A novel familial SCN5A exon 20 deletion is associated with a heterogeneous phenotype

Kohli, Utkarsh; Sriram, Chenni S.; Nayak, Hemal M.

doi:10.1016/j.jelectrocard.2021.04.011

Cited by 4 publications

(7 citation statements)

References 24 publications

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“…The spontaneous type 1 ECG pattern appears to be a more frequent finding among SCN5A(+) probands, suggesting a more stable pattern of repolarization abnormalities in this group and increased arrhythmogenicity [ 28 , 29 ]. T-wave abnormalities have also been reported in conjunction with SCN5A gene mutations [ 30 , 31 ]. Whole-heart conduction disorder appears to be more severe in SCN5A(+) individuals, as evidenced by an increased PQ interval, QRS duration, and HV interval [ 28 , 32 ].…”

Section: Resultsmentioning

confidence: 99%

“…A majority of rare SCN5A variant carriers do not have BrS [ 7 , 60 ], while most BrS patients do not have SCN5A mutations [ 2 ]. Additionally, carriers of a specific SCN5A mutation may have different clinical phenotypes, as shown by the aggregation of various cardiac disorders within the same family and in cohorts with the same mutation [ 30 , 61 ]. Various members of a family may present with syncope, atrial fibrillation, sick sinus syndrome, or may be asymptomatic [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, carriers of a specific SCN5A mutation may have different clinical phenotypes, as shown by the aggregation of various cardiac disorders within the same family and in cohorts with the same mutation [ 30 , 61 ]. Various members of a family may present with syncope, atrial fibrillation, sick sinus syndrome, or may be asymptomatic [ 30 ]. In addition, it is possible to find atrioventricular conduction disorders, atrial standstill, sudden cardiac death, and others associated with the same mutation [ 31 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

“…Genetic etiology in BrS has important pathophysiological, clinical, and prognostic implications. There is increasing evidence that SCN5A(+) patients have a higher MAE rate and a more complex phenotype, with associated cardiac and systemic disorders [ 28 , 30 , 55 , 61 ]. Some of these may also be present in family members, with or without associated BrS [ 30 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

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The SCN5A Gene Is a Predictor of Phenotype Severity in Brugada Syndrome: A Comprehensive Literature Review

et al. 2022

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Objective: The purpose of this review is to ascertain whether patients with Brugada syndrome (BrS) having SCN5A mutations have a more severe clinical phenotype and prognosis than do patients without SCN5A mutations. Methods: A comprehensive Scopus database search was conducted; studies were selected by using Brugada syndrome and SCN5A as keywords for the main query. Results: The available literature consistently shows greater electrophysiological abnormalities in patients with Brugada syndrome having SCN5A-related etiology. These include conduction disorder evidenced by longer QRS, PQ and His-ventricular interval duration. Novel lines of evidence suggest that SCN5A mutations are predictors of malignant arrhythmic events. In addition, SCN5A-positive patients and their carrier relatives frequently suffer from various abnormal cardiac phenotypes such as sick sinus syndrome and progressive conduction disorder. Rare variants have also been shown to play a role in cases of epilepsy, hyperthyroidism, irritable bowel syndrome and malignancy. Conclusion: In this review, we show how the SCN5A mutation status predicts phenotypic characteristics and prognosis in patients with BrS. We conclude that SCN5A mutations weakly predict greater malignant arrhythmic event risk in BrS patients. However, SCN5A mutations do not show robust enough associations with severity indicators to be an independent part of current risk stratification strategies. With advancing knowledge of BrS genetics, the integration of data on rare variants of SCN5A and polygenic risk scores could make an impact on clinical decision making.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The SCN5A Gene Is a Predictor of Phenotype Severity in Brugada Syndrome: A Comprehensive Literature Review

et al. 2022

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“…Most of the women (77.6%) had good pregnancy outcomes, possibly because CNL in these subjects did not affect the functional region of the AD gene, partial exon deletion did not affect the protein integrity, loss of function was not the pathogenic mechanism of the disease, loss of function was at the 3’ terminal, or the gene had multiple transcripts [ 20 – 23 ]. In addition, certain autosomal dominant genetic diseases have incomplete penetrance, late onset age, and variable expressivity [ 24 – 26 ].…”

Section: Discussionmentioning

confidence: 99%

Analysis of autosomal dominant genes impacted by copy number loss in 24,844 fetuses without structural abnormalities

et al. 2022

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Background The broad application of high-resolution chromosome detection technology in prenatal diagnosis has identified copy number loss (CNL) involving autosomal dominant (AD) genes in certain fetuses. Exon sequencing of fetuses exhibiting structural anomalies yields diagnostic information in up to 20% of cases. However, there is currently no relevant literature about the genetic origin and pregnancy outcome of CNL involving AD genes in fetuses without structural abnormalities. Results This was a prospective study involving pregnant women who underwent amniocentesis for fetal copy number variation sequencing (CNVseq). Detection of parent-of-origin was suggested in cases of samples with CNL involving AD genes and the pregnancy outcome was monitored. Amniotic fluid samples from 24,844 fetuses without structural abnormalities were successfully tested via CNVseq. The results showed that 134 fetuses (0.5%) had small CNL (< 10 Mb) containing AD genes, after excluding microdeletion and microduplication syndrome and polymorphisms. By monitoring the pregnancy outcomes of the 134 fetuses, we found that 104 (77.6%) were good, 13 (9.7%) were adverse, and 17 (12.7%) pregnant women voluntarily chose to terminate pregnancy. Of the 13 fetuses with adverse pregnancy outcomes, only 2 fetuses had phenotypes consistent with those of diseases caused by AD genes involved in CNL. Conclusions The overall prognosis for fetuses without family history or structural abnormalities but with small CNL containing AD genes detected during pregnancy is good. The genetic origin, overlap status of established haploinsufficient gene and/or region, size of the CNL, and genetic mode may affect the pathogenicity of the CNL.

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Sinus node dysfunction and atrial fibrillation—Relationships, clinical phenotypes, new mechanisms, and treatment approaches

Duan

2023

Ageing Research Reviews

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A novel familial SCN5A exon 20 deletion is associated with a heterogeneous phenotype

Cited by 4 publications

References 24 publications

The SCN5A Gene Is a Predictor of Phenotype Severity in Brugada Syndrome: A Comprehensive Literature Review

The SCN5A Gene Is a Predictor of Phenotype Severity in Brugada Syndrome: A Comprehensive Literature Review

Analysis of autosomal dominant genes impacted by copy number loss in 24,844 fetuses without structural abnormalities

Sinus node dysfunction and atrial fibrillation—Relationships, clinical phenotypes, new mechanisms, and treatment approaches

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