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Page 32 Loong et al. J Transl Genet Genom 2023;7:27-49 https://dx.doi.org/10.20517/jtgg.2022.20

INTRODUCTION
Interest in inherited cardiovascular conditions (ICC) has risen as resources are devoted to its study .
[1]
[2]
Cardiovascular diseases are the most common cause of death worldwide, with numbers increasing yearly .
A significant proportion of these diseases are ICCs, notable for their high degree of heritable features. ICCs
are broadly classified as cardiomyopathies, channelopathies, vasculopathies, heritable lipid conditions, and
neuromuscular disorders involving the cardiovascular system.

The rapid advancement of DNA sequencing, from Watson and Crick’s description of the three-dimensional
structure of DNA in 1953, to Sanger and Gilbert’s development of Sanger sequencing in 1977, to the most
recent advanced third-generation long-read sequencing offered by Oxford Nanopore Technologies and
[3]
Pacific Biosciences expands our understanding of ICCs . An elucidation of the ICC genomic landscape
enables the development of diagnostic guidelines, the discovery of potential therapeutic targets, and the
creation of novel therapeutics. These have opened the field to precision and translational medicine in
cardiology. One recent example is the US Food and Drug Administration’s approval of the first-ever drug
for symptomatic obstructive hypertrophic cardiomyopathy (HCM) that works by modulating cardiac
myosin .
[4,5]
Against this background, it is essential for healthcare institutes and systems to develop contextual
frameworks making use of updated guidelines to provide holistic care for patients with ICCs . For
[6,7]
example, we must tackle the characterization of variants of uncertain significance (VUS), report incidental
findings, navigate the myriad ethical considerations, and address the socioeconomic implications for the
successful implementation of ICC genetics.

In this review, we offer insights from our experience as an ICC clinic in Singapore and introduce three case
examples from our clinic.

Importance of setting up an ICC program
Current studies suggest that the prevalence of HCM, dilated cardiomyopathy (DCM), arrhythmogenic
cardiomyopathy (ACM), and channelopathies are approximately 1/500, 1/250, 1/5000, and 1/2000 to 1/5000,
respectively [8-12] . These are derived predominantly from studies in Western populations and extrapolated to
estimate prevalence worldwide [8,11] . It is challenging to define the epidemiology due to the heterogeneity of
clinical presentations and outcomes. Many ICC symptoms are shared with other common non-ICC cardiac
conditions. Epidemiological estimates are likely to be conservative. One such example is HCM, where the
phenotype of left ventricular hypertrophy (LVH), although sometimes accompanying unique
echocardiographic features of the systolic anterior motion of the mitral valve for HCM, can be confounded
[13]
by more common conditions such as hypertension or physiological LVH in athletes . An additional issue
is age-related penetrance or incomplete disease expression, which also hinders the diagnoses, leading to
conservative estimates.

The high proportion of sudden death among the young linked to ICC [14,15] and the high prevalence of other
ICCs suggests a significant burden to healthcare worldwide. To address this burden, accurate diagnosis is
imperative, followed by early lifestyle and medical modifications and cascade gene testing. For example,
following the diagnosis of long QT syndrome (LQTS), lifestyle changes, β-blocker therapy, left cardiac
sympathetic denervation, and device therapy can be implemented early to reduce the risk of severe
morbidities or sudden cardiac death (SCD) . We have worked toward a systematic workflow to identify
[16]
and manage ICC patients in our tertiary referral center. We follow the recommendations for a
[6,7]
comprehensive ICC program highlighted in published genetic testing guidelines .