Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes
Abstract
:1. Introduction
2. Results
2.1. SCN5A Mutation Analysis on TD and IDL Segments in BrS Patients at High Risk of SCD
2.2. Characterization of IDRs within IDLs in the NaV1.5 Channel
2.3. PTM Analysis
3. Discussion
4. Materials and Methods
4.1. Study Population and Clinical Data
4.2. Genetic Analysis and Mutation Classification
4.3. Assessment of Arrhythmogenic Substrates
4.4. Prediction of Protein Disorder
4.5. PTMs In Silico Prediction
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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SCN5A Variants in TD Domains (n = 27; 75%) | SCN5A Variants in IDL Domains (n = 9; 25%) | p Value | |
---|---|---|---|
Mutation prediction (benign%) | 3 (15) | 4 (44) | 0.0286 * |
Male, n (%) | 20 (74) | 4 (44) | 0.1024 |
Age (years) (mean ± SD) | 42.35 ± 12.08 | 39.77 ± 10.88 | 0.1772 |
Spontaneous type 1 pattern, n (%) | 7 (25) | 3 (33) | 0.6674 |
Family history of sudden death, n (%) | 6 (22) | 4 (44) | 0.1973 |
Aborted cardiac arrest, n (%) | 5 (18) | 1 (10) | 0.6055 |
Syncope, n (%) | 11 (40) | 7 (77) | 0.0026 * |
Spontaneous VT/VF requiring ICD therapy, n (%) | 13 (48) | 2 (22) | 0.1718 |
Atrial fibrillation, n (%) | 9 (33) | 6 (66) | 0.0789 |
Atrial flutter, n (%) | 1 (4) | 0 | 0.4008 |
QRS duration ≥ 120 ms, n (%) | 13 (48) | 2 (22) | 0.0865 |
f-QRSd (mean ± SD) | 127.4 ± 17.85 | 107.9 ± 17.42 | 0.0099 |
RMS40 (mean ± SD) | 15,482 ± 84.19 | 13,842 ± 10.33 | 0.3124 |
LAS40 (mean ± SD) | 49.29 ± 18.65 | 46.67 ± 15.52 | 0.9160 |
Substrate size baseline (cm2) | 9.042 ± 3.507 | 5.125 ± 4.824 | 0.0556 |
Potential duration baseline (ms) | 133.0 ± 46.43 | 109.3 ± 37.51 | 0.2809 |
Substrate size after ajmaline (cm2) | 20.29 ± 5.982 | 17.66 ± 9.131 | 0.5027 |
Potential duration after ajmaline (ms) | 231.0 ± 27.67 | 214.5 ± 21.03 | 0.0991 |
Protein | Length (AA) | N.of IDR | Average Prediction Score | N.of Disordered AA | Percentage of IDR |
---|---|---|---|---|---|
NaV1.1 | 2009 | 29 | 0.275 | 517 | 25.73 |
NaV1.2 | 2005 | 25 | 0.276 | 538 | 26.83 |
NaV1.3 | 2000 | 23 | 0.268 | 520 | 26 |
NaV1.4 | 1836 | 19 | 0.253 | 437 | 23.80 |
NaV1.5 | 2016 | 25 | 0.328 | 637 | 31.60 |
NaV1.6 | 1980 | 24 | 0.268 | 504 | 25.45 |
NaV1.7 | 1988 | 29 | 0.282 | 538 | 27.08 |
NaV1.8 | 1956 | 25 | 0.272 | 498 | 25.46 |
NaV1.9 | 1791 | 21 | 0.219 | 330 | 18.43 |
NaV | % Identity | D2 (aa 718–938) | IDR1 (aa 20–66) | IDR2 (aa 441–532) | IDR3 (aa 993–1111; 1125–1162) | IDR4 (aa 1932–1980) |
---|---|---|---|---|---|---|
NaV1.1 | 71.17 | 80.82 | 44.19 | 62.18 | 48.49 | 47.06 |
NaV1.2 | 71.95 | 81.74 | 47.73 | 58.10 | 53.50 | 57.58 |
NaV1.3 | 72.09 | 83.11 | 47.73 | 72.38 | 52.75 | 50.00 |
NaV1.4 | 73.92 | 82.65 | 55.00 | 38.89 | 46.68 | 55.56 |
NaV1.6 | 71.41 | 80.82 | 43.18 | 52.00 | 51.46 | 35.71 |
NaV1.7 | 70.16 | 79.00 | 46.51 | 52.82 | 40.79 | 53.12 |
NaV1.8 | 71.96 | 76.64 | 51.16 | 46.75 | 53.00 | 56.25 |
NaV1.9 | 63.24 | 69.71 | 57.14 | 53.12 | 36.60 | 16.00 |
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Tarantino, A.; Ciconte, G.; Ghiroldi, A.; Mastrocinque, F.; Micaglio, E.; Boccellino, A.; Negro, G.; Piccoli, M.; Cirillo, F.; Vicedomini, G.; et al. Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes. Int. J. Mol. Sci. 2023, 24, 16658. https://doi.org/10.3390/ijms242316658
Tarantino A, Ciconte G, Ghiroldi A, Mastrocinque F, Micaglio E, Boccellino A, Negro G, Piccoli M, Cirillo F, Vicedomini G, et al. Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes. International Journal of Molecular Sciences. 2023; 24(23):16658. https://doi.org/10.3390/ijms242316658
Chicago/Turabian StyleTarantino, Adriana, Giuseppe Ciconte, Andrea Ghiroldi, Flavio Mastrocinque, Emanuele Micaglio, Antonio Boccellino, Gabriele Negro, Marco Piccoli, Federica Cirillo, Gabriele Vicedomini, and et al. 2023. "Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes" International Journal of Molecular Sciences 24, no. 23: 16658. https://doi.org/10.3390/ijms242316658
APA StyleTarantino, A., Ciconte, G., Ghiroldi, A., Mastrocinque, F., Micaglio, E., Boccellino, A., Negro, G., Piccoli, M., Cirillo, F., Vicedomini, G., Santinelli, V., Anastasia, L., & Pappone, C. (2023). Challenges in Brugada Syndrome Stratification: Investigating SCN5A Mutation Localization and Clinical Phenotypes. International Journal of Molecular Sciences, 24(23), 16658. https://doi.org/10.3390/ijms242316658