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Boshe et al. J Transl Genet Genom 2018;2:12 Journal of Translational
DOI: 10.20517/jtgg.2018.18 Genetics and Genomics

Original Article Open Access

Which came first: validity or clinical testing? The
example of long QT genes

Lacey Boshe , A. Katherine M. Foreman , Jennifer L. Goldstein , Natasha T. Strande , Jonathan S. Berg ,
3
2
2
1
2
Julianne M. O’Daniel 2
1 School of Medicine, University of North Carolina, Chapel Hill, NC 27516, USA.
2 Department of Genetics, University of North Carolina, Chapel Hill, NC 27516, USA.
3 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27516, USA.
Correspondence to: Prof. Julianne M. O’Daniel, Department of Genetics, University of North Carolina, Campus Box # 7264, Chapel Hill,
NC 27599, USA. E-mail: jodaniel@med.unc.edu
How to cite this article: Boshe L, Foreman AKM, Goldstein JL, Strande NT, Berg JS, O’Daniel JM. Which came first: validity or clinical
testing? The example of long QT genes. J Transl Genet Genom 2018;2:12. https://doi.org/10.20517/jtgg.2018.18

Received: 1 Jul 2018 First Decision: 4 Jul 2018 Revised: 17 Aug 2018 Accepted: 17 Aug 2018 Published: 30 Aug 2018
Science Editor: Sheng-Ying Qin Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu

Abstract
Aim: To investigate the potential relationship between the strength of evidence for a gene-disease association and
inclusion of the gene on a targeted, indication-based gene panel test for hereditary long QT syndrome (LQTS) and to
explore factors that may influence laboratory decisions about the inclusion or exclusion of genes from these clinical
tests.

Methods: A comprehensive literature search was performed to quantify existing evidence supporting putative LQTS
gene-disease associations. This evidence included the year that the gene was first implicated in LQTS, the total number
of published cases of LQTS attributed to the gene, and the presence of published segregation and functional data for the
gene. To explore the possible relationship between the published evidence for clinical validity of each gene and availability
of clinical genetic testing, semi-structured interviews were conducted with key laboratory stakeholders. Representatives
from nine US laboratories offering clinical LQTS gene testing agreed to be interviewed regarding decision-making about
when and why genes comprising their clinical LQTS test offerings were added.

Results: Genes associated with LQTS before 2006 generally had more reported cases of LQTS and the greatest amount
of supporting segregation and functional data prior to being offered as a clinical test. For genes first linked to LQTS
after 2006, these trends are less linear and the timeframe between initial report and inclusion on clinical test menus
decreased substantially. Advances in technology, lifting of patents, clinician request, and literature searches were cited
as the main factors that influence composition of LQTS gene panel tests. Paradoxically, one lab director noted that it may
require more evidence to remove a gene than to add a gene to a clinical test panel.

Conclusion: Our evaluation of the LQTS genes illustrates the nuanced relationship between published evidence
supporting a gene-disease association and availability of clinical testing. Expert assessment of clinical validity of gene-
© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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