Catecholaminergic polymorphic ventricular tachycardia (and seizure) caused by a novel homozygous likely pathogenic variant in CASQ2 gene

Askarinejad, Amir; Esmaeili, Shiva; Dalili, Mohamad; Biglari, Alireza; Kohansal, Erfan; Maleki, Majid; Kalayinia, Samira

doi:10.1016/j.gene.2023.148012

Cited by 2 publications

(1 citation statement)

References 41 publications

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“…Mutations primarily result in reduced expression or complete absence of CASQ2 in cardiac tissues, leading to compromised Ca 2+ buffering, dysregulated RyR2 activity and structural remodeling of the sarcoplasmic reticulum ultrastructure along with its constituent proteins [ 29 ]. Novel variants potentially associated with additional neurological manifestations have also been recently identified in patients with CPVT2 [ 30 ].…”

Section: Genetics and Pathophysiologymentioning

confidence: 99%

Catecholaminergic Polymorphic Ventricular Tachycardia: Clinical Characteristics, Diagnostic Evaluation and Therapeutic Strategies

Aggarwal,

Stolear,

Alam

et al. 2024

JCM

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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe hereditary arrhythmia syndrome predominantly affecting children and young adults. It manifests through bidirectional or polymorphic ventricular arrhythmia, often culminating in syncope triggered by physical exertion or emotional stress which can lead to sudden cardiac death. Most cases stem from mutations in the gene responsible for encoding the cardiac ryanodine receptor (RyR2), or in the Calsequestrin 2 gene (CASQ2), disrupting the handling of calcium ions within the cardiac myocyte sarcoplasmic reticulum. Diagnosing CPVT typically involves unmasking the arrhythmia through exercise stress testing. This diagnosis emerges in the absence of structural heart disease by cardiac imaging and with a normal baseline electrocardiogram. Traditional first-line treatment primarily involves β-blocker therapy, significantly reducing CPVT-associated mortality. Adjunctive therapies such as moderate exercise training, flecainide, left cardiac sympathetic denervation and implantable cardioverter-defibrillators have been utilized with reasonable success. However, the spectrum of options for managing CPVT has expanded over time, demonstrating decreased rates of arrhythmic events. Furthermore, ongoing research into potential new therapies including gene therapies has the potential to further enhance treatment paradigms. This review aims to succinctly encapsulate the contemporary understanding of the clinical characteristics, diagnostic approach, established therapeutic interventions and the promising future directions in managing CPVT.

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Section: Genetics and Pathophysiologymentioning

confidence: 99%

Catecholaminergic Polymorphic Ventricular Tachycardia: Clinical Characteristics, Diagnostic Evaluation and Therapeutic Strategies

Aggarwal,

Stolear,

Alam

et al. 2024

JCM

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Integrative multi-omics summary-based mendelian randomization identifies key oxidative stress-related genes as therapeutic targets for atrial fibrillation and flutter

Chen,

Sun,

Wen

et al. 2024

Front. Genet.

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BackgroundAtrial fibrillation (AF) is a prevalent cardiac arrhythmia associated with substantial morbidity and mortality. Oxidative stress (OS) has been implicated in the pathogenesis of AF, suggesting that targeting OS-related genes could offer novel therapeutic opportunities. This study aimed to identify causal OS-related genes contributing to AF through a comprehensive multi-omics Summary-based Mendelian Randomization (SMR) approach.MethodsThis study integrated data from genome-wide association studies (GWAS) with methylation quantitative trait loci (mQTL), expression QTL (eQTL), and protein QTL (pQTL) to explore the relationships between oxidative stress-related (OS-related) genes and AF risk. Genes associated with oxidative stress and AF were obtained from the Nielsen et al. study (discovery) and the FinnGen study (replication). The SMR analysis and HEIDI test were utilized to assess causal associations, followed by Bayesian co-localization analysis (PPH4 > 0.5) to confirm shared causal variants. Multi-omics data were employed to analyze the associations within mQTL-eQTL pathways. A two-sample MR analysis was conducted for sensitivity verification. The significance of findings was determined using a false discovery rate (FDR) < 0.05 and p_HEIDI > 0.01.ResultsAt the DNA methylation level, 19 CpG sites near 7 unique genes were found to have causal effects on AF and strong co-localization evidence support (PPH4 > 0.70). At the gene expression level, six oxidative stress-related genes from eQTLGen and three from GTEx (v8), including TNFSF10, CDKN1A, ALOX15, TTN, PTK2, ALB, KCNJ5, and CASQ2, were found to have causal effects on AF in the sensitivity and co-localization analyses (PPH4 > 0.50). At the circulating protein level, both ALAD (OR 0.898, 95% CI 0.845–0.954, PPH4 = 0.67) and APOH (OR 0.896, 95% CI 0.844–0.952, PPH4 = 0.93) were associated with a lower risk of AF, and APOH was validated in the replication group. After integrating the multi-omics data between mQTL and eQTL, we identified two oxidative stress-related genes, TTN and CASQ2. The methylation of cg09915519 and cg10087519 in TTN was associated with higher expression of TTN and a lower risk of AF, which aligns with the negative effect of TTN gene expression on AF risk. TTN may play a protective role in AF.ConclusionThis study identified several OS-related genes, particularly TTN, as having causal roles in AF, which were verified across three-omics pathways. The findings underscore the importance of these genes in AF pathogenesis and highlight their potential as therapeutic targets. The integration of multi-omics data provides a comprehensive understanding of the molecular mechanisms underlying AF, paving the way for targeted therapeutic strategies.

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Catecholaminergic polymorphic ventricular tachycardia (and seizure) caused by a novel homozygous likely pathogenic variant in CASQ2 gene

Cited by 2 publications

References 41 publications

Catecholaminergic Polymorphic Ventricular Tachycardia: Clinical Characteristics, Diagnostic Evaluation and Therapeutic Strategies

Catecholaminergic Polymorphic Ventricular Tachycardia: Clinical Characteristics, Diagnostic Evaluation and Therapeutic Strategies

Integrative multi-omics summary-based mendelian randomization identifies key oxidative stress-related genes as therapeutic targets for atrial fibrillation and flutter

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