[Diagnostic criteria for the Brugada syndrome: can they be improved?]

Diagnosis of Brugada syndrome (BS) currently requires documentation of a characteristic repolarization pattern (type 1 Brugada ECG). Mutations in the SCN5A gene, which codes for sodium channel Na(v) 1.5, are found in 38% of familial cases of BS. Sodium current dysfunction negatively affects the cardiac fast response action potential, particularly in atrial and ventricular myocytes and in the fast-conducting Purkinje system.

To detect carriers of SCN5A mutations without using the characteristic repolarization pattern (type 1 Brugada ECG).

Of a total of 141 members of three different families including 55 carriers of two nonsense SCN5A mutations causing BS, all those aged over 16 (113 individuals, 42 carriers) were studied. The PR interval (PR) and QT dispersion (QTd) between leads V1 and V3 were measured on conventional ECG. Using signal-averaged ECG the total duration of the filtered QRS complex (fQRS), the root-mean-square (RMS40) and the low-amplitude signal (LAS) were measured. The following procedures were developed to detect carriers/To detect carriers the following procedures were developed: (1) a screening test (ScreenTest) with PS (PR+fQRS) > or = 250 (250ms is 80% of the theoretical maximum in healthy individuals); and (2) a diagnostic test (DiagTest) for the simultaneous fulfillment of four conditions: PS > or = 250 and QTd > or = 10 and LAS > 26 and RMS40 < or = 29 (the latter two cut-offs are approximately 70% of the theoretical maximum in healthy carriers).

Significant differences in PR, QTd, QRSf, RMS40 and LAS were found between carriers and non-carriers. The SCN5A gene was associated with all these variables, the strongest association being with PR. Both tests were applied to 63 family members (38 carriers). The ScreenTest was positive in 38 of 38 carriers, with eight false positives in 27 non-carriers (sensitivity [SE] = 100% and specificity [SP] = 66.67%). From ROC curve analysis a cut-off of PS = 252.5 shows SE = 100% and SP = 76% and a cut-off of PS = 260 shows SE=94.7% and SP = 84%. The DiagTest was positive in 36 of 38 carriers, with three false positives: SE = 94.74% and SP = 88.89%. From ROC curve analysis a multivariate logistic model identifies a cut-off with SE = 92% and SP = 92%. In the same group the SE and SP of the characteristic spontaneous repolarization pattern (type 1 Brugada ECG) to detect carriers were 52.4% and 97.2%, respectively, and the difference between the SE of the DiagTest and of the typical repolarization pattern is statistically significant.

The ScreenTest and DiagTest are more effective tools than the characteristic repolarization pattern to discriminate between carriers and non-carriers of these two nonsense SCN5A mutations. We suggest their use in first-degree relatives of Brugada patients when the results of genetic testing are not available, in a score of disease probability in individuals with idiopathic Brugada ECG, and in patients with arrhythmias or other Brugada-related symptoms presenting type 2 or type 3 Brugada ECG.