• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • An ERP in the ECG has


    An ERP in the ECG has been shown to be familial [187–189]. ERP and ERS have been associated with variants in 7 genes. Consistent with the findings that IK-ATP activation can generate an ERP in canine ventricular wedge preparations, variants in KCNJ8 and ABCC9, responsible for the pore- forming and ATP-sensing subunits of the IK-ATP channel, have been reported in patients with ERS [156,158,190]. Loss-of- function variations in the α1, β2, and α2δ subunits of the cardiac L-type calcium channel (CACNA1C, CACNB2, CACNA2D1) and the α1 subunit of NaV1.5 and NaV1.8 (SCN5A, SCN10A) have been reported in patients with ERS [113,152,177]. It is important to point out that only a small fraction of identified genetic variants in the genes associated with BrS and ERS have been examined using functional expression studies to ascertain causality and establish a plausible contribution to pathogenesis. Only a handful have been studied in genetically engineered animal models, and very few have been studied in native cardiac acetanilide or in induced pluripotent stem cell-derived cardiac myocytes isolated from ERS and BrS patients. Computational strategies developed to predict the functional consequences of mutations are helpful, but these methods have not acetanilide been rigorously tested. The lack of functional or biologic validation of mutation effects remains the most severe limitation of genetic test interpretation, as recently highlighted by Schwartz et al. [191]. Recent technological advances have resulted in expansion of disease-specific panels [192]. Large public databases of genetic variation from next-generation sequencing programs such as the 1000 Genomes Project, the National Heart Lung and Blood Institute Grand Opportunity Exome Sequencing Project (GO-ESP), and the Exome Aggregation Consortium (ExAC), have challenged drastically our understanding of the “normal” burden and extent of background genetic variation within cardiac channelopathy susceptibility genes [193–195]. 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 genes [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.