Castelletti, Silvia

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P =0.0078). Among SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P =0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P =0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P =0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

The gene encoding SAP97 ( DLG1) joins a growing list of genes encoding ion channel interacting proteins (ChIPs) identified as potential channelopathy-susceptibility genes because of their ability to regulate the trafficking, targeting, and modulation of ion channels that are critical for the generation and propagation of the cardiac electrical impulse. In this study we provide the first data supporting DLG1-encoded SAP97’s candidacy as a minor Brugada syndrome susceptibility gene.

Background: Long QT syndrome is a potentially lethal yet highly treatable cardiac channelopathy. Although β-blocker therapy is standard for most patients, concomitant therapy with sodium channel blockers, like mexiletine, is often utilized for patients with sodium channel–mediated type 3 long QT syndrome (LQT3). The potential role of sodium channel blockers in patients with potassium channel–mediated long QT syndrome (ie, LQT1 and LQT2) has not been investigated in detail. Methods: We performed a retrospective chart review on 12 patients (5 females; median age at diagnosis 14.1 years (interquartile range [IQR], 7.7–23; range, 0–59, median heart rate–corrected QT interval [QTc] at diagnosis 557 ms (IQR, 529–605) with genetically established LQT2 (10) or a combination of LQT1/LQT2 (1) or LQT2/LQT3 (1), who received mexiletine. Data were collected on symptomatic status, treatments, and breakthrough cardiac events after diagnosis and initiation of treatment. Additionally, 12-lead ECGs were collected at diagnosis, before initiation of mexiletine and following mexiletine to evaluate the drug’s effect on QTc. Results: Before diagnosis, 6 patients were symptomatic and, before initiation of mexiletine, 4 patients experienced ≥1 breakthrough cardiac event on β-blocker. Median age at first mexiletine dose was 24.3 years (IQR, 14–32.4). After mexiletine, the median QTc decreased by 65±45 ms from 547 ms (IQR, 488–558) premexiletine to 470 ms (IQR, 409–529) postmexiletine ( P =0.0005) for all patients. In 8 patients (67%), the QTc decreased by ≥ 40 ms with a mean decrease in QTc of 91 ms ( P < 0.008). For the 11 patients maintained on mexiletine therapy, there have been no breakthrough cardiac events during follow-up. Conclusions: Although commonly prescribed in patients with LQT3, mexiletine also shortens the QTc significantly in two-thirds of a small subset of patients with potassium channel–mediated LQT2. In patients with LQT2, pharmacological targeting of the physiological late sodium current may provide added therapeutic efficacy to β-blocker therapy.