Characterization of an N-terminal Nav1.5 channel variant – a potential risk factor for arrhythmias and sudden death?

Scheiper-Welling, Stefanie; Zuccolini, Paolo; Rauh, Oliver; Beckmann, Britt-Maria; Geisen, Christof; Moroni, Anna; Thiel, Gerhard; Kauferstein, Silke

doi:10.1186/s12881-020-01170-3

Cited by 3 publications

(2 citation statements)

References 29 publications

(52 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These sodium channels are abundantly expressed in cardiac muscle cells. Mutation in this gene has been associated with various cardiac disorders, including some types of arrhythmias and sudden cardiac death 64 . Although the exact mechanism of the mutant gene in SCAD pathogenesis remains to be elucidated, this association is more than a coincidence.…”

Section: Discussionmentioning

confidence: 99%

The genetics of spontaneous coronary artery dissection: a scoping review

Memar Montazerin,

Hassanzadeh,

Najafi

et al. 2024

Journal of Cardiovascular Medicine

View full text Add to dashboard Cite

Background Spontaneous coronary artery dissection (SCAD) is a multifactorial process that involves predisposing factors and precipitating stressors. Genetic abnormality has been implicated to play a mechanistic role in the development of SCAD. This systematic review aims to summarize the current evidence concerning the link between SCAD and genetic abnormalities. Methods We reviewed original studies published until May 2023 that reported SCAD patients with a genetic mutation by searching PubMed, Embase Ovid, and Google Scholar. Registries, cohort studies, and case reports were included if a definitive SCAD diagnosis was reported, and the genetic analysis was performed. Exclusion criteria included editorials, reviews, letters or commentaries, animal studies, meeting papers, and studies from which we were unable to extract data. Data were extracted from published reports. Results A total of 595 studies were screened and 55 studies were identified. Among 116 SCAD patients with genetic abnormalities, 20% had mutations in the COL gene, 13.70% TLN1 gene, and 8.42% TSR1 gene. Mutations affecting the genes encoding COL and TLN1 were most frequently reported (20 and 13.7%, respectively). Interestingly, 15 genes of this collection were also reported in patients with thoracic aortic diseases as well. The genetic commonality between fibromuscular dysplasia (FMD) and SCAD was also included. Conclusion In this review, the inherited conditions and reported genes of undetermined significance from case reports associated with SCAD are collected. A brief description of the encoded protein and the clinical features associated with pathologic genes is provided. Current data suggested that the diagnostic yield of genetic studies for patients with SCAD would be low and routine genetic screening of such patients with no clinical features indicative of associated disorders remains debatable. This review can be used as a guide for clinicians to recognize inherited syndromic and nonsyndromic disorders associated with SCAD.

show abstract

Section: Discussionmentioning

confidence: 99%

The genetics of spontaneous coronary artery dissection: a scoping review

Memar Montazerin,

Hassanzadeh,

Najafi

et al. 2024

Journal of Cardiovascular Medicine

View full text Add to dashboard Cite

show abstract

“…A range of prediction tools are available to address this question, but these often suffer from poor specificity and consequently result in highly false-positive rates. Although functional testing can give some insights about a variant's clinical validation [30][31][32], it is insufficient to conclude that altered protein function is the probable underlying cause of death.…”

Section: Discussionmentioning

confidence: 99%

Variant interpretation in molecular autopsy: a useful dilemma

et al. 2022

Self Cite

View full text Add to dashboard Cite

Sudden cardiac death (SCD) in adolescents and young adults may be the first manifestation of an inherited arrhythmic syndrome. Thus identification of a genetic origin in sudden death cases deemed inconclusive after a comprehensive autopsy and may help to reduce the risk of lethal episodes in the remaining family. Using next-generation sequencing (NGS), a large number of variants of unknown significance (VUS) are detected. In the majority of cases, there is insufficient evidence of pathogenicity, representing a huge dilemma in current genetic investigations. Misinterpretation of such variants may lead to inaccurate genetic diagnoses and/or the adoption of unnecessary and/or inappropriate therapeutic approaches. In our study, we applied current (ACMG) recommendations for variant classification in post-mortem genetic screening of a cohort of 56 SCD victims. We identified a total 53 rare protein-altering variants (MAF < 0.2%) classified as VUS or worse. Twelve percent of the cases exhibited a clinically actionable variant (pathogenic, likely pathogenic or VUS – potentially pathogenic) that would warrant cascade genetic screening in relatives. Most of the variants detected by means of the post-mortem genetic investigations were VUS. Thus, genetic testing by itself might be fairly meaningless without supporting background data. This data reinforces the need for an experienced multidisciplinary team for obtaining reliable and accountable interpretations of variant significance for elucidating potential causes for SCDs in the young. This enables the early identification of relatives at risk or excludes family members as genetic carriers. Also, development of adequate forensic guidelines to enable appropriate interpretation of rare genetic variants is fundamental.

show abstract

"Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders"

Martin,

Jenewein,

Geisen

et al. 2024

BMC Cardiovasc Disord

View full text Add to dashboard Cite

Background Genetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders. Methods Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts. Results We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017–2019, with rates ranging from 50 to 60%. Conclusion The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.

show abstract

Characterization of an N-terminal Nav1.5 channel variant – a potential risk factor for arrhythmias and sudden death?

Cited by 3 publications

References 29 publications

The genetics of spontaneous coronary artery dissection: a scoping review

The genetics of spontaneous coronary artery dissection: a scoping review

Variant interpretation in molecular autopsy: a useful dilemma

"Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders"

Contact Info

Product

Resources

About