Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic  SCN1B  variants

Gray, Belinda; Hasdemir, Can; Ingles, Jodie; Aiba, Takeshi; Makita, Naomasa; Probst, Vincent; Wilde, Arthur A.M.; Newbury‐Ecob, Ruth; Sheppard, Mary N.; Semsarian, Christopher; Sy, Raymond W.; Behr, Elijah R.

doi:10.1016/j.hrthm.2018.03.015

Cited by 15 publications

(10 citation statements)

References 16 publications

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“…Voltage-gated sodium channel β1 subunits, encoded by SCN1B, play important roles in cardiac physiology. SCN1B variants are linked to human cardiac disease, including Brugada syndrome and atrial fibrillation, although recent work suggests that SCN1B may not be a monogenic cause of Brugada syndrome (36). Our previous work showed that Other ion channel proteins have been shown to participate in transcriptional regulation (30,(48)(49)(50)(51).…”

Section: Discussionmentioning

confidence: 99%

Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Bouza¹,

Edokobi²,

Hodges³

et al. 2021

JCI Insight

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Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. β1 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming α subunits. They also participate in cell-cell and cell-matrix adhesion, resulting in intracellular signal transduction, promotion of cell migration, calcium handling, and regulation of cell morphology. Here, we investigated regulated intramembrane proteolysis (RIP) of β1 by BACE1 and γ-secretase and show that β1 subunits are substrates for sequential RIP by BACE1 and γ-secretase, resulting in the generation of a soluble intracellular domain (ICD) that is translocated to the nucleus. Using RNA sequencing, we identified a subset of genes that are downregulated by β1-ICD overexpression in heterologous cells but upregulated in Scn1b -null cardiac tissue, which lacks β1-ICD signaling, suggesting that the β1-ICD may normally function as a molecular brake on gene transcription in vivo. We propose that human disease variants resulting in SCN1B LOF cause transcriptional dysregulation that contributes to altered excitability. Moreover, these results provide important insights into the mechanism of SCN1B -linked channelopathies, adding RIP-excitation coupling to the multifunctionality of sodium channel β1 subunits.

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Section: Discussionmentioning

confidence: 99%

Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Bouza¹,

Edokobi²,

Hodges³

et al. 2021

JCI Insight

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“…Furthermore, a study by Yuan and colleagues [49] identified the H162P mutation in the SCN1Bb gene in a BrS patient, and, extrapolating that mutation to in vitro studies, found that this mutation reduces the action potential amplitude and conduction velocity, creating an increased risk of ventricular arrhythmia. However, genotype-phenotype correlations in families with BrS and reported pathogenic SCN1B or SCN1Bb variants are lacking [48]. Additionally, studies report identifying variants in the SCN1B gene in BrS patients with low prevalence [90] and low evidence of pathogenicity [17].…”

Section: Sodium Channel Mutationsmentioning

confidence: 99%

Brugada Syndrome: Oligogenic or Mendelian Disease?

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70-85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant's frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype-phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

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“…Currently, a total of 23 genes have been implicated in Brugada syndrome (BrS1-BrS23), and the vast majority of them are very rare. 196 Clinically, the disease manifests with syncope or SD, predominantly in the third or fourth decade of life, with fever as a trigger for arrhythmias.…”

Section: Channelopathiesmentioning

confidence: 99%

The Brazilian Society of Cardiology and Brazilian Society of Exercise and Sports Medicine Updated Guidelines for Sports and Exercise Cardiology - 2019

Ghorayeb¹,

Stein²,

Daher³

et al. 2019

Arquivos Brasileiros De Cardiologia

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Lack of genotype-phenotype correlation in Brugada Syndrome and Sudden Arrhythmic Death Syndrome families with reported pathogenic SCN1B variants

Abstract: The lack of genotype-phenotype concordance among families, combined with the high frequency of previously reported mutations in the Genome Aggregation Database browser, suggests that SCN1B is not a monogenic cause of BrS or SADS.

Cited by 15 publications

References 16 publications

Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling

Brugada Syndrome: Oligogenic or Mendelian Disease?

The Brazilian Society of Cardiology and Brazilian Society of Exercise and Sports Medicine Updated Guidelines for Sports and Exercise Cardiology - 2019

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