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BACKGROUND: Swimming is a genotype-specific trigger in long QT syndrome type 1 (LQT1). OBJECTIVE: To examine the autonomic response to water activities in children and adolescents with LQT1. METHODS: In this cross-sectional study, LQT1 patients were age and sex matched to one healthy control subject. Electrocardiograms (ECGs) were recorded during face immersion (FI), swimming, diving, and whole-body submersion (WBS). Heart rate (HR) and heart rate variability (HRV) was measured. The high frequency (HF) component of HRV was interpreted to reflect parasympathetic activity, while the low frequency (LF) component was interpreted as reflecting the combined influence of sympathetic and parasympathetic activity on autonomic nervous modulation of the heart. RESULTS: Fifteen LQT1 patients (aged 7-19 years, all on beta-blocker therapy) and fifteen age and sex matched non-medicated controls were included. No significant ventricular arrhythmias were observed in the LQT1 population during the water activities. Out of these 15 matched pairs, 12 pairs managed to complete FI and WBS for more than 10 seconds and were subsequently included in HR and HRV analyses. In response to FI, the LQT1 group experienced a drop in HR of 48 bpm, compared to 67 bpm in the control group (p = 0.006). In response to WBS, HR decreased by 48 bpm in the LQT1 group and 70 bpm in the control group (p = 0.007). A significantly lower PTOT (p < 0.001) and HF (p = 0.011) component was observed before, during and after FI in LQT1 patients compared with the controls. Before, during and after WBS, a significantly lower total power (p < 0.001), LF (p = 0.002) and HF (p = 0.006) component was observed in the LQT1 patients. CONCLUSION: A significantly lower HR decrease in response to water activities was observed in LQT1 subjects on beta-blocker therapy, compared to matched non-medicated controls. The data suggests an impaired parasympathetic response in LQT1 children and adolescents. An aberrant autonomic ner

BACKGROUND: There are conflicting reports with regard to the allele-specific gene suppression effects of single nucleotide polymorphisms (SNPs) in the 3’untranslated region (3’UTR) of the KCNQ1 gene in long QT syndrome type 1 (LQT1) populations. Here we assess the allele-specific effects of 3 previously published 3’UTR-KCNQ1’s SNPs in a LQT1 founder population segregating a dominant-negative mutation. METHODS AND RESULTS: Bidirectional sequencing of the KCNQ1’s 3’UTR was performed in the p.Y111C founder population (n=232, 147 genotype positive), with a minor allele frequency of 0.1 for SNP1 (rs2519184) and 0.6 for linked SNP2 (rs8234) and SNP3 (rs107980). Allelic phase was assessed in trios aided by haplotype data, revealing a high prevalence of derived SNP2/3 in cis with p.Y111C (89%). Allele-specific association analyses, corrected using a relatedness matrix, were performed between 3’UTR-KCNQ1 SNP genotypes and clinical phenotypes. SNP1 in trans was associated with a significantly higher proportion of symptomatic phenotype compared with no derived SNP1 allele in trans (58% versus 32%, corrected P=0.027). SNP2/3 in cis was associated with a significantly lower proportion of symptomatic phenotype compared with no derived SNP2/3 allele in cis (32% versus 69%, corrected P=0.010). CONCLUSIONS: Allele-specific modifying effects on symptomatic phenotype of 3’UTR-KCNQ1 SNPs rs2519184, rs8234, and rs107980 were seen in a LQT1 founder population segregating a dominant-negative mutation. The high prevalence of sup-pressive 3’UTR-KCNQ1 SNPs segregating with the founder mutation could contribute to the previously documented low incidence of cardiac events in heterozygous carriers of the p.Y111C KCNQ1 mutation.

Long QT Syndrome (LQTS) is an autosomal dominant inherited cardiac disorder associated with life-threatening arrhythmias. In northern Sweden, a LQTS founder mutation (p.Y111C, KCNQ1 gene) was verified by genetic haplotype analysis and genealogical studies, and a common ancestor couple was identified. Clinical studies of this population revealed an apparent mild phenotype. However, due to early commencement of prophylactic treatment, the natural history of this disorder cannot be properly assessed based only on clinical data. By using the family tree mortality ratio method (FTMR), we assessed the natural history of the untreated LQTS founder population. The principle of FTMR is to compare the age-specific mortality rates in a historic population harboring an inherited disorder with the corresponding mortality rates in an unaffected control population. Initially, we used the general Swedish population during the same period for comparison and observed an apparent increased longevity in the p.Y111C study population. However, when using a control population born in the same area, we observed no differences regarding overall mortality. Moreover, patterns suggesting age- and sex-stratified excess mortality, in accordance with previous LQTS studies, were evident. This study shows the importance of being aware of historical demographic patterns to avoid misinterpreting when comparing historical data.

Sympathetic activation is an established trigger of life-threatening cardiac events in long QT syndrome type 1 (LQT1). KCNQ1 loss-of-function variants, which underlie LQT1, have been associated with both cardiac arrhythmia and neuronal hyperactivity pathologies. However, the LQT1 sympathetic neuronal phenotype is unknown. Here, we aimed to study human induced pluripotent stem cell (hiPSC)-derived sympathetic neurons (SNs) to evaluate neuronal functional phenotype in LQT1. We generated hiPSC-SNs from two patients with LQT1 with a history of sympathetically triggered arrhythmia and KCNQ1 loss-of-function genotypes (c.781_782delinsTC and p.S349W/p.R518X). Characterization of hiPSC-SNs was performed using immunohistochemistry, enzyme-linked immunosorbent assay, and whole cell patch clamp electrophysiology, and functional LQT1 hiPSC-SN phenotypes compared with healthy control (WT) hiPSC-SNs. hiPSC-SNs stained positive for tyrosine hydroxylase, peripherin, KCNQ1, and secreted norepinephrine. hiPSC-SNs at 60 +/- 2.2 days in vitro had healthy resting membrane potentials (-60 +/- 1.3 mV), and fired rapid action potentials with mature kinetics in response to stimulation. Significant hyperactivity in LQT1 hiPSC-SNs was evident via increased norepinephrine release, increased spontaneous action potential frequency, increased total inward current density, and reduced afterhyperpolarization, compared with age-matched WT hiPSC-SNs. A significantly higher action potential frequency upon current injection and larger synaptic current amplitudes in compound heterozygous p.S349W/p.R518X hiPSC-SNs compared with heterozygous c.781_782delinsTC hiPSC-SNs was also observed, suggesting a potential genotype-phenotype correlation. Together, our data reveal increased neurotransmission and excitability in heterozygous and compound heterozygous patient-derived LQT1 sympathetic neurons, suggesting that the cellular arrhythmogenic potential in LQT1 is not restricted to cardiomyocytes. NEW & NOTE

We present the case of a twin pregnancy of heterozygous andhomozygous long QT syndrome (LQTS) type 1 (LQT1)genotype, referred because of in utero bradycardia in thehomozygous twin at 19 weeks of gestation, with follow-upuntil.12 months of age. Fetal heart rate may predict bothgenotype and disease severity, as previously shown in2 LQTS founder populations.1This unique case report is acomparison of fetal heart rate and clinical outcome in twinprobands of heterozygous and homozygous genotype, in afamily without prior diagnosis of LQTS. In this setting, wediscuss the early management of LQTS and Jervell andLange-Nielsen syndrome (JLNS) detected in utero.

Objective: 1. Determine if fetal heart rate (FHR) predicts LQTS across gestational ages (GA). 2. Ascertain genotype specific effects on FHR and rhythm. Study Design: FHR and rhythm data were ascertained from fetuses with maternal or paternal LQTS1, LQTS2 or LQTS3 genotype at 8 international centers. We reviewed obstetrical history including maternal beta blocker (BB) use. At each obstetrical visit, FHRs were calculated from an average of 3 heart beats (ultrasound) or 3 10-second periods of FHR auscultation (Doppler monitor) measured during fetal quiescence. Postnatal genetic testing was performed by commercial laboratories. We compared FHR in the 1st, 2nd and 3rd trimesters between fetuses with (LQTS+) and without (LQTS-) the family mutation by t-test. Differences in FHR between LQTS genotypes were compared by ANOVA. Log FHR was analyzed by a linear mixed effect model with GA as the continuous variable and adjusting for maternal BB use. The predictive ability of FHR to discriminate LQTS+ from LQTS- was addressed by ROC analysis, evaluating the magnitude of FHR (intercept) and change in FHR (slope) across GA. Results: Data were available on 51 LQTS+ and 27 LQTS-. Mean FHR differed between LQTS+ and LQTS- fetuses in 2nd and 3rd but not in the 1st trimesters (Table). The magnitude of FHR change in 2nd and 3rd trimesters discriminated LQTS + from LQTS- (both, p<0.05); with AUC of 0.81. FHR effect was most pronounced for LQTS1 and differed significantly between genotypes. LQTS3 did not exhibit a FHR effect at any GA. Only LQTS2 had signature LQTS arrhythmias (2◦ AV block and/or torsade de pointes). Maternal BB had no significant effect on FHR. Conclusion: In this study with a preponderance of LQTS1, FHR discriminated LQTS+ from LQTS- fetuses in the 2nd and 3rd trimesters. LQTS genotype appears to affect the fetal presentation of LQTS. These findings provide insight into the natural history of LQTS before birth and may facilitate early detection of LQTS1 and LQTS2 fetu

Aims: To clarify the clinical characteristics and outcomes of children with SCN5A-mediated disease and to improve their risk stratification.Methods and results: A multicentre, international, retrospective cohort study was conducted in 25 tertiary hospitals in 13 countries between 1990 and 2015. All patients ≤16 years of age diagnosed with a genetically confirmed SCN5A mutation were included in the analysis. There was no restriction made based on their clinical diagnosis. A total of 442 children {55.7% boys, 40.3% probands, median age: 8.0 [interquartile range (IQR) 9.5] years} from 350 families were included; 67.9% were asymptomatic at diagnosis. Four main phenotypes were identified: isolated progressive cardiac conduction disorders (25.6%), overlap phenotype (15.6%), isolated long QT syndrome type 3 (10.6%), and isolated Brugada syndrome type 1 (1.8%); 44.3% had a negative electrocardiogram phenotype. During a median follow-up of 5.9 (IQR 5.9) years, 272 cardiac events (CEs) occurred in 139 (31.5%) patients. Patients whose mutation localized in the C-terminus had a lower risk. Compound genotype, both gain- and loss-of-function SCN5A mutation, age ≤1 year at diagnosis in probands and age ≤1 year at diagnosis in non-probands were independent predictors of CE.Conclusion: In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Background: Sequence variants in the NOS1AP gene have repeatedly been reported to influence QTc, albeit with moderate effect sizes. In the long QT syndrome (LQTS), this may contribute to the substantial QTc variance seen among carriers of identical pathogenic sequence variants. Here we assess three non-coding NOS1APsequence variants, chosen for their previously reported strong association with QTc in normal and LQTS populations, for association with QTc in two Swedish LQT1 founder populations. Methods: This study included 312 individuals (58% females) from two LQT1 founder populations, whereof 227 genotype positive segregating either Y111C (n = 148) or R518* (n = 79) pathogenic sequence variants in the KCNQ1 gene, and 85 genotype negatives. All were genotyped for NOS1AP sequence variants rs12143842, rs16847548 and rs4657139, and tested for association with QTc length (effect size presented as mean difference between derived and wildtype, in ms), using a pedigree-based measured genotype association analysis. Mean QTc was obtained by repeated manual measurement (preferably in lead II) by one observer using coded 50 mm/s standard 12-lead ECGs. Results: A substantial variance in mean QTc was seen in genotype positives 476 ± 36 ms (Y111C 483 ± 34 ms; R518* 462 ± 34 ms) and genotype negatives 433 ± 24 ms. Female sex was significantly associated with QTc prolongation in all genotype groups (p < 0.001). In a multivariable analysis including the entire study population and adjusted for KCNQ1 genotype, sex and age, NOS1AP sequence variants rs12143842 and rs16847548 (but not rs4657139) were significantly associated with QT prolongation, +18 ms (p = 0.0007) and +17 ms (p = 0.006), respectively. Significant sex-interactions were detected for both sequent variants (interaction term r = 0.892, p < 0.001 and r = 0.944, p < 0.001, respectively). Notably, across the genotype groups, when stratified by sex neither rs12143842 nor rs16847548 were significantly associated with Q

Objectives. To investigate the possible association between Jervell and Lange-Nielsen Syndrome (JLNS) genotype and vestibular dysfunction. Design. In 15 cases with JLNS, clinical data obtained from a semi-structured interview and full medical records were reviewed and post-rotatory nystagmus testing was performed. Results. All genotyped cases (n = 14) had double KCNQ1 mutations. Symptoms of impaired balance were reported in 14/14 deaf JLNS cases. Gross motor developmental delay (not walking without support at 18 months of age) was seen in 11/12 cases with available data (mean age for walking: 24 months). A pathologic post-rotatory test was seen in 9/9 tested subjects, and in 3 subjects clinical testing had been performed showing complete lack of vestibular function. Vestibular dysfunction was seen in deaf JLNS cases with (n = 5) and without (n = 9) cochlear implants, including subjective symptoms (5/5 vs. 9/9) and gross motor developmental delay (5/5 vs. 6/8). Conclusions. We identified a high frequency of symptoms and signs associated with vestibular dysfunction in deaf JLNS cases, irrespective of previous cochlear implantation. Disruption of endolymph homeostasis in the inner ear, including cochlea and vestibular system, by profound KCNQ1 function loss is the proposed mechanism.

Background—Early diagnosis and risk stratification is of clinical importance in the long QT syndrome (LQTS), however, little genotype-specific data are available regarding fetal LQTS. We investigate third trimester fetal heart rate, routinely recorded within public maternal health care, as a possible marker for LQT1 genotype and phenotype. Methods and Results—This retrospective study includes 184 fetuses from 2 LQT1 founder populations segregating p.Y111C and p.R518X (74 noncarriers and 110KCNQ1 mutation carriers, whereof 13 double mutation carriers). Pedigree-based measured genotype analysis revealed significant associations between fetal heart rate, genotype, and phenotype; mean third trimester prelabor fetal heart rates obtained from obstetric records (gestational week 29–41) were lower per added mutation (no mutation, 143±5 beats per minute; single mutation, 134±8 beats per minute; double mutations, 111±6 beats per minute; P<0.0001), and lower in symptomatic versus asymptomatic mutation carriers (122±10 versus 137±9 beats per minute; P<0.0001). Strong correlations between fetal heart rate and neonatal heart rate (r=0.700; P<0.001), and postnatal QTc (r=−0.762; P<0.001) were found. In a multivariable model, fetal genotype explained the majority of variance in fetal heart rate (−10 beats per minute per added mutation; P<1.0×10–23). Arrhythmia symptoms and intrauterine β-blocker exposure each predicted −7 beats per minute, P<0.0001. Conclusions—In this study including 184 fetuses from 2 LQT1 founder populations, third trimester fetal heart rate discriminated between fetal genotypes and correlated with severity of postnatal cardiac phenotype. This finding strengthens the role of fetal heart rate in the early detection and risk stratification of LQTS, particularly for fetuses with double mutations, at high risk of early life-threatening arrhythmias.