scholarly journals A candidate genetic modifier and autosomal recessive cause of Brugada syndrome that may alter the circadian expression of SCN5A

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
L Seed ◽  
T Hearn
Keyword(s):  
Circadian Clock ◽  
Brugada Syndrome ◽  
Autosomal Recessive ◽  
Genetic Modifier ◽  
Cardiac Conduction ◽  
P Value ◽  
Functional Assay ◽  
Genetic Modifiers ◽  
Monogenic Diseases ◽  
Support Fund

Abstract Funding Acknowledgements Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This work was supported by a generous grant from the Newnham College Senior Members Research Support fund. Introduction Inherited cardiac arrhythmias (ICAs) are a major cause of sudden cardiac death (SCD) in the young. ICAs are caused by variants in genes encoding ion channels that predispose individuals to life-threatening arrhythmic events. Early diagnosis to facilitate implementation of effective clinical interventions that greatly reduce SCD risk is critical. ICAs have traditionally been considered monogenic diseases. However, the genomic architecture of ICAs is likely a continuum, ranging from monogenic and near-monogenic (strong genetic factor influenced by a few genetic modifiers) to oligogenic (cumulative effects of coinheritance of many genetic modifiers). The circadian clock, which is predicted to control the expression of one third of the protein-coding genome, has been implicated in contributing to ICAs because the incidence of arrhythmic events in ICA patients oscillates with a period of 24 hours. We therefore hypothesised that it may contribute to oligogenic disease. Purpose To identify variants that may contribute to ICAs and that are located in cis-regulatory motifs that are both functionally predicted to be binding sites for clock transcription factors and located in the promoters of ICA-associated genes predicted to exhibit diurnal rhythmic expression. Methods Genes associated with ICAs and predicted to be rhythmically expressed were identified and the region 1kb upstream of their transcription start sites screened for mammalian circadian motifs. Whole genome sequencing data from participants with ICAs in The 100,000 Genomes Project was interrogated for variants within these motifs. Results Two variants in the SCN5A promoter were significantly associated with Brugada syndrome (BrS) (OR = 2.77, p-value <2.2E-16; OR = 2.11, p-value = 6.23E-14). The variants were found in high linkage disequilibrium (D’=0.988, p-value <2.2E-16). This 2-variant haplotype was enriched in BrS patients who did (OR = 2.43, p-value = 7.07E-08; OR = 1.32, p-value = 0.0204) and did not (OR = 3.00, p-value <2.2E-16; OR = 1.78, p-value = 8.30E-09) have a likely genomic cause, implying that it may be a genetic modifier of BrS. This haplotype in the homozygous state was significantly enriched in individuals with BrS in whom a likely genomic cause had not been identified, suggesting it may be an autosomal recessive cause (OR = 0.102, Fisher’s p-value = 0.0120). Conclusion This haplotype has previously been reported to modulate BrS severity in a large family with a pathogenic SCN5A variant and has demonstrated a trend towards reduced SCN5A expression in murine cardiomyocytes – a molecular mechanism that slows cardiac conduction, predisposing individuals to BrS. Therefore, this 2-variant haplotype, or 1 variant therein, in the SCN5A promoter is a putative genetic modifier and autosomal recessive cause of BrS. Future work includes functional assay in human cardiomyocytes to characterise its molecular consequences on SCN5A expression and the circadian clock.

Genetic Modifiers of Tauopathy in Drosophila

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1233-1242
Author(s):  
Joshua M Shulman ◽  
Mel B Feany
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Genetic Modifier ◽  
Genetic Modifiers ◽  
Protein Tau ◽  
Major Class ◽  
Drosophila Model ◽  
Tau Kinases

Abstract In Alzheimer's disease and related disorders, the microtubule-associated protein Tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles. Mutations in the tau gene cause familial frontotemporal dementia. To investigate the molecular mechanisms responsible for Tau-induced neurodegeneration, we conducted a genetic modifier screen in a Drosophila model of tauopathy. Kinases and phosphatases comprised the major class of modifiers recovered, and several candidate Tau kinases were similarly shown to enhance Tau toxicity in vivo. Despite some clinical and pathological similarities among neurodegenerative disorders, a direct comparison of modifiers between different Drosophila disease models revealed that the genetic pathways controlling Tau and polyglutamine toxicity are largely distinct. Our results demonstrate that kinases and phosphatases control Tau-induced neurodegeneration and have important implications for the development of therapies in Alzheimer's disease and related disorders.

Brugada Syndrome: Fatal Consequences of a Must-Not-Miss Diagnosis

2021 ◽  
Vol 41 (5) ◽  
pp. 15-22
Author(s):  
L. Douglas Smith ◽  
Sarah Gast ◽  
Danielle F. Guy
Keyword(s):  
At Risk ◽  
Critical Care ◽  
Sudden Cardiac Death ◽  
Ventricular Arrhythmia ◽  
Brugada Syndrome ◽  
Cardiac Death ◽  
Lifestyle Modification ◽  
Genetic Disorder ◽  
Cardiac Conduction ◽  
St Segment Elevation

Background Brugada syndrome is a genetic disorder of cardiac conduction that predisposes patients to spontaneous ventricular arrhythmia and sudden cardiac death. Although Brugada syndrome is one of the most common causes of sudden cardiac death, patients presenting with the syndrome often go misdiagnosed. This error has potentially fatal consequences for patients, who are at risk for sudden cardiac death without appropriate management. Objective To increase the critical care professional’s knowledge of Brugada syndrome through detailed description of the characteristic electrocardiographic findings, an algorithmic approach to electrocardiogram evaluation, and a case report of a patient with a previously missed diagnosis of Brugada syndrome. The essential concepts of epidemiology, pathophysiology, clinical presentation, risk stratification, and management are reviewed for critical care professionals who may encounter patients with the syndrome. Diagnosis Patients typically present with syncope or cardiac arrest and an abnormal electrocardiographic finding of ST-segment elevation in the precordial leads. The diagnosis of Brugada syndrome centers on identification of its electrocardiographic characteristics by critical care professionals who routinely evaluate electrocardiograms. Critical care professionals, especially nurses and advanced practice nurses, should be proficient in recognizing the electrocardiographic appearance of Brugada syndrome and initiating appropriate management. Interventions Management strategies include prevention of sudden cardiac death through lifestyle modification and placement of an implantable cardioverter-defibrillator. Critical care professionals should be aware of commonly used medications that may exacerbate ventricular arrhythmia and place patients at risk for sudden cardiac death. Conclusion Increased awareness of Brugada syndrome among critical care professionals can decrease patient morbidity and mortality.

scholarly journals Identifying genetic modifiers of autosomal recessive polycystic kidney disease (1179.1)

2014 ◽  
Vol 28 (S1) ◽  
Author(s):  
Michael Flister ◽  
Bradley Endres ◽  
Matthew Hoffman ◽  
Howard Jacob ◽  
William Sweeney ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Polycystic Kidney Disease ◽  
Autosomal Recessive ◽  
Genetic Modifiers ◽  
Polycystic Kidney

Sodium channel kinetic changes that produce Brugada syndrome or progressive cardiac conduction system disease

2007 ◽  
Vol 292 (1) ◽  
pp. H399-H407 ◽  
Author(s):  
Zhu-Shan Zhang ◽  
Joseph Tranquillo ◽  
Valentina Neplioueva ◽  
Nenad Bursac ◽  
Augustus O. Grant
Keyword(s):  
Action Potential ◽  
Sodium Channel ◽  
Brugada Syndrome ◽  
Sodium Current ◽  
Conduction System ◽  
Cardiac Conduction ◽  
Cardiac Conduction System ◽  
Wild Type ◽  
System Disease ◽  
Conduction System Disease

Some mutations of the sodium channel gene NaV1.5 are multifunctional, causing combinations of LQTS, Brugada syndrome and progressive cardiac conduction system disease (PCCD). The combination of Brugada syndrome and PCCD is uncommon, although they both result from a reduction in the sodium current. We hypothesize that slow conduction is sufficient to cause S-T segment elevation and undertook a combined experimental and theoretical study to determine whether conduction slowing alone can produce the Brugada phenotype. Deletion of lysine 1479 in one of two positively charged clusters in the III/IV inter-domain linker causes both syndromes. We have examined the functional effects of this mutation using heterologous expression of the wild-type and mutant sodium channel in HEK-293-EBNA cells. We show that ΔK1479 shifts the potential of half-activation, V1/2m, to more positive potentials ( V1/2m = −36.8 ± 0.8 and −24.5 ± 1.3 mV for the wild-type and ΔK1479 mutant respectively, n = 11, 10). The depolarizing shift increases the extent of depolarization required for activation. The potential of half-inactivation, V1/2h, is also shifted to more positive potentials ( V1/2h = −85 ± 1.1 and −79.4 ± 1.2 mV for wild-type and ΔK1479 mutant respectively), increasing the fraction of channels available for activation. These shifts are quantitatively the same as a mutation that produces PCCD only, G514C. We incorporated experimentally derived parameters into a model of the cardiac action potential and its propagation in a one dimensional cable (simulating endo-, mid-myocardial and epicardial regions). The simulations show that action potential and ECG changes consistent with Brugada syndrome may result from conduction slowing alone; marked repolarization heterogeneity is not required. The findings also suggest how Brugada syndrome and PCCD which both result from loss of sodium channel function are sometimes present alone and at other times in combination.

scholarly journals GSTM3 variant is a novel genetic modifier in Brugada syndrome, a disease with risk of sudden cardiac death

EBioMedicine ◽  
2020 ◽  
Vol 57 ◽  
pp. 102843 ◽  
Author(s):  
Jyh-Ming Jimmy Juang ◽  
Anna Binda ◽  
Shyh-Jye Lee ◽  
Juey-Jen Hwang ◽  
Wen-Jone Chen ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Brugada Syndrome ◽  
Cardiac Death ◽  
Genetic Modifier

scholarly journals Dual Variations in SCN5A and CACNB2b Underlie Cardiac Conduction Disease without Brugada Syndrome

2009 ◽  
Vol 96 (3) ◽  
pp. 261a ◽  
Author(s):  
Dan Hu ◽  
Hector Barajas Martinez ◽  
Ryan Pfeiffer ◽  
Alejandra Guerchicoff ◽  
Jonathan M. Cordeiro ◽  
...  
Keyword(s):  
Brugada Syndrome ◽  
Cardiac Conduction

scholarly journals Different Fumarate Hydratase Gene Variants Are Associated With Distinct Cancer Phenotypes

2021 ◽  
pp. 1568-1578
Author(s):  
Junne Kamihara ◽  
Carrie Horton ◽  
Yuan Tian ◽  
Jing Zhou ◽  
Marcy Richardson ◽  
...  
Keyword(s):  
Kidney Cancer ◽  
Odds Ratio ◽  
Autosomal Recessive ◽  
Fumarate Hydratase ◽  
Clinical Importance ◽  
Interquartile Range ◽  
P Value ◽  
Panel Testing ◽  
Pathogenic Variants ◽  
Negative Controls

PURPOSE Whether individuals with monoallelic FH pathogenic variants (PVs) associated with autosomal recessive fumarate hydratase (FH) deficiency are also at risk of autosomal dominant FH-associated tumors is of paramount clinical importance. METHODS A retrospective study of individuals with a PV in the FH gene identified via multigene panel testing from 2012 to 2019 through a single testing laboratory was performed. Cancer histories of individuals with PVs in FH ( FH PV) were compared to those with PVs associated only with autosomal recessive FH deficiency (FH-d PV) and to FH-negative controls. Cancer histories of individuals with truncating versus nontruncating FH PV were also compared. RESULTS Individuals with FH PV were more likely to have kidney cancer than those with FH-d PV (odds ratio, 9.0; 95% CI, 4.4 to 20.0; P < .001) or FH-negative controls (odds ratio, 7.6; 95% CI, 5.2 to 11.2; P value < .001). The FH PV cohort had kidney cancer at a significantly younger age (median age: 35.0 years; interquartile range, 26.0-45.0 years) than the FH-d PV cohort (median age: 44.5 years; interquartile range, 43.5-53.5 years; P = .011). Within the FH PV cohort, there were no differences in the frequency or age at kidney cancer between those with truncating versus nontruncating PV. CONCLUSION Unlike FH PV, FH-d PV are not associated with kidney cancers at early ages of onset. The FH-d PV cohort had a cancer phenotype that resembled FH-negative controls. These data may inform genetic counseling and risk assessment of individuals with FH-d PV.

P6582Control and stability theory, modelling ventricular dynamics in superficial 12-lead ECG as a novel contribution to non-invasive risk stratification of Brugada ECG patterns(?)

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Sabatini
Keyword(s):  
Risk Stratification ◽  
Brugada Syndrome ◽  
Stability Theory ◽  
Cardiac Conduction ◽  
Polymorphic Ventricular Tachycardia ◽  
Ecg Signal ◽  
Stability Parameters ◽  
Poles And Zeros ◽  
Brugada Pattern

Abstract Background Brugada syndrome (BrS) risk stratification in asymptomatic subjects is still currently the most important yet unresolved clinical problem to determine the subset of patients with BrS requiring ICD implantation. The underlying pathophysiological mechanisms responsible for BrS ECG patterns remain unknown, as well as the mechanisms of the sudden onset of polymorphic ventricular tachycardia which leads to ventricular fibrillation and sudden cardiac death (SCD). Purpose This study aims to analyze from a totally alternative perspective, superficial 12-lead ECG signals. It departs from the numerous and various attempts to characterize and measure single morphology of specific and individual ECG segments, intervals and waves, rather focusing on and studying the dynamics and stability of the superficial 12-lead ECG signal as a whole to determine stability parameters able to contribute to BrS ECG pattern risk stratification and differential diagnosis of BrS. Methods A quantitative stability control closed loop system has been designed to model the electrophysiology dynamics of the cardiac conduction system with a 12-lead superficial ECG signal being the input and output of the system (Fig. 1). A normal ECG signal and a type-1 coved Brugada pattern ECG-V2 portion have been scanned, digitized and quantitatively processed to obtain stability parameters (poles and zeros in the S-plane). Scanning was performed by Digitizeit – Digital River GmbH. Processing in the S-plane was performed by ©2019 Wolfram Demonstrations Project & Contributors, http://demonstrations.wolfram.com/, poles and zeros and Microsoft Excel software was also used. Results Poles and zeros of the system for type-1 coved Brugada pattern ECG-V2 and for the normal ECG-V2 are shown in Fig. 2, together with stability. Conclusions Based on our data, 1. It appears that portions of the ECG patterns, approximated by mathematical continuous time models representing, at the infinitesimal limit, every possible pattern and behaviors of an ECG signal, such as repolarization patterns, may exhibit interesting dynamics characteristics of stability and can be stratified as stable, marginally stable or unstable. 2. Such a classification may then be implemented to risk stratify repolarization patterns. When tending to instability, such patterns seem to be associated to high risk repolarization patterns such as BrS coved type-1 pattern, hence indicating higher risk of developing polymorphic VT or SCD. In conclusion, more work will be needed to further this methodology to improve the understanding of the effects of the various physiological and pathological substrates involved with malignant arrhythmias and to improve risk stratification strategies to determine the subset of patients with Brugada syndrome requiring ICD insertion. Control systems and stability theory may indeed indicate an interesting and effective procedure for future work.

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