Giudicessi, John R.

Background Sorbs2b (sorbin and SH3 domain‐containing 2b) was recently identified as a cardiomyopathy gene from a zebrafish mutagenesis screen. However, cardiac functions of its mammalian ortholog remain elusive. Methods and Results We conducted a detailed expression and subcellular localization analysis of Sorbs2 ortholog in mice and a phenotypic characterization in Sorbs2 knockout mice. Sorbs2 is highly expressed in the mouse heart and encodes an adhesion junction/desmosome protein that is mainly localized to the intercalated disc. A mutation with near complete depletion of the Sorbs2 protein in mice results in phenotypes characteristic of human arrhythmogenic cardiomyopathy (ACM), including right ventricular dilation, right ventricular dysfunction, spontaneous ventricular tachycardia, and premature death. Sorbs2 is required to maintain the structural integrity of intercalated disc. Its absence resulted in profound cardiac electrical remodeling with impaired impulse conduction and action potential derangements. Targeted sequencing of human patients with ACM identified 2 rare splicing variants classified as likely pathogenic were in 2 unrelated individuals with ACM from a cohort of 59 patients with ACM. Conclusions The Sorbs2 knockout mouse manifests several key features reminiscent of human ACM. Although the candidacy of SORBS2 as a new ACM‐susceptibility gene is supported by preliminary human genetics study, future validation in larger cohorts with ACM is needed.

Abstract Prior to the recognition of distinct clinical entities, such as Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and long QT syndrome, all sudden cardiac arrest (SCA) survivors with ventricular fibrillation (VF) and apparently structurally normal hearts were labelled as idiopathic ventricular fibrillation (IVF). Over the last three decades, the definition of IVF has changed substantially, mostly as result of the identification of the spectrum of SCA-predisposing genetic heart diseases (GHDs), and the molecular evidence, by post-mortem genetic analysis (aka, the molecular autopsy), of cardiac channelopathies as the pathogenic basis for up to 35% of unexplained cases of sudden cardiac death (SCD) in the young. The evolution of the definition of IVF over time has led to a progressively greater awareness of the need for an extensive diagnostic assessment in unexplained SCA survivors. Nevertheless, GHDs are still underdiagnosed among SCA survivors, due to the underuse of pharmacological challenges (i.e. sodium channel blocker test), misrecognition of electrocardiogram (ECG) abnormalities/patterns (i.e. early repolarization pattern or exercise-induced ventricular bigeminy) or errors in the measurement of ECG parameters (e.g. the heart-rate corrected QT interval). In this review, we discuss the epidemiology, diagnostic approaches, and the controversies related to role of the genetic background in unexplained SCA survivors with a default diagnosis of IVF.

Background: Some long QT syndrome (LQTS) patients experience breakthrough cardiac events (BCEs) despite maximal therapy. Small studies have shown that intentional permanent atrial pacing (IPAP) is beneficial in refractory LQTS. As such, we sought to determine the genotype-specific utilization and efficacy of IPAP in a single-center LQTS registry. Methods and Results: In this retrospective study, electronic medical records from 1,065 LQTS patients were used to identify individuals that received IPAP. Pre- and post-IPAP heart rate, heart rate-corrected QT (QTc) values, annual BCE rate, and IPAP-related complications were compared between genotypes. BCEs were defined as LQTS-associated syncope/seizures, ventricular arrhythmia (VA)-terminating ICD therapies, and sudden cardiac arrest/death. Overall, 52/1065 LQTS patients received adjunctive IPAP therapy [77% female; median age 18.5 (IQR 1-35.5) years; 73% with prior VA]. Over an average IPAP follow-up of 121  82 months, the average heart rate increased from 65.8  20.4 bpm to 78.9  17.1 bpm; (p<0.01) and the average QTc decreased from 533.4  66.6 ms to 488.3  52.4 ms; (p<0.01). The mean BCE rate dropped from 0.88 to 0.19 per patient-year (p=0.01), driven by a marked decrease in LQT2 patients (1.01 BCE/year to 0.02 BCE/year; p=0.003). No serious IPAP-related complications were observed. Conclusion: In high-risk LQTS patients, namely those with recalcitrant LQT2, IPAP appears to be a safe and efficacious adjunct therapy. The beneficial effects of IPAP may stem from attenuating the QTc and circumventing a pause-dependent trigger. Whether IPAP might obviate the need for an ICD in some instances warrants further study.

Background: Long-QT syndrome (LQTS) is characterized by a prolonged heart rate–corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ≈8% to 10% of QTc variation in the general population. Methods: Overall, 423 patients with LQT1, LQT2, or LQT3 were genotyped for 61 QTc-associated genetic variants used in a prototype QTc–polygenic risk score (QTc-PRS). A weighted QTc-PRS (range, 0–154.8 ms) was calculated for each patient, and the FHS (Framingham Heart Study) population-based reference cohort (n=853). Results: The average QTc-PRS in LQTS was 88.0±7.2 and explained only ≈2.0% of the QTc variability. The QTc-PRS in LQTS probands (n=137; 89.3±6.8) was significantly greater than both FHS controls (87.2±7.4, difference-in-means±SE: 2.1±0.7, P <0.002) and LQTS genotype-positive family members (87.5±7.4, difference-in-mean, 1.8±.7, P <0.009). There was no difference in QTc-PRS between symptomatic (n=156, 88.6±7.3) and asymptomatic patients (n=267; 87.7±7.2, difference-in-mean, 0.9±0.7, P=0.15). LQTS patients with a QTc≥480 ms (n=120) had a significantly higher QTc-PRS (89.3±6.7) than patients with a QTc<480 ms (n=303, 87.6±7.4, difference-in-mean, 1.7±0.8, P <0.05). There was no difference in QTc-PRS or QTc between genotypes. Conclusions: The QTc-PRS explained <2% of the QTc variability in our LQT1, LQT2, and LQT3 cohort, contributing 5× less to their QTc value than in the general population. This prototype QTc-PRS does not distinguish/predict the clinical outcomes of individuals with LQTS.

Background: Triadin knockout syndrome (TKOS) is a potentially lethal arrhythmia disorder caused by recessively inherited null variants in TRDN -encoded cardiac triadin. Despite its malignant phenotype, the prevalence of TKOS in sudden infant death syndrome and sudden unexplained death in the young is unknown. Methods: Exome sequencing was performed on 599 sudden infant death syndrome and 258 sudden unexplained death in the young cases. Allele frequencies of all TRDN null variants identified in the cardiac-specific isoform of TRDN in the Genome Aggregation Database were used to determine the estimated prevalence and ethnic distribution of TKOS. Results: No triadin null individuals were identified in 599 sudden infant death syndrome and 258 sudden unexplained death in the young exomes. Using the Genome Aggregation Database, we estimate the overall prevalence of TKOS to be ≈1:22.7 million individuals. However, TKOS prevalence is 5.5-fold higher in those of African descent (≈1:4.1 million). Conclusions: TKOS is an exceedingly rare clinical entity that does not contribute meaningfully to either sudden infant death syndrome or sudden unexplained death in the young. However, despite its rarity and absence in large sudden death cohorts, TKOS remains a malignant and potentially lethal disorder which requires further research to better care for these patients.

Abstract Aims To determine the prevalence and in vitro electrophysiological (EP) phenotype of ultra-rare SCN5A variants of uncertain significance (VUS) identified in unexplained sudden cardiac arrest (SCA) survivors. Methods and results Retrospective review of 73 unexplained SCA survivors was used to identify all patients that underwent a form of genetic testing that included comprehensive SCN5A analysis. Ultra-rare SCN5A variants (minor allele frequency &lt; 0.005) were adjudicated according to the 2015 American College of Medical Genetics and Genomics (ACMG) guidelines. Variants designated as VUS were expressed heterologously and characterized using the whole-cell patch clamp technique. Overall, 60/73 (82%; the average age at SCA 28 ± 12 years) unexplained SCA survivors had received SCN5A genetic testing. Of these, 5/60 (8.3%) had an ultra-rare SCN5A variant. All SCN5A variants were classified as VUS. Whereas the single SCN5A VUS (p.Asp872Asn-SCN5A) identified in an unexplained SCA survivor with PR interval prolongation and inferior early repolarization conferred a loss-of-function phenotype (46.2% reduction in peak current density; 16 ms slower recovery from inactivation), the four other SCN5A VUS (p.Glu30Gly-SCN5A, p.Gln245Lys-SCN5A, p.Pro648Leu-SCN5A, and p.Glu1240Gln-SCN5A) identified in unexplained SCA survivors without early repolarization/conduction delay were indistinguishable from wild-type Nav1.5 channels. Conclusion In the absence of a phenotype(s) potentially attributable to sodium channel dysfunction, all SCN5A VUS identified in unexplained SCA survivors conferred a wild-type EP phenotype in vitro. As the background rate of SCN5A genetic variation is not trivial, great care must be taken to avoid prioritizing genotype over phenotype when attempting to ascertain the root cause of an individual's SCA.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6–52.2]; P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.