| Summary: | 博士 === 國立臺灣大學 === 生理學研究所 === 107 === Brugada syndrome (BrS) is an inheritable arrhythmic disease with a hereditary pattern of autosomal dominance, which could cause ventricular fibrillation and lead to sudden death. It accounts for 4% of sudden cardiac death (SCD). It has the highest prevalence in the Southeast Asia, about 0.12%, and it is also not uncommon in Taiwan. In order to prevent the tragedy, the prevalence and characteristics of the patients with BrS in Taiwan should be investigated, as well as identification of the high-risk population.
The mean age of SCD attributed to BrS is around 40 years old. Thus, risk stratification in the young patients should be done aggressively, and implantable cardioverter-defibrillator (ICD) may prevent SCD in high-risk population. However, it is unclear that if the elderly patients also have the risk of SCD, and if an aggressive attitude is still necessary. In a cohort of 5,214 apparently healthy elders (mean 69.3 years old), I found 4 participants (0.077%) with typical type 1 Brugada electrocardiographic pattern (BrP), and the elders with BrP by either the criteria from HRS/EHRA/APHRS or ISHNE didn''t have a higher mortality rate than those without BrP in the 4-year follow-up. It seems that BrP in the apparently healthy elders is relatively benign.
Furthermore, most patients with BrS are male (male : female = 9 : 1), which is thought to be related to the impact of sexual hormones on the ion channels, and I am interested that if it may also have a prognostic effect in female BrS. Because of the male predominance, most of the past studies reflected the characteristics of male BrS, which could not apply on the female BrS. Therefore, I tried to compare the gender differences of BrS in Taiwan. Although there was no difference in the risk of SCD or syncope between genders, females suffered from syncope earlier than males and had a longer QTc, and the percentage of family history of SCD in females was slightly higher than males. Besides, the females with SCD or syncope had a slightly slower heart rate than those with no or mild symptom. As a result, female BrS deserves more medical attention, especially the female patients with low heart rate, and the potential patients among their family members should be discovered.
Because of the heritability of BrS, it is necessary to do family screening in order to find out the potential patients and prevent SCD. Along with electrocardiograms, genetic screening is of class I recommendation, and the way to determine the pathogenicity of a variant is crucial. Currently, the most relevant gene is SCN5A, and several disease databases including ClinVar and HGMD (the Human Gene Mutation Database) analyzed the pathogenicity of the variants reported before. As the technique of sequencing improves and becomes available, the allele frequency of a variant among many areas and countries could be obtained via internet, and it is evident that there is the genetic diversity among ancestries. I found that several previously reported pathogenic rare variants were relative common in some ancestries, especially non-SCN5A variants, whose pathogenicity should be reassessed. This finding emphasized the importance of the large-scaled reference in every ancestry, and the allele frequencies of a variant in different ancestries should be taken into account when determining its pathogenicity.
Although SCN5A is currently the most relevant gene in BrS, there were only 16.5% of Taiwanese patients with BrS having SCN5A causative variants according to my study. It is of great value in family screening if other relevant genes could be found. However, several genes reported to be associated with BrS are still controversial. SCN10A is a relevant gene appealing many attentions in these years, which could interact with SCN5A and influence the sodium current. I used the SKAT-O algorithm and found that rare variants (allele frequencies < 1%) of SCN10A were significantly enriched in the BrS patients, which implied the pathogenic role in BrS in Taiwan. Moreover, there were 3.4% of the patients having SCN10A causative variants, which was not uncommon and deserved for screening.
According to the above findings, I provided the characteristics and prognosis of the elderly and female patients with BrS in Taiwan, and revealed the importance of allele frequencies of a variant among the thorought ancestries when judging its pathogenicity. Besides, SCN10A has an important role in BrS, and it should be included in the screening panel and deserves further investigation for the mechanism of pathogenesis.
|
|---|
