Compound Heterozygous Mutations in the SCN5A-Encoded Nav1.5 Cardiac Sodium Channel Resulting in Atrial Standstill and His-Purkinje System Disease

Baskar, Shankar; Ackerman, Michael J.; Clements, Diane; Mayuga, Kenneth A.; Aziz, Peter F.

doi:10.1016/j.jpeds.2014.07.036

Cited by 19 publications

(36 citation statements)

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“…Functional studies on SCN5A p.T220I in mammalian cell lines showed a small degree of inactivation delay compared to wild-type cells (the p.R1623X variant encoded non-functional sodium channels, almost inexistent in the plasma membrane) [ 30 , 31 ]. The p.T220I variant was also found in two relatives with DCM [ 32 ], an individual with early onset atrial fibrillation [ 33 ], as well as an individual with progressive SND who was a compound heterozygote for the SCN5A p.T220I and p.1048SfsX97 variants [ 34 ]. Altogether, although the role of the known pathogenic APOB variant in the development of SND is currently unknown, it may be possible that the altered lipid metabolism caused by the APOB variant could have exacerbated the effect of the SCN5A variant.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel

et al. 2015

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BackgroundThe etiology of conduction disturbances necessitating permanent pacemaker (PPM) implantation is often unknown, although familial aggregation of PPM (faPPM) suggests a possible genetic basis. We developed a pan-cardiovascular next generation sequencing (NGS) panel to genetically characterize a selected cohort of faPPM.Materials and MethodsWe designed and validated a custom NGS panel targeting the coding and splicing regions of 246 genes with involvement in cardiac pathogenicity. We enrolled 112 PPM patients and selected nine (8%) with faPPM to be analyzed by NGS.ResultsOur NGS panel covers 95% of the intended target with an average of 229x read depth at a minimum of 15-fold depth, reaching a SNP true positive rate of 98%. The faPPM patients presented with isolated cardiac conduction disease (ICCD) or sick sinus syndrome (SSS) without overt structural heart disease or identifiable secondary etiology. Three patients (33.3%) had heterozygous deleterious variants previously reported in autosomal dominant cardiac diseases including CCD: LDB3 (p.D117N) and TRPM4 (p.G844D) variants in patient 4; TRPM4 (p.G844D) and ABCC9 (p.V734I) variants in patient 6; and SCN5A (p.T220I) and APOB (p.R3527Q) variants in patient 7.ConclusionFaPPM occurred in 8% of our PPM clinic population. The employment of massive parallel sequencing for a large selected panel of cardiovascular genes identified a high percentage (33.3%) of the faPPM patients with deleterious variants previously reported in autosomal dominant cardiac diseases, suggesting that genetic variants may play a role in faPPM.

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Section: Discussionmentioning

confidence: 99%

Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel

et al. 2015

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“…Atrial arrhythmias associated with SCN5A variants mostly include familial atrial standstill and atrial fibrillation. Atrial standstill (AS) is caused by atrial electrical and mechanical impairment, manifested by disappeared P wave, bradycardia, or borderline escape rhythm (Baskar et al, 2014 ). Missense variants such as R367H caused electrophysiological disorders with a non-functional Na + channel, which could finally lead to AS and BrS (Takehara et al, 2004 ).…”

Section: Cardiac Arrhythmiamentioning

confidence: 99%

SCN5A Variants: Association With Cardiac Disorders

et al. 2018

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The SCN5A gene encodes the alpha subunit of the main cardiac sodium channel Nav1.5. This channel predominates inward sodium current (INa) and plays a critical role in regulation of cardiac electrophysiological function. Since 1995, SCN5A variants have been found to be causatively associated with Brugada syndrome, long QT syndrome, cardiac conduction system dysfunction, dilated cardiomyopathy, etc. Previous genetic, electrophysiological, and molecular studies have identified the arrhythmic and cardiac structural characteristics induced by SCN5A variants. However, due to the variation of disease manifestations and genetic background, impact of environmental factors, as well as the presence of mixed phenotypes, the detailed and individualized physiological mechanisms in various SCN5A-related syndromes are not fully elucidated. This review summarizes the current knowledge of SCN5A genetic variations in different SCN5A-related cardiac disorders and the newly developed therapy strategies potentially useful to prevent and treat these disorders in clinical setting.

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“…The I1660V channel trapped in intracellular organelles, likely in the endoplasmic reticulum, and could not properly traffic to the plasma membrane (38). Additionally, the two kinds of double mutations, including A735V and D1792N(39), P1048SfsX97 and T220I (40), could lead to sinus node dysfunction, sick sinus syndrome, atrial standstill and Purkinje fiber system disease, but the interaction and electrophysiological mechanism in double mutations were unknown. Interestingly, not all double mutations or multiple mutations would aggravate the clinical phenotype.…”

Section: Phenotypes Associated With Compound Mutations Of the Scn5a Gmentioning

confidence: 99%

More Severe Loss-of-Function Sodium Channel induced by Compound SCN5A R965C and R1309H Mutants lead to Complex Familial Arrhythmia Syndrome

Lin

Qin

Shen

et al. 2019

Preprint

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Objective: A complex familial arrhythmia syndrome was identified in a Chinese Han family, characterized by sick sinus syndrome, progressive conduction block, atrial fibrillation, atrial standstill and Brugada syndrome. The underlying mechanism associated with the genetic mutation was investigated. Methods: Genetic analysis was conducted for probands in the coding and splicing regions of genes susceptible to cardiac arrhythmia diseases. The stable cell lines overexpressing wild-type (WT) or mutant SCN5A gene were generated in HEK293T cells and electrophysiological recordings were performed to evaluate the functional changes of mutant Na V 1.5 channels. Results: We identified a rare double R965C and R1309H mutations in Na V 1.5 channel, as a heterozygous and compound pattern, locating in the same chromosome.Compared to WT, a single mutation of R965C or R1309H, the compound mutations of R965C-R1309H most dramatically reduced the peak current of Na V 1.5 channel with testing potentials ranging from -35 mV to 25 mV. Notably, the maximal peak current of Na V 1.5 channel carrying R1309H only and R965C-R1309H mutations displayed significant decreases by 31.5% and 73.34%, respectively, compared to WT. Additionally, compared to single mutations of R965C or R1309H, the R965C-R1309H mutations resulted in more obviously depolarization-shifted activation and hyperpolarization-shifted inactivation, also caused most significantly changed time constant, V 1/2 and slope factor of activation and inactivation. Conclusions:The compound mutations of R965C-R1309H led to more dramatically reduced current density of Na v 1.5 channel, as well as more depolarization-shifted activation and hyperpolarization-shifted inactivation than single mutation of R965C or R1309H, which may provide more understanding on the molecular mechanisms underlying the familial arrhythmia syndrome. Author summarySeveral limited types of research about the interaction of compound mutations and the mechanism of interaction remains controversial. Here we report a novel compound mutation R965C-R1309H in SCN5A gene.The compound mutations of R965C-R1309H markedly reduced the Na + current density of Na v 1.5 channel and caused significant depolarization-shifted activation and hyperpolarization-shifted inactivation, suggesting that R965C mutation aggravated the pore gating changes of sodium channel containing R1309H mutation. The R965C located in the S4-like region in the intracellular loop between DII and DIII, and the R1309H located in the S4 helix of DIII as voltage sensor, which thus potentially had synergistic and interacting effects on pore gating properties of the sodium channel. Additionally, the complex familial arrhythmia syndrome simultaneously complicated of early young onset of arrhythmia and harmful prognosis of recurrent ischemic cerebral stroke, even though effective Warfarin anticoagulation. overlap syndrome, heritable/familial arrhythmia syndrome or SCN5A syndrome induced by a single or several SCN5A mutations.Here, we report a Han Chinese family presen...

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Compound Heterozygous Mutations in the SCN5A-Encoded Nav1.5 Cardiac Sodium Channel Resulting in Atrial Standstill and His-Purkinje System Disease

Cited by 19 publications

References 9 publications

Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel

Evaluation of the Genetic Basis of Familial Aggregation of Pacemaker Implantation by a Large Next Generation Sequencing Panel

SCN5A Variants: Association With Cardiac Disorders

More Severe Loss-of-Function Sodium Channel induced by Compound SCN5A R965C and R1309H Mutants lead to Complex Familial Arrhythmia Syndrome

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