SCN5A Nonsense Mutation and NF1 Frameshift Mutation in a Family With Brugada Syndrome and Neurofibromatosis

Micaglio, Emanuele; Monasky, Michelle M.; Ciconte, Giuseppe; Vicedomini, Gabriele; Conti, Manuel; Mecarocci, Valerio; Giannelli, Luigi; Giordano, Federica; Pollina, Alberto; Saviano, Massimo; Crisà, Simonetta; Borrelli, Valeria; Ghiroldi, Andrea; D'Imperio, Sara; Resta, Chiara Di; Benedetti, Sara; Ferrari, Maurizio; Santinelli, Vincenzo; Anastasia, Luigi; Pappone, Carlo

doi:10.3389/fgene.2019.00050

Cited by 13 publications

(10 citation statements)

References 42 publications

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“…A total of 309 NF1 patients were selected on the basis of the inclusion and exclusion criteria and included in the study; 255 were recruited from the authors' institutions (92 with OPG and 163 without OPG) and 54 were retrieved from the recent literature (40 with OPG and 14 without OPG) [33][34][35][36][37][38][39][40][41]. One hundred and thirty-two patients were included in the NF1 OPG group (61 females, 57 males; the sex of 14 patients retrieved from the literature was not reported) and 177 in the NF1 non-OPG group (91 females, 76 males; 10 unknown).…”

Section: Resultsmentioning

confidence: 99%

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Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Melloni

Eoli

Cesaretti

et al. 2019

Cancers

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The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring NF1 mutations in the 5’ tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of NF1 mutation with the development of OPG was analysed using the χ2 test and Fisher’s exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni’s correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype–phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.

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Section: Resultsmentioning

confidence: 99%

“…The literature review allowed us to select 54 patients; there were more patients in the OPG group (40) than in the non-OPG group (14) [33][34][35][36][37][38][39][40][41].…”

Section: Literature Reviewmentioning

confidence: 99%

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Melloni

Eoli

Cesaretti

et al. 2019

Cancers

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“…Given the uncertain significance of many variants found in BrS patients, including the variability between people with the same variant and the lack of functional studies in most cases, recent studies have focused on understanding the phenotypic effect of individual variants within the SCN5A gene [16,19,28,42,43,77,79,80], as well as the search for additional genes involved in this multi-causative pathology [32,77,[81][82][83]. As previously mentioned, one such study demonstrated the similarity in phenotype between patients harboring SCN10A variants, as opposed to SCN5A variants, including personal history of cardiac arrest/syncope, spontaneous BrS electrocardiogram pattern, family history of sudden death, and arrhythmic substrate [77].…”

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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“…Novel mutations in the SCN5A gene and their likely causative role in BrS have been of recent interest [9][10][11][12][13][14][15], as well as new candidate genes [13,16,17]. Most studies have reported autosomal dominant inheritance with incomplete penetrance [18][19][20], with a few suggesting a recessive or X linked inheritance [21,22] and a possible involvement of mitochondrial mutations [23].…”

Section: Introductionmentioning

confidence: 99%

Novel SCN5A p.V1429M Variant Segregation in a Family with Brugada Syndrome

Monasky

Micaglio

Ciconte

et al. 2020

IJMS

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Brugada syndrome (BrS) is diagnosed by the presence of an elevated ST-segment and can result in sudden cardiac death. The most commonly found mutated gene is SCN5A, which some argue is the only gene that has been definitively confirmed to cause BrS, while the potential causative effect of other genes is still under debate. While the issue of BrS genetics is currently a hot topic, current knowledge is not able to result in molecular confirmation of over half of BrS cases. Therefore, it is difficult to develop research models with wide potential. Instead, the clinical genetics first need to be better understood. In this study, we provide crucial human data on the novel heterozygous variant NM_198056.2:c.4285G>A (p.Val1429Met) in the SCN5A gene, and demonstrate its segregation with BrS, suggesting a pathogenic effect. These results provide the first disease association with this variant and are crucial clinical data to communicate to basic scientists, who could perform functional studies to better understand the molecular effects of this clinically-relevant variant in BrS.

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SCN5A Nonsense Mutation and NF1 Frameshift Mutation in a Family With Brugada Syndrome and Neurofibromatosis

Cited by 13 publications

References 42 publications

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype–Phenotype Correlations in a Large Independent Cohort

Brugada Syndrome: Oligogenic or Mendelian Disease?

Novel SCN5A p.V1429M Variant Segregation in a Family with Brugada Syndrome

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