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Page 36 Loong et al. J Transl Genet Genom 2023;7:27-49 https://dx.doi.org/10.20517/jtgg.2022.20

Several registries focused on studying ATTR-CM provided many insights into this condition [68,69] . It is now
widely understood that the underlying TTR variant significantly affects the clinical presentation of patients
[66]
V
w i t h T T R amyloidosis . a r i a n t s s u c h a s N M _ 0 0 0 3 7 1 . 4 : c . 8 8 T > C ( p . C y s 3 0 A r g ) a n d
NM_000371.4:c.349G>T (p.Ala117Ser) are associated with neurological features. Others, such as
NM_000371.4:c.424G>A (p.Val142Ile), are associated with cardiac features. For the commonly encountered
NM_000371.4:c.148G>A (p.Val50Met) variant, early-onset disease is associated with prominent
neurological dysfunction with favorable outcomes following isolated liver transplantation, while late-onset
NM_000371.4:c.148G>A (p.Val50Met) is associated with mixed neurological and cardiac dysfunction .
[66]
With such distinct genotype-phenotype correlations for vATTR disease presentation, accurate genotyping
will enable more effective clinical management. The genotype also affects treatment decisions, especially
regarding selection for liver transplantation, which is reserved mainly for early-onset
NM_000371.4:c.148G>A (p.Val50Met), given the favorable outcomes of this genotype following liver
transplantation .
[68]

Inherited channelopathies
Inherited channelopathies comprise the next most significant disease caseload in the ICC clinic. These may
be spontaneously manifest or only revealed on provocation testing and systematic workup. The latter
include sudden cardiac arrest (SCA) survivors with normal coronary arteries and structurally normal hearts,
for whom identification of an underlying channelopathy has therapeutic and familial implications. This
section covers the common inherited channelopathies: LQTS, BrS, and catecholaminergic polymorphic
ventricular tachycardia (CPVT).

BrS
BrS is characterized by a coved-type ST segment elevation in the right precordial leads of an ECG and
increased risk of SCD in the absence of structural abnormalities; it was first recognized in 1992 by the
Brugada brothers . The characteristic ECG patterns can present spontaneously or are unmasked upon
[70]
provocative by sodium channel blockers such as ajmaline, procainamide, or flecainide . BrS can be
[71]
potentially life-threatening, with patients presenting with syncope, seizures, and nocturnal agonal breathing
due to polymorphic ventricular tachycardia or ventricular fibrillation (VF). SCD may result from sustained
polymorphic ventricular tachycardia or VF [71,72] . Because BrS is associated with a familial carriage,
researchers have studied its genetic basis. The first genetic evidence for this condition reported in 1998
[73]
pointed to the SCN5A gene .

Various sodium, calcium, and potassium channel genes have been implicated in BrS pathophysiology. These
include SCN4A, SCN10A, KCNH2, CACNA1C, and CACNA2D1 . However, only the SCN5A gene is a
[74]
“definite” gene, according to an expert panel from the ClinGen consortium . BrS is a monogenic
[75]
Mendelian disease with an autosomal dominant inheritance pattern [74,76,77] . However, affected families
[78]
frequently show incomplete penetrance, with up to 60% presenting with no family history . SCN5A
pathogenic variants contributed to increased severity, allowing for genetic-based risk stratification .
[79]
Importantly, a genome-wide association study suggested that BrS was associated with common variants,
[80]
contributing to another hypothesis that BrS is a complex polygenic disease .

Nevertheless, genetic testing offers genetic confirmation and risk stratification [74,81] . Indeed, clinical
guidelines recommend that high-risk patients receive an ICD to prevent SCD . However, this decision
[82]
requires careful consideration and counseling, owing to many long-term psychological sequelae aggravated
[83]
by inappropriate shocks from the ICD . Despite recent advances in clinical diagnoses and genetic testing,