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notably since 2006. Interestingly, within the 2006-2010 timeframe, many gene patents for LQTS genes were
being reversed, and new laboratories began offering panel tests for LQTS. Whether this relationship is causal
or coincidental cannot be determined from our investigation. However, new laboratories may have been ea-
ger to quickly become competitive, adding genes with less supporting evidence, thereby creating panels that
included genes that are lower yielding or with more uncertainty with respect to natural history than initially
expected.

In terms of the relationship of the evidence base to time to testing, it is not surprising that the first eight
genes associated with LQTS have more reported cases than the last seven to be asserted. The first gene-
disease associations were likely those that account for the majority of cases and thus more amenable to gene
discovery. Overall, the earlier genes also had a higher level of segregation data and functional data with a
few key exceptions. CAV3 and AKAP9 were associated with disease before SNTA1, KCNJ5, and CALM1 but
have less segregation data. However, CAV3 and AKAP9 have a higher amount of functional and experimen-
tal evidence compared to other genes discovered since 2006. This may explain why they have remained on
LQTS panels despite a low number of total cases and no segregation data. It was also noted that one lab, lab
4, includes AKAP9 but not KCNJ5 on its panels even though KCNJ5 has more published clinical cases. This
may reflect that AKAP9 was associated with LQTS > 10 years ago, and initially expected to be a major con-
tributing gene based on significant gene function studies. It may also reflect the trend not to remove genes
from panel tests once they are added. To date, only ~3 cases are attributed to AKAP9 in clinical literature
and databases.

Clinical testing for a gene with limited evidence for disease association creates obstacles for interpretation.
There is a need for uniform assessment of the validity of gene-disease associations, especially since our study
found no correlation between gene-specific evidence and placement on panels. Genetic disorders with de-
creased penetrance and unclear genotype-phenotype correlations are in particular need of more knowledge.

Developing and disseminating these assessments is paramount and has become the focus of several interna-
tional efforts. A trusted source documenting clinical validity of gene-disease associations may help combat
competitive pressure to have the largest panel in favor of having a well-curated, clinically valid panel. Clin-
Gen is an NIH-funded organization that aims to create an authoritative central resource to define the clini-
[2]
cal relevance of genes and variants for use in precision medicine and research . The ClinGen framework
includes case-level, case-control, and supporting experimental data to allow curators and disease experts to
[24]
assess of the validity of a gene-disease relationship and assign a clinical validity classification . The classifi-
cations are publically available at: https://www.clinicalgenome.org/curation-activities/gene-disease-validity/
results/.

At the time of writing, a ClinGen Gene Curation Expert Panel for Long QT Syndrome had begun to curate
and assess the clinical validity of LQTS genes. (https://www.clinicalgenome.org/working-groups/clinical-
domain/cardiovascular-clinical-domain-working-group/long-qt-gene-curation-expert-panel/).

Similarly, Genomics England PanelApp is a public database that serves to create virtual gene panels that can
be reviewed by experts around the world with the goal of establishing a final “green” panel for every dis-
order to simplify development of appropriate indication-based gene panel tests and thereby interpretation.
PanelApp has reviewed LQTS genes and published their recommendation regarding placement of genes on
an indication-based panel at: https://panelapp.genomicsengland.co.uk/panels/76/. At this time, however, no
groups or regulatory bodies make specific recommendations for labs regarding what level of clinical validity
[25]
evidence should be required for inclusion on a clinical test .

MPS technology enables options to attempt balance between the generation of clinical case evidence, the
ability to rapidly add clinically valid genes, and ensuring that clinically available testing is based on sound