ORPHA: 130; DO: 0110220;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12p13.33 | Brugada syndrome 3 | 611875 | Autosomal dominant | 3 | CACNA1C | 114205 |
A number sign (#) is used with this entry because of evidence that Brugada syndrome-3 (BRGDA3) is caused by heterozygous mutation in the gene encoding the alpha-1C subunit of the L-type voltage-dependent calcium channel (CACNA1C; 114205) on chromosome 12p13.
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 of Brugada syndrome, see BRGDA1 (601144).
Antzelevitch et al. (2007) reported 2 probands with Brugada syndrome who also had shortened QT intervals on ECG. One was a 41-year-old man of Turkish descent who presented with atrial fibrillation and a QTc of 346 ms. Ajmaline administration led to further elevation of the ST segments in leads V1 to V2, and monomorphic ventricular tachycardia was inducible. The patient had a brother who died of cardiac arrest at 45 years of age, and 2 daughters with QTc intervals of 360 and 373 ms, respectively. The other proband was a 44-year-old man of European descent who had prominent ST segment elevation in V1, saddleback ST segment elevation in V2, a prominent J wave in lead III, and a QTc of 360 ms; he was also recently diagnosed with facioscapulohumeral muscular dystrophy (see 158900). His mother had 2 syncopal episodes at age 48 that resulted in sudden cardiac death; his father, 2 sibs, and 3 children declined examination but reportedly did not exhibit the Brugada phenotype.
In 2 probands who had 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 mutation in the CACNA1C gene, G490R (114205.0003) and A39V (114205.0004), respectively. The 2 daughters of the Turkish proband with the G490R mutation also carried the mutation; the daughter with the longer QTc (373 ms) also had a known K897T polymorphism in the KCNH2 gene (152427).
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]