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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 33

Overview of cases in the ICC clinic
The National University Heart Centre, Singapore (NUHCS) ICC research program was initiated in the early
2010s for patients with HCM, DCM (including arrhythmogenic right ventricular cardiomyopathy [ARVC,
or now called ACM]), inherited arrhythmias and inherited aortopathies. Over time, these have been
expanded to include systemic conditions with cardiac involvement, including familial hyperlipidemia and
Anderson-Fabry disease. In this section, we offer a breakdown of the conditions, with relevant genetic and
clinical details pertinent to the respective conditions. We only reviewed conditions that were frequently seen
in our adult ICC program. For the section on inherited aortopathies, we included Marfan syndrome (MFS)
because that is the most common patient we see routinely. Other aortopathies, such as Ehlers-Danlos
syndrome and Loeys-Dietz syndrome, are rarely seen in our ICC program as of the writing of this
manuscript; our pediatric colleagues manage them.

Inherited cardiomyopathy
Inherited cardiomyopathies form the most significant proportion of cases among our patients, with cases
being classified as HCM, DCM, ARVC, and left ventricular non-compaction (LVNC).

HCM
HCM is characterized by LVH unexplained by secondary causes such as hypertension, aortic stenosis, or
physiological enlargement, usually with preserved or increased ejection fraction. It is estimated to be present
in 1 of 500 individuals . The phenotypic presentation of HCM is heterogenous in progression and
[17]
[18]
demographics, especially age, leading to conservative epidemiological statistics . While most HCM cases
follow a relatively benign course, HCM remains a significant cause of SCD, especially among younger
patients [14,19] .

Pathogenic variants in genes encoding sarcomeric proteins, including MYBPC3, MYH7, TNNT2, TNNI3,
TPM1, ACTC1, MYL3, and MYL2 contribute most (up to 50%) of disease-causing variants, and these genes
are commonly on HCM-specific gene panels [20,21] . Disease-causing variants contribute to varying degrees to
the phenotypic presentation. For example, disease-causing TNNT2 variants are associated with poor
prognosis and a high risk of SCD, while disease-causing MYBPC3 variants are associated with a delayed
onset of disease and more favorable outcomes [22,23] . Risk stratification based on the mutated genes has a
[18]
limited impact on patient management .

Substantial attention has been paid to genotype-negative HCM cases (i.e., cases lacking disease-causing
variants in known HCM genes), the absence of prior family history for HCM, and the possibility of de novo
HCM (cases where the variant is present in the proband but not the parents), where the disease is
[24]
potentially non-familial or non-Mendelian in nature . This phenomenon impacts cascade testing. In some
rare instances, genotype-negative HCM cases may be explained by storage disorders (phenocopies) such as
LAMP2- or PRKAG2-associated multisystem glycogen-storage disease, where the clinical presentation may
[25]
not differ substantially from HCM .
Research is underway to establish guidelines for genotype-negative HCM cases and provide management
strategies and therapeutics for the various HCM subsets. Management includes symptomatic treatment and
prevention of SCD, with strategies aimed at addressing complications of the disease, such as LV obstruction
or heart failure, and prophylactic measures, such as implantable cardioverter defibrillator (ICD)
implantation in high-risk individuals [26,27] . It is encouraging that the first cardiac myosin inhibitor
(Mavacamten) was recently approved by the United States Food and Drug Administration to treat
obstructive HCM . This approval opens the doors for future drugs targeting the underlying
[5]
pathophysiology of HCM and (broadly) ICC in the move toward precision cardiology.