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RESULTS
Literature search and gene curation
Results from the literature search and gene evidence curation are displayed in Table 1. The first LQTS genes
to be identified molecularly and associated with the condition were KNCH2 and SCN5A in 1995. Notably,
loci for many of the LQTS subtypes were defined by linkage, often preceding the discovery of a putative
disease-associated gene; thus the subtype nomenclature does not necessarily correlate directly with the year
of the first “clinical case.” The rate of discovery of LQTS genes has remained fairly steady with about one
new gene-disease association asserted every 1-2 years on average. KCNQ1 and SCN5A associated LQTS have
significantly more known cases than the other LQTS genes with greater than 100 reported cases each in the
literature. In comparison, CAV3, SCN4B, AKAP9, SNTA1 and KCNJ5 have fewer than 10 reported LQTS
cases each.

Whereas the rate of discovery has not changed, the time from assertion to testing has decreased. It took
between 4-9 years for genes discovered from 1995-2004 to be incorporated on a multi-gene panel, whereas
genes with reported associations after 2006 required 2 years or fewer to be incorporated on a panel.

Regarding segregation of variants with a LQTS phenotype, KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, CAC-
NA1C, and KCNJ5 have the strongest support with gene variants segregating with disease in at least one large
family. KCNE2, KCNJ2, SCN4B, SNTA1, and CALM1 have a lesser amount of segregation evidence in smaller
families. No segregation data was identified for CAV3, AKAP9, and CALM2. Regarding functional data,
KCNQ1, KCNH2, SCN5A, ANK2, KCNE1, KCNE2, KCNJ2, CACNA1C, CAV3, and AKAP9 have the highest
level. SCN4B, SNTA1, and KCNJ5 have moderate associated functional data. CALM1 and CALM2 have mini-
mal associated functional data.

Stakeholder interviews
The composition of each laboratory’s LQTS panel test over time is presented in Table 2. At the time of the
interviews, seven of nine laboratories tested at least for the three genes that constitute the majority of patho-
[22]
genic variants in LQTS patients (KCNQ1, KCNH2 and SCN5A) . The two outliers, lab 6 and lab 9, had more
restricted test offerings that reflected specific laboratory interests, small laboratory size, and the limitations of
Sanger sequencing. Both labs expanded their panels after implementing massively parallel sequencing (MPS).
In general, multiple informants noted that advancing from Sanger sequencing to MPS was a major factor in
the ability to expand gene panels due to increased speed of gene testing and decreased cost of test develop-
ment. Lab 5 initially offered only sequencing of SCN5A due to gene patents. When these were dissolved, add-
ing KCNQ1 and KCNH2 was prioritized to achieve the highest yield possible balancing development costs at
that time using Sanger sequencing, which was quoted at $500-10,000 per gene. Lab 5 later expanded its panel
after implementing MPS technology to incorporate additional LQTS genes.

Laboratories 1, 3, 4, and 7 did not join the market until 2013 or later. By this time, MPS technology was stan-
dard and 13 genes had already been identified which may explain why their initial test included all or nearly
all genes. Notably, intellectual property played a significant role in panel development prior to 2008 when
[23]
one lab held most of the LQTS gene patents . In 2008 a second lab acquired licensing rights to multiple
LQTS genes and shortly thereafter the available market tests were expanded from 5 genes to 10 genes. This is
reflected in Table 1.

In addressing what genes to include on a panel, many informants referred to the balance between offering
a clinically valid yet competitive test in the current genetic test market. Several informants mentioned the
importance of general evidence criteria for a gene to be placed on a panel. In addition to scientific support,
clinician/customer request and competitive pressures from other laboratories were independently mentioned
as factors by some. Most also noted that these factors would likely continue to have influence in deciding
which genes to add.