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Boshe et al. J Transl Genet Genom 2018;2:12. I https://doi.org/10.20517/jtgg.2018.18 Page 3 of 10

condition. The diagnosis of LQTS can, thus, be made solely on identification of a pathogenic variant in an
[11]
LQTS gene in the absence of symptoms . Because sudden cardiac death is a possible presentation of LQTS,
an affected individual may not be available for genetic testing. This can lead to the situation in which a pre-
sumed pathogenic variant is identified only in asymptomatic individuals. Asymptomatic individuals with
pathogenic variants in LQTS-associated genes may also be identified incidentally when undergoing exome
or genome-scale genetic tests for other clinical indications.

For individuals with a “molecular” diagnosis of LQTS based solely on a reported pathogenic variant, it is
not possible to predict if or when symptoms may present. Penetrance, or the chance that an individual with
[12]
LQTS will experience clinical symptoms in their lifetime, is incomplete for all LQTS genes . Furthermore,
it is not possible to fully adjudicate a suspected molecular diagnosis of LQTS given that a normal ECG can-
[13]
not exclude the possibility of future symptoms . Because of the risk for sudden, serious cardiac events,
these patients must be followed for the possibility of LQTS symptoms. Recommended treatment includes
beta blocker therapy and lifestyle modifications to avoid high intensity activity, emotional stressors, loud
[5]
noises, and QT-prolonging drugs . The European Society for Cardiology recommends that beta-blockers be
[14]
considered in asymptomatic carriers of a causative LQTS mutation who have normal QT interval . The re-
sulting impact of living with risk to develop LQTS symptoms is associated with significantly reduced quality
of life and higher parental anxiety [15,16] .

Given the health and psychological burden of living “at-risk” for LQTS, accurate interpretation of panel test
results is crucial to ensure a correct molecular diagnosis. Interpretation requires both that the variant be
pathogenic and the gene be causative of LQTS. Reaching agreement on the interpretation of pathogenicity
[13]
for a variant has been shown to be difficult among laboratories. Van Driest et al. demonstrated discor-
dance in the interpretation of variants in two of the most well-evidenced LQTS genes, KCNH2 and SCN5A.
For genes with limited evidence of a causal relationship, interpretation is further complicated by whether
any variant can be considered pathogenic. Reporting results in genes that are not clinically valid can cause
irreparable harm, leading to unnecessary worry and repeated cardiac workup for some and incorrect reas-
surance for others. Given that early diagnosis and treatment can be life-saving, clinicians and laboratories
must balance the desire to increase test sensitivity with the ability to conclusively interpret the identified
variants and implement appropriate surveillance and preventive measures.

METHODS
Literature search and gene evidence curation
OMIM was queried to identify the genes associated with hereditary LQTS and references supporting the as-
sociation between each gene and LQTS. A comprehensive PubMed query was conducted to identify relevant
information for the curation of each gene as described below. PubMed search syntax included the gene sym-
bol and disease name (e.g., LQTS1, “KCNQ1 AND Long QT Syndrome”).

The gene evidence curated from the literature search included: (1) the year each gene was first asserted to be
associated with LQTS; (2) the number of clinical cases associated with each gene; (3) the size and number of
affected families that exhibit segregation of the phenotype with the genotype; and (4) the robustness of the
associated functional data [Table 1]. Cases were included in the total count if the patient had a variant plus
either a prolonged QTc on an EKG or clinical symptoms. Segregation data was considered strong if a gene
variant was found in the majority of symptomatic or EKG positive members of at least one large family (3 or
more generations) without being found in asymptomatic or EKG negative members. Segregation data was
considered moderate if the same criteria were met in small families (1 or 2 generations). The robustness of
functional data was determined based on the presence of multiple lines of supportive experiments that dem-
onstrated the role for that particular gene in the LQTS disease phenotype. Examples of functional data con-
sidered to be supportive of a gene-disease correlation include gene expression analysis that demonstrates the