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evidence. One option applied by some laboratories is to separate genes on indication-based panels into a
“clinical” panel and a masked “research” list of genes. The clinical panel genes are those that demonstrate
strong evidence for clinical validity and would be analyzed and reported. Research genes would include
those with minimal evidence for clinical validity. These research genes could be analyzed with patient con-
sent, but not reported. Once a research gene gains enough evidence to be clearly associated with disease, it
could be moved to the clinical gene list. Some laboratories that have included genes of various levels of evi-
dence on clinical test offerings have attempted to differentiate genes that have only preliminary evidence of
association with the panel test indication, allowing clinicians to opt-in to analysis of those genes or not.

In advocating for these efforts, there must be a distinction between clinical care and clinical research. The
precipitous drop in time between discovery and market presents a complex scenario in which robust rep-
lication studies may be lacking. On one hand, many diseases are exceedingly rare, and waiting for large
numbers of cases is not feasible. On the other hand, a gene could later be determined to have a lesser or no
association with the particular disease. While identifying the underlying molecular diagnosis could provide
guidance to patients and their treating clinicians, providing an erroneous diagnosis could lead to harms in
over treatment (false positive) or failing to make the correct diagnosis (false negative). These difficulties of
weighing the harms and benefits of rapid bench discovery to clinical market and increasing size and clinical
scope of multi-gene panel tests have been a concern noted by investigators in a variety of diseases with ge-
netic heterogeneity including cancers and vascular disease [26-28] .

In conclusion, our evaluation of the LQTS genes illustrates the nuanced relationship between published
evidence supporting gene-disease associations and availability of clinical testing. Genetic tests are expand-
ing, and laboratories may be resistant to remove genes from panels once they are added. Furthermore, once
a genetic test result has been reported clinically, it may be very difficult to “withdraw” that result from the
clinician and patient perspective, even if the gene-disease association is later called into question.

Thus, it is essential for genes on indication-based panels to be supported by appropriate levels of evidence
to ensure good clinical care. We have presented the example of LQTS genes which represents generalizable
themes across the clinical reality of genomic medicine and in particular for diseases with genetic heteroge-
neity. This work highlights the importance of and continual need for expert assessment of the clinical valid-
ity of gene-disease relationships such as those being conducted by the ClinGen consortium. Additional study
is required to explore the ultimate impact of clinical validity information on the composition of clinical gene
tests as well as their utilization by clinicians, coverage by health insurance policies, and impact on patients.

DECLARATIONS
Acknowledgments
We wish to thank Michael Adams, Debra Skinner, and Bradford Powell for their valuable comments and
contributions to this paper.

Authors’ contributions
Design: Boshe L, Berg JS, O’Daniel JM
Literature research: Boshe L
Data analysis: Boshe L, O’Daniel JM
Manuscript writing: Boshe L, Foreman AKM, Goldstein JL, Strande NT, Berg JS, O’Daniel JM
Manuscript editing: Boshe L, O’Daniel JM

Availability of data and materials
Data from the literature review can be made available on request. Key informant interview notes can be pro-
vided in aggregate themes to protect informant confidentiality and privacy.