ORPHA: 130; DO: 0110225;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 15q24.1 | Brugada syndrome 8 | 613123 | 3 | HCN4 | 605206 |
A number sign (#) is used with this entry because of evidence that Brugada syndrome-8 (BRGDA8) is caused by heterozygous mutation in the HCN4 gene (605206) on chromosome 15q24.
Brugada syndrome is characterized by an ST segment elevation in the right precordial electrocardiogram leads (so-called type 1 ECG) and a high incidence of sudden death in patients with structurally normal hearts. The syndrome typically manifests during adulthood, with a mean age of sudden death of 41 +/- 15 years, but also occurs in infants and children (summary by Antzelevitch et al., 2005).
For a discussion of genetic heterogeneity of Brugada syndrome, see BRGDA1 (601144).
Ueda et al. (2009) studied a 41-year-old man who had recurrent episodes of syncope at rest and whose electrocardiogram (ECG) showed saddleback ST segment elevation in leads V1 and V2, incomplete right bundle branch block, and QT intervals at the upper limit of normal. A 24-hour ECG revealed polymorphic ventricular tachycardia during sleep, and electrophysiologic study showed that ventricular fibrillation was reproducibly induced by programmed ventricular stimulation without drug provocation. The patient was diagnosed with Brugada syndrome, and an internal cardioverter defibrillator (ICD) was implanted. There was no family history of sudden cardiac death.
In a 41-year-old man with Brugada syndrome who was negative for mutation in the SCN5A gene (600163), Ueda et al. (2009) identified heterozygosity for a splice site mutation in the HCN4 gene (605206.0005) that was not found in 190 healthy controls.
Reclassified Variants
The S84L mutation (605206.0006) in the HCN4 gene has been reclassified as a variant of unknown significance. In a 64-year-old woman with Brugada syndrome, Crotti et al. (2012) identified a heterozygous missense mutation in the HCN4 gene (S84L; 605206.0006). The woman was 1 of 129 unrelated patients with possible or probable Brugada syndrome who were screened for mutation in 12 Brugada syndrome 'susceptibility genes.'
Antzelevitch, C., Brugada, P., Borggrefe, M., Brugada, J., Brugada, R., Corrado, D., Gussak, I., LeMarec, H., Nademanee, K., Perez Riera, A. R., Shimizu, W., Schulze-Bahr, E., Tan, H., Wilde, A. Brugada syndrome: report of the second consensus conference. Circulation 111: 659-670, 2005. Note: Erratum: Circulation 112: e74, 2005. [PubMed: 15655131] [Full Text: https://doi.org/10.1161/01.CIR.0000152479.54298.51]
Crotti, L., Marcou, C. A., Tester, D. J., Castelletti, S., Giudicessi, J. R., Torchio, M., Medeiros-Domingo, A., Simone, S., Will, M. L., Dagradi, F., Schwartz, P. J., Ackerman, M. J. Spectrum and prevalence of mutations involving BrS1- through BrS12-susceptibility genes in a cohort of unrelated patients referred for Brugada syndrome genetic testing. J. Am. Coll. Cardiol. 60: 1410-1418, 2012. [PubMed: 22840528] [Full Text: https://doi.org/10.1016/j.jacc.2012.04.037]
Ueda, K., Hirano, Y., Higashiuesato, Y., Aizawa, Y., Hayashi, T., Inagaki, N., Tana, T., Ohya, Y., Takishita, S., Muratani, H., Hiraoka, M., Kimura, A. Role of HCN4 channel in preventing ventricular arrhythmia. J. Hum. Genet. 54: 115-121, 2009. [PubMed: 19165230] [Full Text: https://doi.org/10.1038/jhg.2008.16]