Page 38 - Read Online

Page 2 of 10 Boshe et al. J Transl Genet Genom 2018;2:12. I https://doi.org/10.20517/jtgg.2018.18

disease associations may help laboratories to determine gene panel content. The ultimate impact of such information on
the composition of clinical gene tests as well as their utilization by clinicians and coverage by health insurance policies
remains to be seen.

Keywords: Clinical validity, NGS tests, long QT syndrome, gene panels, PanelApp, ClinGen

INTRODUCTION
Advances in genomic sequencing technology enable laboratories to sequence large numbers of genes from
a single sample at a relatively low cost. Massively parallel sequencing based multi-gene tests or “panel tests”
have rapidly become a standard offering from clinical diagnostic laboratories. Gene discovery research also
[1]
benefits from the use of this technology leading to an escalating pace for new gene discovery . This may
result in rapid incorporation of a gene onto indication-based panel tests after the initial report of the gene’s
role in disease, without necessarily the accumulation of substantial corroborating evidence.

Multi-gene panel tests have clear advantages for diagnosis of conditions with significant genetic heterogene-
ity. At this point, however, minimum evidence thresholds to demonstrate a clinically valid gene-disease as-
sociation have not been established. Panel tests may therefore include genes with a wide range of evidence.
Given the sheer number of genes on some panel tests, ordering clinicians may have varying degrees of fa-
miliarity with any given gene and the evidence supporting its role as causative for a particular symptom or
disease.

[2]
International efforts such as those by the Clinical Genome Resource (ClinGen) , the Transforming Genetic
[4]
[3]
Medicine Initiative , and the Genomics England PanelApp aim to provide insight into the strength of
evidence for gene-disease relationships. The process by which decisions are made by laboratorians to include
genes on indication-based panel tests is likely impacted by multiple factors beyond simply reviewing the
gene-disease evidence, however, and has not been previously described in the literature. This study aimed to
investigate the potential relationship between the strength of evidence for a gene-disease association and in-
clusion of the gene on a targeted, indication-based gene panel test using the case of long QT syndrome (LQTS)
and 15 of the genes associated with it. Further, we explored factors influencing laboratory decisions about the
inclusion or exclusion of genes on a targeted, indication-based panel.

LQTS
[5]
LQTS is an inherited cardiac electrophysiological disorder with an estimated prevalence of 1:2,500 . It is
characterized by prolongation of the QTc interval, which causes the heart muscle to take longer to prepare
for each beat and may lead to torsade de pointes (TdP), a ventricular tachycardia that can progress to ven-
[6]
[5]
tricular fibrillation and sudden death . Syncope is the most common impetus for clinical evaluation .
[7]
Alternatively, a prolonged QTc can remain clinically asymptomatic for an individual’s entire life . Cardiac
events can occur at any age but are most common in children and adolescents, often with serious complica-
[8,9]
tions that frequently correlate with exercise, intense emotional states, or auditory stimuli . Complicating
the etiologic assessment is the fact that some exogenous factors (e.g., pharmacologic agents) can induce a
[10]
prolonged QTc interval, perhaps in combination with genetic risk factors .

LQTS is divided into different types based on the underlying genetic cause as well as whether the long QT
phenotype is isolated or part of a broader, multisystem syndrome. For the purposes of this study, we focused
on genes associated with the nonsyndromic, autosomal dominant forms of LQTS.

Ideally, genetic testing for LQTS is initiated in a symptomatic individual. If a pathogenic variant in a LQTS-
associated gene is identified, family members can have specific testing of that variant to learn if they have the