is relatively straightforward in terms of reporting
and interpretation. Sanger confi rmation is used as complementary testing to “rescue”
missing data from bases or regions that are not supported by a suffi cient number of
reads to confi dently call variants. For disease-specifi c targeted panels, the clinical
laboratory should establish the estimated clinical sensitivity of the test based upon
a combination of analytical performance parameters and the known contribution of
the targeted set of genes and types of variants detectable for that disease. In contrast,
reporting for WES is very challenging. Currently, the best NGS tests can only cover
90-95 % of the targeted exome (Cirulli et al. 2010 ). WGS covers both coding and
noncoding regions. Due to limitations in the interpretation of noncoding variants,
coding regions are often analyzed fi rst. For WES/WGS and certain large gene pan-
els, it is acceptable to report results without complete coverage at a predefi ned mini-
mum. The clinical laboratory director typically uses his/her discretion to judge the
need for Sanger sequencing to fi ll-in missing areas of a test. Therefore, additional
metrics that may be helpful for determining data quality include the percentage of
reads aligned to the human genome, the percentage of bases corresponding to tar-
geted sequences, and the percentage of targeted bases with no coverage. For WES/
WGS of patients with undiagnosed disorders, it is typically not feasible to calculate
a theoretical clinical sensitivity for the test given its dependency on the applications
and indications for testing. However, empirical data from one recent study suggests
that these tests have a clinical sensitivity of approximately 24 % (Gahl et al. 2012 ).
Long term, each clinical laboratory should track and share success rates across dif-
ferent disease areas to aid in setting realistic expectations for the likelihood of an
etiology being detected for certain types of indications.
One strategy some clinical laboratories are adopting is to perform WES, but
proceed with the interpretation of only genes already known to be disease-associated.
This will post great challenge to estimate the sensitivity and specifi city of these
“panel” tests. It is the responsibility of the clinical laboratory to clarify the test
methodology in the report for this type of testing, which is critical information to
understand a “no mutation found” case and proceed to genetic counseling.
Informed Consent and Genetic Counseling
Pre- and posttest genetic counseling are essential steps for patients and their fami-
lies to understand the implication with NGS-based testing. Unlike other genetic
tests, NGS-based testing is more complex and the implications of the test results
may not be as straightforward. Findings generated from these tests from different
clinical laboratories using different technologies may have different implications
for the patients and their family. For example, test results may reveal nonpaternity
and other secondary fi ndings that may change the clinical care for the patient and
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