Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome

Hirose, Sachiko; Murayama, Takashi; Tetsuo, Naoyuki; Hoshiai, Minako; Kise, Hiroaki; Yoshinaga, Masao; Aoki, Hisaaki; Fukuyama, Megumi; Wuriyanghai, Yimin; Wada, Yuko; Kato, Koichi; Makiyama, Takeru; Kimura, Takeshi; Sakurai, Takashi; Horie, Minoru; Kurebayashi, Nagomi; Ohno, Seiko

doi:10.1093/europace/euab250

Cited by 28 publications

(27 citation statements)

References 21 publications

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“…They suggested that patients with RYR2 variants and bradycardia should be carefully diagnosed to avoid misdiagnosing CPVT patients as LQTS patients [ 61 ]. Hirose et al revealed RYR2 loss-of-function mutations causing QT prolongation [ 62 ]. We found that most LQTS-related variants reported in previous studies [ 18 , 42 , 48 , 63 ] and in our present study were located on the large cytosolic region of the N-terminal side ( Fig 1 ).…”

Section: Discussionmentioning

confidence: 99%

Targeted deep sequencing analyses of long QT syndrome in a Japanese population

et al. 2022

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Long QT syndrome (LQTS) is one of the most common inherited arrhythmias and multiple genes have been reported as causative. Presently, genetic diagnosis for LQTS patients is becoming widespread and contributing to implementation of therapies. However, causative genetic mutations cannot be detected in about 20% of patients. To elucidate additional genetic mutations in LQTS, we performed deep-sequencing of previously reported 15 causative and 85 candidate genes for this disorder in 556 Japanese LQTS patients. We performed in-silico filtering of the sequencing data and found 48 novel variants in 33 genes of 53 cases. These variants were predicted to be damaging to coding proteins or to alter the binding affinity of several transcription factors. Notably, we found that most of the LQTS-related variants in the RYR2 gene were in the large cytoplasmic domain of the N-terminus side. They might be useful for screening of LQTS patients who had no known genetic factors. In addition, when the mechanisms of these variants in the development of LQTS are revealed, it will be useful for early diagnosis, risk stratification, and selection of treatment.

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Section: Discussionmentioning

confidence: 99%

Targeted deep sequencing analyses of long QT syndrome in a Japanese population

et al. 2022

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“…Several publications support the fact that pathogenic variants in KCNQ1 , ANK2 , KCNE1 , KCNE2 , KCNH2 , KCNJ2 and SCN5A can lead to a complex overlapping phenotype of LQTS, CPVT and ventricular ectopy [ 42 , 48 , 92 ]. Hirose et al, recently described in a cohort of children (<16 years old) the association of loss-of-function pathogenic variants in RYR2 with various types of arrhythmia, including LQTS, VF and scTdP, depending on the alteration of channel activity [ 83 , 84 ]. The pathogenic variants p.I4855M and deletion of exon 3 in the RYR2 gene have been associated with the rare syndrome of left ventricular non-compaction (LVNC) overlap and CPVT, presenting a high lethality [ 85 ].…”

Section: Genetic Overlapmentioning

confidence: 99%

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

et al. 2022

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Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

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“…However, a recent study identified a loss-of-function mutation D3291V, which markedly reduced luminal Ca 2+ sensitivity, and blunted response to adrenergic stimulation, also exhibiting a CPVT phenotype ( 116 ). The relationship between gain-of-function or loss-of-function and the clinical phenotype still needs to be elucidated ( 117 ). The calsequestrin encoded by CASQ2 is a calcium-binding protein that regulates the amount of calcium released from the SR during excitation-contraction coupling by buffering the calcium in the SR ( 118 , 119 ).…”

Section: Genetic Factors Of Ventricular Arrhythmias Without Structura...mentioning

confidence: 99%

The Genetics and Epigenetics of Ventricular Arrhythmias in Patients Without Structural Heart Disease

Wang

2022

Front. Cardiovasc. Med.

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Ventricular arrhythmia without structural heart disease is an arrhythmic disorder that occurs in structurally normal heart and no transient or reversible arrhythmia factors, such as electrolyte disorders and myocardial ischemia. Ventricular arrhythmias without structural heart disease can be induced by multiple factors, including genetics and environment, which involve different genetic and epigenetic regulation. Familial genetic analysis reveals that cardiac ion-channel disorder and dysfunctional calcium handling are two major causes of this type of heart disease. Genome-wide association studies have identified some genetic susceptibility loci associated with ventricular tachycardia and ventricular fibrillation, yet relatively few loci associated with no structural heart disease. The effects of epigenetics on the ventricular arrhythmias susceptibility genes, involving non-coding RNAs, DNA methylation and other regulatory mechanisms, are gradually being revealed. This article aims to review the knowledge of ventricular arrhythmia without structural heart disease in genetics, and summarizes the current state of epigenetic regulation.

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Loss-of-function mutations in cardiac ryanodine receptor channel cause various types of arrhythmias including long QT syndrome

Cited by 28 publications

References 21 publications

Targeted deep sequencing analyses of long QT syndrome in a Japanese population

Targeted deep sequencing analyses of long QT syndrome in a Japanese population

Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population

The Genetics and Epigenetics of Ventricular Arrhythmias in Patients Without Structural Heart Disease

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