Although SCN A variants account for of

Although SCN5A variants account for 18–28% of BrS [196], SCN5A genetic testing is complicated by an approximately 3–5% “benign” variant frequency in the general population [194]. Therefore, even in the most common genetic cause of BrS, 1 in 10 “positive” tests could be a “false- positive” even if found in an individual with a robust BrS phenotype. To date, there are more than 20 JWS susceptibility azilsartan medoxomil [146,195,197]. However, these additional genes have only magnified the issues of interpretation by adding to the overall “genetic noise” without significantly increasing the true mutation yield [178,198–200]. In fact, 1 study revealed that 1:23 individuals in the GO-ESP population possess a previously published BrS-associated variant that would prompt a “positive” genetic test had it been identified in a patient [201]. These issues reinforce the necessity to interpret JWS genetic test results as strictly probabilistic, rather than binary/deterministic, in nature. Additional lines of evidence [202] can be amassed to aid in the probabilistic interpretation of variants in JWS susceptibility genes, such as case phenotype [203], segregation, functional studies [204], in silico predictions [205–208], variant type and location [194], and variant frequency in cases and control databases [193]. Despite these aids, a large number of variants remain in “genetic purgatory,” and this number will only increase as exome/genome sequencing becomes more utilized. This then demands the development and utilization of a uniform variant repository that would include clinical assertions and evidence for variant classification. Even with these issues, the emergence of exome/genome sequencing holds promise for the opportunity to study genetic variation like never before, holding the promise of improvements in diagnostic, prognostic, and therapeutics for the JWSs and the other heritable cardiac channelopathies. Kapplinger et al. [209]. recently reported the synergistic use of up to 7 in silico tools to help promote or demote a variant׳s pathogenic status and alter its relegation to genetic purgatory. It is noteworthy that in a recent study, Le Scouarnec et al. [199]. estimated the burden of rare coding variation in arrhythmia susceptibility genes among 167 BrS index patients and compared that with 167 individuals ≥65 years old with no history of cardiac arrhythmia. The authors concluded that, except for SCN5A, rare coding variations in all previously reported BrS susceptibility genes do not contribute significantly to the occurrence of BrS in a population of European ancestry, emphasizing that caution should be taken when interpreting genetic variations in these other genes because rare coding variants are observed to a similar extent in both cases and controls [199]. Similar data were obtained and a similar conclusion was reached by Kapplinger et al. [209]. by analyzing the prevalence of rare variants in the BrS susceptibility genes in the publicly available ExAC exomes. Collectively, these data suggest the possibility that. in the individual patient, BrS and the susceptibility to VF and SCD may not be due to a single mutation (classic mendelian view) but rather to inheritance of multiple BrS susceptibility variants (oligogenic) acting in concert through one or more mechanistic pathways [167]. This also fits with the findings of Probst et al. [210] that in 5 of 13 large families with a putative SCN5A mutation, the genotype did not co-segregate with the phenotype. In addition to the multifactorial nature of the genetics, expressivity of the syndrome may be multifactorial in that the genetic predisposition can be modulated by hormonal (testosterone [211,212], thyroxine [213]) and other environmental factors, as well as morphologic changes (fibrosis) [76].
Update on the ionic and cellular mechanisms underlying BrS and ERS The JWSs are so named because they involve accentuation of the ECG J wave. Experimental evidence indicates that the J wave is inscribed as a consequence of a transmural voltage gradient caused by the manifestation of an AP notch in epicardium but not endocardium due to a heterogeneous transmural distribution of Ito[104]. An end of QRS notch, resembling a J wave, has been proposed to be due to intraventricular conduction delays. The 2 ECG manifestations can be distinguished based on their response to rate, with the latter showing accentuation at faster rates [24,59]. The cellular mechanisms underlying JWS have long been a matter of debate [214,215]. In the case of BrS, 2 principal hypotheses have been advanced. (1) The repolarization hypothesis asserts that an outward shift in the balance of currents in RV epicardium can lead to repolarization abnormalities resulting in the development of phase 2 reentry, which generates closely coupled premature beats capable of precipitating VT/VF. (2) The depolarization hypothesis suggests that slow conduction in the RVOT, secondary to fibrosis and reduced Cx43 leading to discontinuities in indeterminate conduction, plays a primary role in the development of the ECG and arrhythmic manifestations of the syndrome. Conduction slowing is not necessarily limited to the RVOT area. Some investigators have postulated that changes in ion channel current responsible for BrS (i.e., loss of function INa and ICa and gain of function of Ito) can alter AP morphology so as to reduce the safety of conduction at high-resistance junctions, such as regions of extensive fibrosis [216,217]. Others have argued that this is highly unlikely because conduction at critical junctions of current-to-load mismatch is exquisitely sensitive to changes in rate. The typical behavior of patients with BrS to acceleration of rate is diminution of ST-segment elevation, opposite to that expected at a site of discontinuous conduction. The diminution of ST-segment elevation is consistent with the reduced availability of Ito at the faster rate due to slow recovery of the current from inactivation [59,214]. The repolarization and depolarization theories are not necessarily mutually exclusive and may indeed be synergistic.