ORPHA: 130; DO: 0110221;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 10p12.33-p12.31 | Brugada syndrome 4 | 611876 | Autosomal dominant | 3 | CACNB2 | 600003 |
A number sign (#) is used with this entry because of evidence that Brugada syndrome-4 (BRGDA4) is caused by heterozygous mutation in the gene encoding the beta-2 subunit of the voltage-dependent L-type calcium channel (CACNB2; 600003) on chromosome 10p12.
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 the genetic heterogeneity in Brugada syndrome, see BRGDA1 (601144).
Antzelevitch et al. (2007) described a 25-year-old white male of European descent who presented with aborted sudden cardiac death and had a QTc of 330 ms on ECG, with coved-type ST segment elevation in V1 and V2 after ajmaline challenge. His 23-year-old brother had a 2-year history of syncope, but the rest of the family was asymptomatic. Programmed atrial stimulation induced atrial fibrillation in both brothers, and AV nodal reentrant tachycardia in the younger one. Ten family members were evaluated, and 6 were classified as phenotype-positive based on the presence of ST segment elevation greater than or equal to 2 mm at baseline or after ajmaline and a shortened QTc (less than or equal to 360 ms in males or 370 ms in females).
Cordeiro et al. (2009) reported a 34-year-old man who had experienced 2 syncopal attacks. Following procainamide infusion, he was found to have an ST segment elevation in V1 and V2 and a QTc of 488 ms on ECG. Programmed electrical stimulation induced polymorphic ventricular tachycardia. The proband's father had died of a myocardial infarction at age 47.
In affected members of a family with Brugada syndrome and shortened QT intervals on ECG, who were negative for mutation in genes known to be associated with the Brugada and short QT (see SQT1; 609620) syndromes, Antzelevitch et al. (2007) identified heterozygosity for a mutation in the CACNB2 gene (S481L; 600003.0001). The mutation was present in all 6 phenotype-positive individuals and absent in 4 phenotype-negative family members and 400 ethnically matched control alleles.
In a 34-year-old man with Brugada syndrome, Cordeiro et al. (2009) identified a heterozygous missense mutation in the CACNB2 gene (T11I; 600003.0002).
Crotti et al. (2012) analyzed 12 Brugada syndrome susceptibility genes in 129 unrelated patients with possible or probable Brugada syndrome and identified SCN5A (600163) mutations in 21 (16.3%) of the patients; only 6 (4.6%) of the patients carried a mutation in 1 of the other 11 genes, including 2 asymptomatic patients with a type 1 Brugada syndrome ECG pattern who were each heterozygous for a putative pathogenic missense mutation in the CACNB2 gene (V340I and E499D, respectively).
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]
Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., Casis, O., Sanguinetti, M. C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E. P., Jr., and 11 others. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 115: 442-449, 2007. [PubMed: 17224476] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.106.668392]
Cordeiro, J. M., Marieb, M., Pfeiffer, R., Calloe, K., Burashnikov, E., Antzelevitch, C. Accelerated inactivation of the L-type calcium current due to a mutation in CACNB2b underlies Brugada syndrome. J. Molec. Cell. Cardiol. 46: 695-703, 2009. [PubMed: 19358333] [Full Text: https://doi.org/10.1016/j.yjmcc.2009.01.014]
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: implications for genetic testing. J. Am. Coll. Cardiol. 60: 1410-1418, 2012. [PubMed: 22840528] [Full Text: https://doi.org/10.1016/j.jacc.2012.04.037]