Towards Mutation-Specific Precision Medicine in Atypical Clinical Phenotypes of Inherited Arrhythmia Syndromes

Abstract

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine.

A narrative review of inherited arrhythmogenic syndromes in young population: role of genetic diagnosis in exercise recommendations

“…Under physiological conditions, during beta-adrenergic stimulation, these IKs are activated by catecholamines and shorten ventricular repolarisation to avoid malignant arrhythmias at high rates. 58 The early after-depolarisation opens a vulnerable window due to the transmural dispersion of repolarisation that leads to re-entrant arrhythmias such as torsade de pointes . Swimming also provokes events in almost 15% of young adults due to the imbalance between the parasympathetic and sympathetic systems during the immersion.…”

Novel CACNA1C R511Q mutation, located in domain Ⅰ-Ⅱ linker, causes non-syndromic type-8 long QT syndrome

“…Congenital long QT syndrome (LQTS) is an inherited disorder characterized by a prolongation of QT interval and an increased risk of syncope and sudden cardiac death due to polymorphic ventricular tachycardia, torsade de pointes, or ventricular fibrillation [ 1 ]. Seventeen genes have been reported to be causal for type-1 to type-17 LQTS (LQT1-17) thus far.…”

“…However, not all genes appear to be definitely causal for LQTS [ 2 ]. Mutations in the first three identified genes— KCNQ1 for LQT1, KCNH2 for LQT2 and SCN5A for LQT3—account for approximately 90% of genetically affected LQTS patients, while those in other causal genes have rarely been identified [ 1 ].…”

Diverse Phenotypic Manifestations in a Family with a Novel <i>RYR2</i> E4107A Variant

“…1,2) On the other hand, long QT syndrome (LQTS) is a genetic disorder characterized by QT prolongation on an electrocardiogram (ECG), and the occurrence of polymorphic VT, torsades de pointes (TdP), which leads to syncope and SCD. 3,4) Thus, CPVT is defined as a disease entity distinct from LQTS, and genetic backgrounds and arrhythmogenic molecular mechanisms of CPVT are thought to be different from those of LQTS, although CPVT shares common clinical features with LQTS, particularly with type-1 LQTS (LQT1), in terms of the tendency to cause cardiac events during exercise or swimming. 5) RYR2, a leading causative gene for CPVT, encodes the cardiac ryanodine receptor (RyR2) which governs the release of Ca 2+ from the sarcoplasmic reticulum (SR), which is essential for excitation-contraction coupling in the heart.…”