Systematic re‐evaluation of <i>SCN5A</i> variants associated with Brugada syndrome

Denham, Nathan; Pearman, Charles M.; Ding, Wern Yew; Waktare, Johan; Gupta, Dhiraj; Snowdon, Richard; Hall, Mark; Cooper, Robert; Modi, Simon; Todd, Derick; Mahida, Saagar

doi:10.1111/jce.13740

Cited by 47 publications

(69 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We used WES to identify potential candidate gene in incident SUDEP cases and we found a new, rare, harmful variant in SCN5A , absent in epilepsy and non-epilepsy controls. Other variants in SCN5A were previously reported in SUDEP cases,7 12 and potentially predisposing to malignant cardiac arrhythmia 15–17. We also identified two rare qualified variants in KIF6 and TBX16 (previously associated with heart diseases), also absent in epilepsy and non-epilepsy controls.…”

Section: Discussionsupporting

confidence: 63%

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

Ding

Zhu

et al. 2019

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

ObjectiveSudden unexpected death in epilepsy (SUDEP) is a leading cause of epilepsy-related mortality in young adults. It has been suggested that SUDEP may kill over 20 000 people with epilepsy in China yearly. The aetiology of SUDEP is unclear. Little is known about candidate genes for SUDEP in people of Chinese origin as most studies have ascertained this in Caucasians. No candidate genes for SUDEP in Chinese people have been identified.MethodsWe performed whole exome sequencing (WES) in DNA samples collected from five incident cases of SUDEP identified in a large epilepsy cohort in rural China. We filtered rare variants identified from these cases as well as screened for SUDEP, epilepsy, heart disease or respiratory disease-related genes from previous published reports and compared them with publicly available data, living epilepsy controls and ethnicity-match non-epilepsy controls, to identify potential candidate genes for SUDEP.ResultsAfter the filtering process, the five cases carried 168 qualified mutations in 167 genes. Among these genetic anomalies, we identified rare variants in SCN5A (1/5:20% in our cases), KIF6 (1/5:20% in our cases) and TBX18 (1/5:20% in our cases) which were absent in 330 living epilepsy control alleles from the same original cohort and 320 ethnicity-match non-epilepsy control alleles.ConclusionsThese three genes were previously related to heart disease, providing support to the hypothesis that underlying heart disorder may be a driver of SUDEP risk.

show abstract

Section: Discussionsupporting

confidence: 63%

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

Ding

Zhu

et al. 2019

J Neurol Neurosurg Psychiatry

View full text Add to dashboard Cite

show abstract

“…Concerning IAS, Smith et al reported a reclassification after one year of 3% of rare variants [25]. In 2018, a reclassification of rare variants previously considered deleterious in Brugada Syndrome was performed; only 37% were classified as P or LP following current ACMG recommendations [8]. A recent study identified a modification in 52% of rare variants classified as VUS seven years ago [10].…”

Section: Discussionmentioning

confidence: 99%

Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

et al. 2020

View full text Add to dashboard Cite

A B S T R A C TBackground: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings. Methods: In 2010, the rare variants identified through genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations. Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 postmortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance. Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment.

show abstract

“…It is assumed that 25–30% of BrS cases have P variants in SCN5A. However, two recently published re‐evaluations of all SCN5A variants reported in BrS concluded that only 37–47% should remain classified as P/LP for BrS (Denham et al, ; Kroncke et al, ).…”

Section: Discussionmentioning

confidence: 99%

“…ID represents the identifier number of a gene. | 761 remain classified as P/LP for BrS (Denham et al, 2018;Kroncke et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…In 2015, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) published guidelines for the genetic interpretation of rare variants (Richards et al, ). Recently, two systematically re‐evaluations of all reported SCN5A variants in BrS concluded that only 37–47% of identified variants remain classified as pathogenic/likely pathogenic for BrS after incorporation of the ACMG/AMP guidelines (Denham et al, ; Kroncke, Glazer, Smith, Blume, & Roden, ). However, no comprehensive assessment of other genes currently associated with BrS has been published thus far.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Genetic interpretation and clinical translation of minor genes related to Brugada syndrome

et al. 2019

View full text Add to dashboard Cite

Brugada syndrome (BrS) is an inherited arrhythmogenic disease associated with sudden cardiac death. The main gene is SCN5A. Additional variants in 42 other genes have been reported as deleterious, although these variants have not yet received comprehensive pathogenic analysis. Our aim was to clarify the role of all currently reported variants in minor genes associated with BrS. We performed a comprehensive analysis according to the American College of Medical Genetics and Genomics guidelines of published clinical and basic data on all genes (other than SCN5A) related to BrS. Our results identified 133 rare variants potentially associated with BrS. After applying current recommendations, only six variants (4.51%) show a conclusive pathogenic role. All definitively pathogenic variants were located in four genes encoding sodium channels or related proteins: SLMAP, SEMA3A, SCNN1A, and SCN2B. In total, 33.83% of variants in 19 additional genes were potentially pathogenic. Beyond SCN5A, we conclude definitive pathogenic variants associated with BrS in four minor genes. The current list of genes associated with BrS, therefore, should include SCN5A, SLMAP, SEMA3A, SCNN1A, and SCN2B. Comprehensive genetic interpretation and careful clinical translation should be done for all variants currently classified as potentially deleterious for BrS.

show abstract

Systematic re‐evaluation of SCN5A variants associated with Brugada syndrome

Abstract: Based on contemporary ACMG-AMP guidelines, only a minority of SCN5A variants implicated in BrS fulfill the criteria for pathogenicity or likely pathogenicity.

Cited by 47 publications

References 40 publications

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

Genetic variants in incident SUDEP cases from a community-based prospective cohort with epilepsy

Reanalysis and Reclassification of Rare Genetic Variants Associated with Inherited Arrhythmogenic Syndromes

Genetic interpretation and clinical translation of minor genes related to Brugada syndrome

Contact Info

Product

Resources

About