Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome

Denti, Federico; Bentzen, Bo Hjorth; Wojciak, Julianne; Thomsen, Nancy Mutsaers; Scheinman, Melvin M.; Schmitt, Nicole

doi:10.1111/pace.13328

Cited by 5 publications

(8 citation statements)

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“…Mutations in SCN5A are also causative of sudden infant death syndrome [438][439][440][441][442][443][444] as well as in channel ancillary subunits [445][446][447][448]. It is assumed that, as in the case of Brugada syndrome, an SCN5A/Na v 1.5 loss-of-function underlies sudden infant death.…”

Section: Sudden Infant Death Syndromementioning

confidence: 99%

“…It is assumed that, as in the case of Brugada syndrome, an SCN5A/Na v 1.5 loss-of-function underlies sudden infant death. In this context, Tan et al [446] described SCN3B and SCNB4 mutations that decreased peak I Na current but increased I NaL , whereas Neubauer et al [412] and Denti et al [447] identified a novel SCN1B mutations that decreased I Na density, providing thus plausible electrophysiological mechanisms underlying sudden infant death syndrome. Importantly SCN5A mutations in SIDS have also been identified in conjunction with other electrophysiological disorders, such as Brugada syndrome [356].…”

Section: Sudden Infant Death Syndromementioning

confidence: 99%

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Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

Daimi

Lozano-Velasco

Aránega

et al. 2022

IJMS

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Nav1.5 is the predominant cardiac sodium channel subtype, encoded by the SCN5A gene, which is involved in the initiation and conduction of action potentials throughout the heart. Along its biosynthesis process, Nav1.5 undergoes strict genomic and non-genomic regulatory and quality control steps that allow only newly synthesized channels to reach their final membrane destination and carry out their electrophysiological role. These regulatory pathways are ensured by distinct interacting proteins that accompany the nascent Nav1.5 protein along with different subcellular organelles. Defects on a large number of these pathways have a tremendous impact on Nav1.5 functionality and are thus intimately linked to cardiac arrhythmias. In the present review, we provide current state-of-the-art information on the molecular events that regulate SCN5A/Nav1.5 and the cardiac channelopathies associated with defects in these pathways.

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Section: Sudden Infant Death Syndromementioning

confidence: 99%

Section: Sudden Infant Death Syndromementioning

confidence: 99%

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

Daimi

Lozano-Velasco

Aránega

et al. 2022

IJMS

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“…None had a history of cardiac arrhythmia or other cardiac presentation prior to death. While SCN1A [9,27], SCN1B [12,[35][36][37], and SCN5A [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Our literature review found 74 variants in 99 patients with SIDS, SIDS-like presentations, or SUDC affecting 72 different amino acid positions in a VGSC-related gene. 55/75 variants were present in SCN5A, reflecting in some cases the fact that this gene was specifically targeted in some series [13][14][15][16]20,21,24,46].…”

Section: Variant Position and Pathogenicitymentioning

confidence: 99%

“…The tissue-specific expression profiles of α-subunits and β-subunits are shown in Table 1. Variants in the cardiac-expressed SCN5A [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] gene are reported most frequently in association with SIDS and SUDC, but variants in SCN1A [9,27], SCN4A [34], SCN10A [35], SCN1B [12,[35][36][37][38], SCN3B [15,39] and SCN4B [39] have also for use under a CC0 license. This article is a US Government work.…”

Section: Introductionmentioning

confidence: 99%

The role of sodium channels in sudden unexpected death in pediatrics

Rochtus

Goldstein

Holm

et al. 2018

Preprint

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We performed a candidate gene analysis for genes encoding sodium channel subunits in whole exome sequencing (WES) data from 73 SUDP patients. After a thorough literature review, we mapped all reported SUDP-associated sodium channel variants alongside variants from the population on a structural protein model to evaluate whether patient variants clustered in important protein domains compared to controls.In our cohort, 13 variants met criteria for pathogenicity or potential pathogenicity. While SCN1A, SCN1B, and SCN5A have established disease associations, we also considered variants in the paralogs SCN3A, SCN4A and SCN9A. Overall, the patient-associated variants clustered at conserved amino acid sites across the sodium channel gene family that do not tolerate variation in these genes.for use under a CC0 license.This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available (which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/383562 doi: bioRxiv preprint first posted online 3 This study provides a molecular overview of sodium channel variants present in cases with SUDP and reveals key amino acid sites that do not tolerate variation across the SCN paralog family. Further research will lead to an improved understanding of the contribution of sodium channels to SUDP, with a goal of one day implementing prevention strategies to avoid untimely deaths in at-risk children. Author SummaryThe sudden unexplained death of an infant or a child is a tragic event, which is likely caused by the complex interaction of multiple factors. Besides environmental factors, genes related to epilepsy and cardiac arrhythmia have been identified as risk factors.The sodium channel family encompasses genes, related to both cardiac arrhythmia as well as epilepsy, whose proteins share structural homology. We evaluated sodium channel gene variants in our cohort, examined all known variants in sodium genes in SUDP patients from the literature, and mapped patient variants alongside variants from the population on a 3D protein model. The patient variants clustered at conserved amino acid sites with low rates of variation in the general population, not only in the particular gene involved but also in the gene family. This study illustrates that sodium channel variants contribute to the complex phenotype of sudden death in pediatrics, suggesting complex mechanisms of neurologic and/or cardiac dysfunction contributing to death.

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“…Variants in the cardiac‐expressed gene SCN5A (Arnestad et al., 2007; Baruteau et al., 2017; Glengarry et al., 2014; Kato et al., 2014; Millat et al., 2009; Otagiri et al., 2008; Plant et al., 2006; Priori et al., 2000; Tester & Ackerman, 2005; Turillazzi et al., 2008; Wang et al., 2014; Wedekind et al., 2001; Winkel et al., 2015) have been reported in association with SIDS and SUDC. Variants in other VGSCs are only rarely identified in cases with SIDS and SUDC: SCN1A (Brownstein et al., 2018; Halvorsen et al., 2016), SCN4A (Männikkö et al., 2018), SCN10A (Neubauer et al., 2017) , SCN1B (Altshuler et al., 2012; Baruteau et al., 2017; Denti, n.d.; Hu et al., 2012; Neubauer et al., 2017), SCN3B (Tan et al., 2010; Winkel et al., 2015) , and SCN4B (Tan et al., 2010). Variants in epilepsy‐associated VGSC genes expressed in the central nervous system have also been associated with SUDEP: SCN1A (Cooper et al., 2016; Gal et al., 2010), SCN2A (Howell et al., 2015; Myers et al., 2018) , and SCN8A (Johannesen et al., 2018; Myers et al., 2018; Veeramah et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

The role of sodium channels in sudden unexpected death in pediatrics

Rochtus

Goldstein

Holm

et al. 2020

Molec Gen & Gen Med

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Background Sudden Unexpected Death in Pediatrics (SUDP) is a tragic event, likely caused by the complex interaction of multiple factors. The presence of hippocampal abnormalities in many children with SUDP suggests that epilepsy‐related mechanisms may contribute to death, similar to Sudden Unexplained Death in Epilepsy. Because of known associations between the genes SCN1A and SCN5A and sudden death, and shared mechanisms and patterns of expression in genes encoding many voltage‐gated sodium channels (VGSCs), we hypothesized that individuals dying from SUDP have pathogenic variants across the entire family of cardiac arrhythmia‐ and epilepsy‐associated VGSC genes. Methods To address this hypothesis, we evaluated whole‐exome sequencing data from infants and children with SUDP for variants in VGSC genes, reviewed the literature for all SUDP‐associated variants in VGSCs, applied a novel paralog analysis to all variants, and evaluated all variants according to American College of Medical Genetics and Genomics (ACMG) guidelines. Results In our cohort of 73 cases of SUDP, we assessed 11 variants as pathogenic in SCN1A, SCN1B, and SCN10A , genes with long‐standing disease associations, and in SCN3A, SCN4A, and SCN9A , VGSC gene paralogs with more recent disease associations. From the literature, we identified 82 VGSC variants in SUDP cases. Pathogenic variants clustered at conserved amino acid sites intolerant to variation across the VGSC genes, which is unlikely to occur in the general population ( p < .0001). For 54% of variants previously reported in literature, we identified conflicting evidence regarding pathogenicity when applying ACMG criteria and modern population data. Conclusion We report variants in several VGSC genes in cases with SUDP, involving both arrhythmia‐ and epilepsy‐associated genes. Accurate variant assessment as well as future studies are essential for an improved understanding of the contribution of sodium channel‐related variants to SUDP.

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Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome

Abstract: Genetic variation of both sodium channel and its modifiers may contribute to sudden unexplained death in childhood. However, the asymptomatic father suggests that genetic variation of these genes is not sufficient to cause sudden death or clinically detectable SCN5A phenotypes.

Cited by 5 publications

References 50 publications

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

Genomic and Non-Genomic Regulatory Mechanisms of the Cardiac Sodium Channel in Cardiac Arrhythmias

The role of sodium channels in sudden unexpected death in pediatrics

The role of sodium channels in sudden unexpected death in pediatrics

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