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Loong et al. J Transl Genet Genom 2023;7:27-49 https://dx.doi.org/10.20517/jtgg.2022.20 Page 37

risk stratification and management remain challenging in clinical practice, not least because of the lack of
clarity between the monogenic or polygenic disease causality, the frequently incomplete penetrance, and the
lack of other applicable non-genetic-based stratification criteria [74,84] .

LQTS
LQTS is a life-threatening inherited arrhythmia characterized by a prolonged QT interval and the onset of
[85]
syncope or cardiac arrest, sometimes precipitated by emotional or physical stress . LQTS can be lethal,
with untreated symptomatic patients having a high mortality rate of 21% a year following syncope .
[86]
Mortality can be reduced to ~1% with proper and timely intervention involving a formal diagnosis, early
detection, and management (3, 4). Genetic testing is indicated when the clinical suspicion of LQTS is
[16]
[87]
high, and the "Schwartz score" is greater than or equal to 3.5 or QTc>499 msec across multiple ECGs .

With advances in clinical genomics, robust phenotype-genotype correlations have been established for
LQTS, making genomic analysis for this syndrome relatively more straightforward . LQTS is divided into
[85]
16 different subtypes, with each subtype corresponding to a specific gene involvement . By far, the first
[88]
three subtypes (LQT1, LQT2, and LQT3) contribute most, corresponding to the genes KCNQ1, KCNH2,
and SCN5A, respectively . Among these, there is some evidence for genetic risk stratification. For example,
[89]
a variant in KCNQ1, A341V, results in 80% of individuals being symptomatic, with more than 30%
experiencing SCA or SCD . By contrast, pathogenic variants associated with a lower frequency of SCA or
[90]
death are those with LQT2 (KCNH2) and LQT3 (SCN5A) disease-causing variants, with a comparatively
lower risk for life-threatening arrhythmias during exercise .
[85]

After the diagnosis of LQTS is established, the cornerstone for management for symptomatic patients lies
with beta-blocker therapy and lifestyle modification . Different or adjunctive therapeutic options can also
[85]
be considered for various genetic subtypes, including sodium channel blockers for LQT3 or Andersen-Tawil
syndrome (LQT7) patients or calcium channel blockers for Timothy syndrome (LQT8). Other essential
[91]
aspects are treating patients using left cardiac sympathetic denervation and ICD for cardiac arrest
survivors . While the genotype-phenotype relationship of LQTS has been extensively elucidated,
[16]
understanding its complex genetic architecture might yield new management approaches.

CPVT
CPVT is a rare arrhythmogenic disorder characterized by adrenergic-induced bidirectional and
polymorphic VT. The polymorphic VT tends to be reproduced during exercise, intense periods of
emotions, or isoproterenol infusion and can cause syncope and SCD at a young age in the absence of
structural cardiac conditions . The mortality of untreated CPVT is estimated at > 31% when the patient is
[92]
30 years old, and the eight-year cardiac event rate of patients not under beta-blocker therapy is 58% .
[93]
[94]
CPVT is a significant cause of sudden death in the young . Patients with CPVT are often missed or
misdiagnosed due to the lack of obvious clinical signs or structural cardiac abnormalities, highlighting the
critical role of pre-emptive genetic testing .
[95]
Genotype-phenotype correlations are well established for CPVT, with most carrying pathogenic RYR2
(autosomal dominant) or CASQ2 (autosomal recessive) variants. Other disease-causing variants in TRDN
and TECRL have been less often implicated [92,95] . Hayashi et al. showed that cardiac and lethal event rates
were similar between 50 probands and 51 affected family members . This finding provides strong evidence
[96]
for the importance of cascade testing in newly-diagnosed CPVT probands because affected relatives are at
similarly high risk of adverse cardiac events .
[96]