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Brugada Syndrome - epidemiology, genetics and electrocardiography

Anders Niemann

Summary

Brugada syndrome (BrS) was first described in 1992, and is a rare, inherited primary arrhythmia syndrome. That is, a syndrome characterized by the occurrence of malignant ventricular arrhythmias in a structural normal heart. 

BrS patients are typically males diagnosed in their forties and many seem to remain asymptomatic during followup. The arrhythmias and/or sudden cardiac often occur during rest or sleep, whereas exercise does not seem to be a precipitating factor. The syndrome is first and foremost characterized by ECG changes in the right precordial leads (V1‐3). 

This aims of this thesis were: 

1. Characterize the BrS population in Denmark 

2. Examine the genetic basis of BrS

3. Investigate elevated electrode placement ECG recording as a diagnostic tool in BrS 

1.1 BrS population in Denmark We aimed to do a nationwide study of Brugada Syndrome patients using four different modalities to identify all diagnosed patients in Denmark. A total of 43 definite BrS patients and 25 possible BrS patients were identified. We found a low incidence of BrS (1.1 per 100,000) compared to estimates from ECG surveys. Follow‐up data show a much lower rate of inappropriate therapies in ICD carriers than previous studies.

1.2 Genetic basis of BrS Three different studies were performed. In the first we screened the gene MOG1 in 220 patients with AF and BrS and uncovered one non‐synonymous polymorphism, namely a novel heterozygous nonsense variant, c.181G>T (p.E61X, premature stop codon). The variant was present in both patients and control subjects, albeit at a seeming higher frequency in patients than in controls (nonsignificant, P= 0.078). Also, the variant eliminates the sodium current–increasing effect of wild‐type MOG1, thus possibly conferring a loss of function of the sodium current. This indicates that MOG1 may act as a modifier of arrhythmic disease but is unlikely to be the cause of monogenetic syndromes such as BrS. 

Furthermore we screened 42 Danish and Iranian BrS SCN5A negative patients for mutations in SCN1 4B, MOG1, CAV3 and KCND3. In SCN1Bb we found two variants, however only one is possibly disease causing. No other mutations were found and among other data, recently released exome sequencing data, make some of the prior associations of BrS with genes SCN3B, MOG1 and KCND3 less likely. 

Finally we reported a SCN5A mutation causing a wide spectrum of severe phenotypes presenting early in life in the proband, but only mildly affecting his father and perhaps the spectrum of SCN5A loss‐of‐function associated disease entities should be viewed as one syndrome. As such doctors should be vigilant towards the other potential phenotypes in a patient carrying a SCN5A mutation. Version 1.1 Brugada Syndrome  

1.3 Elevated electrode placement ECG Right precordial (V1‐3) elevated electrode placement ECG (EEP‐ECG) is often used in the diagnosis of Brugada syndrome (BrS). However, the specificity of this has only been studied in smaller studies in Asian populations. We aimed to study this in a larger European population. 

Two different populations consisting of healthy subjects where used. A total of 340 subjects were included, 80% were men, the median age was 43 year (interquartile range: 31‐51) and all were of European ethnicity. 

No type 1 ECG patterns were identified but 16 (4.7%) subjects with a type 2 ECG and 32 (9.4%) subjects with a type 3 ECG were identified in any lead placement. 

Elevated electrode placement ECG in the diagnosis of BrS seems to have a very high specificity with regards to the finding of a type 1 ECG pattern in a European population; conversely a finding of a type 2 or 3 pattern is of a significantly lower specificity and should perhaps be disregarded.