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  • 1. Cuneo, Bettina
    et al.
    Clur, Sally Ann
    Swan, Heikki
    Ackerman, Michael
    Herberg, Ulrike
    Etheridge, Susan
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Benson, D. Woodrow
    Schwartz, Peter
    Fetal heart rate and arrhythmia profile predicts long QT syndrome (LQTS) genotype: Results of an 8-center international study2018Ingår i: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 218, nr 1, s. S93-S93Artikel i tidskrift (Övrigt vetenskapligt)
    Abstract [en]

    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 fetuses.

  • 2. Cuneo, Bettina F.
    et al.
    Kaizer, Alexander M.
    Clur, Sally Ann
    Swan, Heikki
    Herberg, Ulrike
    Winbo, Annika
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Haugaa, Kristina
    Etheridge, Susan
    Ackerman, Michael J.
    Dagradi, Federica
    Killen, Stacy A. S.
    Wacker-Gussmann, Annette
    Benson, D. Woodrow
    Wilde, A. A. M.
    Pan, Zhaoxing
    Lam, Aimee
    Spazzolini, Carla
    Horigome, Hitoshi
    Schwartz, Peter J.
    Mothers with long QT syndrome are at increased risk for fetal death: findings from a multicenter international study2020Ingår i: American Journal of Obstetrics and Gynecology, ISSN 0002-9378, E-ISSN 1097-6868, Vol. 222, nr 3, s. 1-11, artikel-id 263.e1-11Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Most fetal deaths are unexplained. Long QT syndrome is a genetic disorder of cardiac ion channels. Affected individuals, including fetuses, are predisposed to sudden death. We sought to determine the risk of fetal death in familial long QT syndrome, in which the mother or father carries the long QT syndrome genotype. In addition, we assessed whether risk differed if the long QT syndrome genotype was inherited from the mother or father. OBJECTIVE: This was a retrospective review of pregnancies in families with the 3 most common heterozygous pathogenic long QT syndrome genotypes in KCNQ1 (LQT1), KCNH2 (LQT2), or SCN5A (LQT3), which occur in approximately 1 in 2000 individuals. The purpose of our study was to compare pregnancy and birth outcomes in familial long QT syndrome with the normal population and between maternal and paternal carriers of the long QT syndrome genotype. We hypothesized that fetal death before (miscarriage) and after (stillbirths) 20 weeks gestation would be increased in familial long QT syndrome compared with the normal population and that the parent of origin would not affect birth outcomes. STUDY DESIGN: Our study was a multicenter observational case series of 148 pregnancies from 103 families (80 mothers, 23 fathers) with familial long QT syndrome (60 with LQT1, 29 with LQT2, 14 with LQT3) who were recruited from 11 international centers with expertise in hereditary heart rhythm diseases, pediatric and/or adult electrophysiology, and high-risk pregnancies. Clinical data-bases from these sites were reviewed for long QT syndrome that occurred in men or women of childbearing age (18-40 years). Pregnancy outcomes (livebirth, stillbirth, and miscarriage), birthweights, and gestational age at delivery were compared among long QT syndrome genotypes and between maternal vs paternal long QT syndrome-affected status with the use of logistic regression analysis. RESULTS: Most offspring (80%; 118/148) were liveborn at term; 66% of offspring (73/110) had long QT syndrome. Newborn infants of mothers with long QT syndrome were delivered earlier and, when the data were controlled for gestational age, weighed less than newborn infants of long QT syndrome fathers. Fetal arrhythmias were observed rarely, but stillbirths (fetal death at >20 weeks gestation) were 8 times more frequent in long QT syndrome (4% vs approximately 0.5%); miscarriages (fetal death at <= 20 weeks gestation) were 2 times that of the general population (16% vs 8%). The likelihood of fetal death was significantly greater with maternal vs paternal long QT syndrome (24.4% vs 3.4%; P = .036). Only 10% of all fetal deaths underwent postmortem long QT syndrome testing; 2 of 3 cases were positive for the family long QT syndrome genotype. CONCLUSION: This is the first report to demonstrate that mothers with long QT syndrome are at increased risk of fetal death and to uncover a previously unreported cause of stillbirth. Our results suggest that maternal effects of long QT syndrome channelopathy may cause placental or myometrial dysfunction that confers increased susceptibility to fetal death and growth restriction in newborn survivors, regardless of long QT syndrome status.

  • 3.
    Diamant, Ulla-Britt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Vectorcardiographic recordings of the Q-T interval in a pediatric long Q-T syndrome population2013Ingår i: Pediatric Cardiology, ISSN 0172-0643, E-ISSN 1432-1971, Vol. 34, nr 2, s. 245-249Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Measurements of the Q-T interval are less reliable in children than in adults. Identification of superior diagnostic tools is warranted. This study aimed to investigate whether a vectorcardiogram (VCG) recorded from three orthogonal leads (X, Y, Z) according to Frank is superior to a 12-lead electrocardiogram (ECG) in providing a correct long Q-T syndrome (LQTS) diagnosis in children. This LQTS group consisted of 35 genetically confirmed carriers of mutations in the KCNQ1 (n = 29) and KCNH2 (n = 6) genes. The control group consisted of 35 age- and gender-matched healthy children. The mean age was 7 years in the LQTS group and 6.7 years in the control group (range, 0.5-16 years). The corrected Q-T interval (QT(c)) was measured manually (QT(man)) by one author (A.W.). The 12-lead ECG automatic measurements (QT(ECG)) and interpretation (QT(Interpret)) of QT(c) were performed with the Mac5000 (GE Medical System), and the VCG automatic measurements (QT(VCG)) were performed with the Mida1000, CoroNet (Ortivus AB, Sweden). By either method, a QT(c) longer than 440 ms was considered prolonged and indicative of LQTS. Of the 35 children with genetically confirmed LQTS, 30 (86 %) received a correct diagnosis using QT(VCG), 29 (82 %) using QT(man), 24 (69 %) using QT(ECG), and 17 (49 %) using QT(Interpret). Specificity was 0.80 for QT(VCG), 0.83 for QT(man), 0.77 for QT(ECG), and 0.83 for QT(Interpret). The VCG automatic measurement of QT(c) seems to be a better predictor of LQTS than automatic measurement and interpretation of 12-lead ECG.

  • 4.
    Diamant, Ulla-Britt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Vahedi, Farzad
    Sahlgrenska Akademin Göteborgs Universitet.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Bergfeldt, Lennart
    Sahlgrenska Akademin Göteborgs Universitet.
    Electrophysiological phenotype in the LQTS mutations Y111C and R518X in the KCNQ1 gene2013Ingår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 115, nr 10, s. 1423-1432Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Long QT syndrome is the prototypical disorder of ventricular repolarization (VR), and a genotype-phenotype relation is postulated. Furthermore, although increased VR heterogeneity (dispersion) may be important in the arrhythmogenicity in long QT syndrome, this hypothesis has not been evaluated in humans and cannot be tested by conventional electrocardiography. In contrast, vectorcardiography allows assessment of VR heterogeneity and is more sensitive to VR alterations than electrocardiography. Therefore, vectorcardiography was used to compare the electrophysiological phenotypes of two mutations in the LQT1 gene with different in vitro biophysical properties, and with LQT2 mutation carriers and healthy control subjects. We included 99 LQT1 gene mutation carriers (57 Y111C, 42 R518X) and 19 LQT2 gene mutation carriers. Potassium channel function is in vitro most severely impaired in Y111C. The control group consisted of 121 healthy subjects. QRS, QT, and T-peak to T-end (Tp-e) intervals, measures of the QRS vector and T vector and their relationship, and T-loop morphology parameters were compared at rest. Apart from a longer heart rate-corrected QT interval (QT heart rate corrected according to Bazett) in Y111C mutation carriers, there were no significant differences between the two LQT1 mutations. No signs of increased VR heterogeneity were observed among the LQT1 and LQT2 mutation carriers. QT heart rate corrected according to Bazett and Tp-e were longer, and the Tp-e-to-QT ratio greater in LQT2 than in LQT1 and the control group. In conclusion, there was a marked discrepancy between in vitro potassium channel function and in vivo electrophysiological properties in these two LQT1 mutations. Together with previous observations of the relatively low risk for clinical events in Y111C mutation carriers, our results indicate need for cautiousness in predicting in vivo electrophysiological properties and the propensity for clinical events based on in vitro assessment of ion channel function alone.

  • 5.
    Diamant, Ulla-Britt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Avdelningen för medicin.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Department of Physiology, University of Auckland, Auckland, New Zealand.
    Marcus, Karlsson
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Edvinsson, Sören
    Umeå universitet, Samhällsvetenskapliga fakulteten, Enheten för demografi och åldrandeforskning (CEDAR).
    Annika, Rydberg
    Department of Physiology, University of Auckland, Auckland, New Zealand.
    LQTS founder population in Northern Sweden – the natural history of a potentially fatal inherited cardiac disorder2021Ingår i: Biodemography and Social Biology, ISSN 1948-5565, E-ISSN 1948-5573, Vol. 66, nr 3-4, s. 191-207Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

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  • 6.
    Diamant, Ulla-Britt
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Kesek, Milos
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Two automatic QT algorithms compared with manual measurement in identification of long QT syndrome2010Ingår i: Journal of Electrocardiology, ISSN 0022-0736, E-ISSN 1532-8430, Vol. 43, nr 1, s. 25-30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Long QT syndrome (LQTS) is an inherited disorder that increases the risk of syncope and malignant ventricular arrhythmias, which may result in sudden death.

    METHODS: We compared manual measurement by 4 observers (QT(manual)) and 3 computerized measurements for QT interval accuracy in the diagnosis of LQTS: 1. QT measured from the vector magnitude calculated from the 3 averaged orthogonal leads X, Y, and Z (QTVCG) and classified using the same predefined QTc cut-points for classification of QT prolongation as in manual measurements; 2. QT measured by a 12-lead electrocardiogram (ECG) program (QTECG) and subsequently classified using the same cut-points as in (1) above; 3. The same QT value as in (2) above, automatically classified by a 12-lead ECG program with thresholds for QT prolongation adjusted for age and sex (QTinterpret). The population consisted of 94 genetically confirmed carriers of KCNQ1 (LQT1) and KCNH2 (LQT2) mutations and a combined control group of 28 genetically confirmed noncarriers and 66 unrelated healthy volunteers.

    RESULTS: QT(VCG) provided the best combination of sensitivity (89%) and specificity (90%) in diagnosing LQTS, with 0.948 as the area under the receiver operating characteristic curve. The evaluation of QT measurement by the 4 observers revealed a high interreader variability, and only 1 of 4 observers showed acceptable level of agreement in LQTS mutation carrier identification (kappa coefficient >0.75).

    CONCLUSION: Automatic QT measurement by the Mida1000/CoroNet system (Ortivus AB, Danderyd, Sweden) is an accurate, efficient, and easily applied method for initial screening for LQTS.

  • 7.
    Kaizer, Alexander M.
    et al.
    Biostatistics and Informatics, Colorado School of Public Health, University of Colorado-Anschutz Medical Campus, CO, Aurora, United States.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Department of Physiology, University of Auckland, Auckland, New Zealand.
    Clur, Sally-Ann B
    Department of Pediatric Cardiology, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, Netherlands; Department of Cardiology, University Medical Center, Amsterdam, Netherlands.
    Etheridge, Susan P.
    Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, UT, Salt Lake City, United States.
    Ackerman, Michael J.
    Department of Cardiovascular Medicine, Division of Heart Rhythm Services, Mayo Clinic, MN, Rochester, United States; Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, MN, Rochester, United States; Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, MN, Rochester, United States; Mayo Clinic, Windland Smith Rice Genetic Heart Rhythm Clinic and Windland Smith Rice Sudden Death Genomics Laboratory, MN, Rochester, United States.
    Horigome, Hitoshi
    Department of Pediatrics, Section of Cardiology, Tsukuba University, Tsukuba, Japan.
    Herberg, Ulrike
    Department of Pediatric Cardiology, RWTH University Hospital Aachen, Aachen, Germany; Department of Pediatric Cardiology, University Hospital Bonn, Bonn, Germany.
    Dagradi, Federica
    Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Via Pier Lombardo 22, Milan, Italy.
    Spazzolini, Carla
    Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Via Pier Lombardo 22, Milan, Italy.
    Killen, Stacy A S
    Department of Pediatrics, Division of Cardiology, Vanderbilt University Medical Center, TN, Nashville, United States.
    Wacker-Gussmann, Annette
    Department of Congenital Heart Disease and Paediatric Cardiology, German Heart Center, Munich, Germany.
    Wilde, Arthur A M
    Department of Cardiology, University Medical Center, Amsterdam, Netherlands; Department of Cardiology, Amsterdam UMC Location University of Amsterdam, Amsterdam, Netherlands; Department of Cardiology, Amseterdam University Medical Center, Amsterdam, Netherlands.
    Sinkovskaya, Elena
    Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Eastern Virginia Medical School, VA, Norfolk, United States.
    Abuhamad, Alfred
    Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Eastern Virginia Medical School, VA, Norfolk, United States.
    Torchio, Margherita
    Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Via Pier Lombardo 22, Milan, Italy.
    Ng, Chai-Ann
    Mark Cowley Lidwill Research Program in Cardiac Electrophysiology, Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia; School of Clinical Medicine, UNSW Sydney, Darlinghurst, NSW, Australia.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Department of Cardiology, University Medical Center, Amsterdam, Netherlands.
    Schwartz, Peter J.
    Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, IRCCS Istituto Auxologico Italiano, Via Pier Lombardo 22, Milan, Italy.
    Cuneo, Bettina F.
    Department of Pediatrics, Section of Cardiology, University of Denver School of Medicine, 13123 16th Ave, Box 100, Aurora, CO 80045, USA.
    Effects of cohort, genotype, variant, and maternal β-blocker treatment on foetal heart rate predictors of inherited long QT syndrome2023Ingår i: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 25, nr 11, artikel-id euad319Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS: In long QT syndrome (LQTS), primary prevention improves outcome; thus, early identification is key. The most common LQTS phenotype is a foetal heart rate (FHR) < 3rd percentile for gestational age (GA) but the effects of cohort, genotype, variant, and maternal β-blocker therapy on FHR are unknown. We assessed the influence of these factors on FHR in pregnancies with familial LQTS and developed a FHR/GA threshold for LQTS.

    METHODS AND RESULTS: In an international cohort of pregnancies in which one parent had LQTS, LQTS genotype, familial variant, and maternal β-blocker effects on FHR were assessed. We developed a testing algorithm for LQTS using FHR and GA as continuous predictors. Data included 1966 FHRs at 7-42 weeks' GA from 267 pregnancies/164 LQTS families [220 LQTS type 1 (LQT1), 35 LQTS type 2 (LQT2), and 12 LQTS type 3 (LQT3)]. The FHRs were significantly lower in LQT1 and LQT2 but not LQT3 or LQTS negative. The LQT1 variants with non-nonsense and severe function loss (current density or β-adrenergic response) had lower FHR. Maternal β-blockers potentiated bradycardia in LQT1 and LQT2 but did not affect FHR in LQTS negative. A FHR/GA threshold predicted LQT1 and LQT2 with 74.9% accuracy, 71% sensitivity, and 81% specificity.

    CONCLUSION: Genotype, LQT1 variant, and maternal β-blocker therapy affect FHR. A predictive threshold of FHR/GA significantly improves the accuracy, sensitivity, and specificity for LQT1 and LQT2, above the infant's a priori 50% probability. We speculate this model may be useful in screening for LQTS in perinatal subjects without a known LQTS family history.

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  • 8.
    Lundström, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Wiklund, Urban
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Department of Physiology, University of Auckland, Auckland, New Zealand.
    Eliasson, Håkan
    Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Karlsson, Marcus
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Radiofysik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Cardiac response to water activities in children with Long QT syndrome type 12023Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 18, nr 12, artikel-id e0295431Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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 nervous system (ANS) response may cause an autonomic imbalance in this patient group.

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  • 9. Mann, Stefan A.
    et al.
    Imtiaz, Mohammad
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Perry, Matthew D.
    Couderc, Jean-Philippe
    Polonsky, Bronislava
    McNitt, Scott
    Zareba, Wojciech
    Hill, Adam P.
    Vandenberg, Jamie I.
    Convergence of models of human ventricular myocyte electrophysiology after global optimization to recapitulate clinical long QT phenotypes2016Ingår i: Journal of Molecular and Cellular Cardiology, ISSN 0022-2828, E-ISSN 1095-8584, Vol. 100, s. 25-34Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In-silico models of human cardiac electrophysiology are now being considered for prediction of cardiotoxicity as part of the preclinical assessment phase of all new drugs. We ask the question whether any of the available models are actually fit for this purpose. We tested three models of the human ventricular action potential, the O'hara-Rudy (ORD11), the Grandi-Bers (GB10) and the Ten Tusscher (TT06) models. We extracted clinical QT data for LQTS1 and LQTS2 patients with nonsense mutations that would be predicted to cause 50% loss of function in I-Ks and I-Kr respectively. We also obtained clinical QT data for LQTS3 patients. We then used a global optimization approach to improve the existing in silico models so that they reproduced all three clinical data sets more closely. We also examined the effects of adrenergic stimulation in the different LQTS subsets. All models, in their original form, produce markedly different and unrealistic predictions of QT prolongation for LQTS1, 2 and 3. After global optimization of the maximum conductances for membrane channels, all models have similar current densities during the action potential, despite differences in kinetic properties of the channels in the different models, and more closely reproduce the prolongation of repolarization seen in all LQTS subtypes. In-silico models of cardiac electrophysiology have the potential to be tremendously useful in complementing traditional preclinical drug testing studies. However, our results demonstrate they should be carefully validated and optimized to clinical data before they can be used for this purpose.

  • 10.
    Stattin, Eva-Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Boström, Ida Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Cederquist, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jonasson, Jenni
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Jonsson, Björn-Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Diamant, Ulla-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing2012Ingår i: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 12, s. 95-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Long QT syndrome (LQTS) is an inherited arrhythmic disorder characterised by prolongation of the QT interval on ECG, presence of syncope and sudden death. The symptoms in LQTS patients are highly variable, and genotype influences the clinical course. This study aims to report the spectrum of LQTS mutations in a Swedish cohort.

    Methods: Between March 2006 and October 2009, two hundred, unrelated index cases were referred to the Department of Clinical Genetics, Umea University Hospital, Sweden, for LQTS genetic testing. We scanned five of the LQTS-susceptibility genes (KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2) for mutations by DHPLC and/or sequencing. We applied MLPA to detect large deletions or duplications in the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes. Furthermore, the gene RYR2 was screened in 36 selected LQTS genotype-negative patients to detect cases with the clinically overlapping disease catecholaminergic polymorphic ventricular tachycardia (CPVT).

    Results: In total, a disease-causing mutation was identified in 103 of the 200 (52%) index cases. Of these, altered exon copy numbers in the KCNH2 gene accounted for 2% of the mutations, whereas a RYR2 mutation accounted for 3% of the mutations. The genotype-positive cases stemmed from 64 distinct mutations, of which 28% were novel to this cohort. The majority of the distinct mutations were found in a single case (80%), whereas 20% of the mutations were observed more than once. Two founder mutations, KCNQ1 p.Y111C and KCNQ1 p.R518*, accounted for 25% of the genotype-positive index cases. Genetic cascade screening of 481 relatives to the 103 index cases with an identified mutation revealed 41% mutation carriers who were at risk of cardiac events such as syncope or sudden unexpected death.

    Conclusion: In this cohort of Swedish index cases with suspected LQTS, a disease-causing mutation was identified in 52% of the referred patients. Copy number variations explained 2% of the mutations and 3 of 36 selected cases (8%) harboured a mutation in the RYR2 gene. The mutation panorama is characterised by founder mutations (25%), even so, this cohort increases the amount of known LQTS-associated mutations, as approximately one-third (28%) of the detected mutations were unique.

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  • 11.
    Winbo, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Long QT syndrome in Sweden: founder effects and associated cardiac phenotypes2012Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Background: We aimed to increase the knowledge regarding the familial arrhythmogenic disorder Long QT Syndrome (LQTS) and its recessive variant Jervell and Lange-Nielsen Syndrome (JLNS) in Sweden, including prevalences and clinical phenotypes. A specific focus was directed towards two KCNQ1 mutations –p.Y111C and p.R518X- commonly identified in Swedish LQTS index cases.

    Methods: Cases and families with LQTS (p.Y111C or p.R518X) and JLNS were recruited via regional clinical practices, national referrals to the Clinical Genetics laboratory, Umeå University Hospital, and a national inventory. Molecular genetics methods were used for case ascertainment. Clinical data was obtained via medical records, a questionnaire, and/or an interview. Electrocardiograms were manually assessed. In p.R518X heterozygotes intra-familial phenotypic variability (QTc and cardiac events) was assessed by analysis of sequence variants (modifier genes). The origins of the mutations p.Y111C and p.R518X were investigated using genealogical and haplotype analysis (microsatellite markers). In families sharing a common haplotype mutation age and associated prevalence was analyzed using ESTIAGE and DMLE computer software.

    Results: We identified p.Y111C (170 mutation-carriers) and p.R518X (101 mutation-carriers) as two major causes of LQTS/JLNS in Sweden. LQTS phenotype was revealed to be relatively benign in p.Y111C and p.R518X (annual incidence of life-threatening cardiac events, before therapy 0.05% and 0.04%, respectively). Gender-specific effects of genetic modifiers on phenotypic expression were seen. A founder origin, approximately 600-700 years ago in two northern river valleys was established for p.Y111C and p.R518X, and a high prevalence of LQTS founder descendants suggested. A minimum JLNS prevalence of 1:200 000 in preadolescent Swedish children was revealed. JLNS phenotype was mainly severe, with a cumulative incidence of life-threatening cardiac events of 53% (annual incidence rate before therapy 5%) and four sudden deaths. Possible founder effects regarding four KCNQ1 mutations; p.Y111C (8%), p.R518X (50%), c.572_576del (17%) and p.Q530X (8%) together explained 83% of the JLNS mutation-spectrum in Sweden, consisting of 8 KCNQ1 mutations.

    Conclusion: The high prevalence of p.Y111C- and p.R518X-related LQTS as well as JLNS revealed in Sweden could be explained by the combination of mild clinical phenotypes in heterozygotes and strong founder effects present during the population development of northern Sweden. Increased knowledge regarding the occurrence of LQTS and JLNS as well as mutation- and/or genotype-specific data constitute prerequisites for possible improvement of patient management.

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  • 12.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Department of Physiology, University of Auckland, Auckland, New Zealand.
    Diamant, Ulla-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Persson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jensen, Steen M.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    To Modify or Not to Modify: Allele-Specific Effects of 3’UTR-KCNQ1 Single Nucleotide Polymorphisms on Clinical Phenotype in a Long QT 1 Founder Population Segregating a Dominant-Negative Mutation2022Ingår i: Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease, ISSN 2047-9980, E-ISSN 2047-9980, Vol. 11, nr 18, artikel-id e025981Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

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  • 13.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Diamant, Ulla-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Persson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Origin of the Swedish long QT syndrome Y111C/KCNQ1 founder mutation2011Ingår i: Heart Rhythm, ISSN 1547-5271, E-ISSN 1556-3871, Vol. 8, nr 4, s. 541-547Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: The Y111C/KCNQ1 mutation causes a dominant-negative effect in vitro albeit a benign clinical phenotype in a Swedish Long QT Syndrome population.

    OBJECTIVE: To investigate the origin (genealogic, geographic, genetic and age) of the Y111C/KCNQ1 mutation in Sweden.

    METHODS: We identified 170 carriers of the Y111C/KCNQ1 mutation in 37 Swedish proband families. Genealogical investigation was performed in all families. Haplotype analysis was performed in 26 probands, 21 family members and 84 healthy Swedish controls, using 15 satellite markers flanking the KCNQ1 gene. Mutation age was estimated using the ESTIAGE and DMLE computer softwares and regional population demographics data.

    RESULTS: All probands were traced back to a northern river valley region. A founder couple born in 1605/1614 connected 26/37 families. Haplotyped probands shared 2-14 (median 10) uncommon alleles, with frequencies ranging between 0.01-0.41 (median 0.16) in the controls. The age of the mutation was estimated to 24 generations (95% CI 18; 34), i.e. 600 years (95% CI 450; 850) if assuming 25 years per generation. The number of now living Swedish Y111C mutation-carriers was estimated to ~200-400 individuals for the mutation age span 22-24 generations and population growth rates 25-27%.

    CONCLUSIONS: The Y111C/KCNQ1 mutation is a Swedish LQTS founder mutation, introduced in the northern population approximately 600 years ago. The enrichment of the mutation was enabled by a mild clinical phenotype and strong regional founder effects during the population development of the northern inland. The Y111C/KCNQ1 founder population constitutes an important asset for future genetic and clinical studies.

  • 14.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Diamant, Ulla-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Low incidence of sudden cardiac death in a Swedish Y111C type 1 long-QT syndrome population2009Ingår i: Circulation: Cardiovascular Genetics, ISSN 1942-325X, E-ISSN 1942-3268, Vol. 2, nr 6, s. 558-564Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: A 10% cumulative incidence and a 0.3% per year incidence rate of sudden cardiac death in patients younger than 40 years and without therapy have been reported in type 1 long-QT syndrome. The Y111C-KCNQ1 mutation causes a severe phenotype in vitro, suggesting a high-risk mutation. This study investigated the phenotype among Y111C-KCNQ1 mutation carriers in the Swedish population with a focus on life-threatening cardiac events.

    Methods and Results: We identified 80 mutation carriers in 15 index families, segregating the Y111C-KCNQ1 mutation during a national inventory of mutations causing the long-QT syndrome. Twenty-four mutation carriers <40 years experienced syncope (30%). One mutation carrier had an aborted cardiac arrest (1.25%). No case of sudden cardiac death was reported during a mean nonmedicated follow-up of 25±20 years. This corresponds to a low incidence rate of life-threatening cardiac events (0.05%/year versus 0.3%/year, P=0.025). In 8 Y111C families connected by a common ancestor, the natural history of the mutation was assessed by investigating the survival over the age of 40 years for 107 nonmedicated ascertained mutation carriers (n=24) and family members (n=83) born between 1873 and 1968. In total, 4 deaths in individuals younger than 40 years were noted: 1 case of noncardiac death and 3 infant deaths between 1873 and 1915.

    Conclusions: The dominant-negative Y111C-KCNQ1 mutation, associated with a severe phenotype in vitro, presents with a low incidence of life-threatening cardiac events in a Swedish population. This finding of discrepancy emphasizes the importance of clinical observations in the risk stratification of long-QT syndrome.

  • 15.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Fosdal, Inger
    Lindh, Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Diamant, Ulla-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Persson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Wettrell, Göran
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Third Trimester Fetal Heart Rate Predicts Phenotype and Mutation Burden in the Type 1 Long QT Syndrome2015Ingår i: Circulation: Arrhythmia and Electrophysiology, ISSN 1941-3149, E-ISSN 1941-3084, Vol. 8, nr 4, s. 806-814Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 16.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Department of Physiology, University of Auckland, Auckland, New Zealand; Manaaki Manawa Centre for Heart Research, University of Auckland, Auckland, New Zealand; Department of Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand; Cardiac Inherited Disease Group (CIDG), Auckland, New Zealand.
    Ramanan, Suganeya
    Eugster, Emily
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jovinge, Stefan
    Skinner, Jonathan R.
    Montgomery, Johanna M.
    Functional hyperactivity in long OT syndrome type 1 pluripotent stem cell-derived sympathetic neurons2021Ingår i: American Journal of Physiology. Heart and Circulatory Physiology, ISSN 0363-6135, E-ISSN 1522-1539, Vol. 321, nr 1, s. H217-H227Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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 & NOTEWORTHY Here, we present the first study of patient-derived LQT1 sympathetic neurons that are norepinephrine secreting, and electrophysiologically functional, in vitro. Our data reveal a novel LQT1 sympathetic neuronal phenotype of increased neurotransmission and excitability. The identified sympathetic neuronal hyperactivity phenotype is of particular relevance as it could contribute to the mechanisms underlying sympathetically triggered arrhythmia in LQT1.

  • 17.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Fetal heart rate reflects mutation burden and clinical outcome in twin probands with KCNQ1 mutations2018Ingår i: HeartRhythm case reports, ISSN 2214-0271, Vol. 4, nr 6, s. 237-240Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

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  • 18.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Vestibular dysfunction is a clinical feature of the Jervell and Lange-Nielsen Syndrome2015Ingår i: Scandinavian Cardiovascular Journal, ISSN 1401-7431, E-ISSN 1651-2006, Vol. 49, nr 1, s. 7-13Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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.

  • 19.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Sandström, Olof
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Palmqvist, Richard
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome2013Ingår i: Cardiology in the Young, ISSN 1047-9511, E-ISSN 1467-1107, Vol. 23, nr 3, s. 325-334Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim We investigated extra-cardiac clinical symptoms and signs in the rare Jervell and Lange-Nielsen Syndrome, characterised by impaired KCNQ1 function, a gene essential for gastric acid secretion. METHODS: All Swedish Jervell and Lange-Nielsen cases with double KCNQ1 mutations (14 cases) were investigated by medical record review, an interview, and were offered laboratory testing for iron-deficiency anaemia and gastrointestinal markers. RESULTS: A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed. Previous endoscopy in five cases had revealed no case of coeliac or inflammatory bowel disease but three cases of mucosal hyperplasia/dysplasia. Current signs of anaemia or iron substitution were present in 9 of 12 tested cases. Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present. A significant correlation between elevated gastrin levels and concurrent iron-deficiency and/or anaemia was revealed (p-value 0.039). CONCLUSIONS: A high frequency of extra-cardiac clinical symptoms and previous medical investigations was found. We propose that the Jervell and Lange-Nielsen Syndrome phenotypically includes gastrointestinal symptoms/signs and secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations. The resultant elevated gastrin level is a potential risk factor for later gastrointestinal cancer. Clinical monitoring with regard to developing anaemia and hypergastrinaemia should be considered in the Jervell and Lange-Nielsen Syndrome.

  • 20.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Diamant, Ulla-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Persson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Prevalence, mutation spectrum, and cardiac phenotype of the Jervell and Lange-Nielsen syndrome in Sweden2012Ingår i: Europace, ISSN 1099-5129, E-ISSN 1532-2092, Vol. 14, nr 12, s. 1799-1806Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    AIMS: To explore the national prevalence, mutation spectrum, cardiac phenotype, and outcome of the uncommon Jervell and Lange-Nielsen syndrome (JLNS), associated with a high risk of sudden cardiac death.

    METHODS AND RESULTS: A national inventory of clinical JLNS cases was performed. Genotype and area of origin were ascertained in index families. Retrospective clinical data were collected from medical records and interviews. We identified 19 cases in 13 Swedish families. A JLNS prevalence >1:200 000 was revealed (five living cases <10 years of age). The mutation spectrum consisted of eight KCNQ1 mutations, whereof p.R518X in 12/24 alleles. Geographic clustering of four mutations (20/24 alleles) and similarities to Norway's mutation spectrum were seen. A high prevalence of heterozygotes was suggested. Three paediatric cases on β-blockers since birth were as yet asymptomatic. Seven symptomatic cases had suffered an aborted cardiac arrest and four had died suddenly. QTc prolongation was significantly longer in symptomatic cases (mean 605 ± 62 vs. 518 ± 50 ms, P = 0.016). β-Blockers reduced, but did not abolish, cardiac events in any previously symptomatic case. β-Blocker type, dosage, and compliance probably affect outcome significantly. Implantable cardioverter-defibrillator therapy (ICD, n = 6) was associated with certain complications; however, no case of sudden death.

    CONCLUSION: Founder effects could explain 83% of the Swedish JLNS mutation spectrum and probably contribute to the high JLNS prevalence found in preadolescent Swedish children. Due to the severe cardiac phenotype in JLNS, the importance of stringent β-blocker therapy and compliance, and consideration of ICD implantation in the case of therapy failure is stressed.

  • 21.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nordin, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Diamant, Ulla-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Klinisk fysiologi.
    Persson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jensen, Steen M
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Medicin.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    The Swedish long QT syndrome R518X/KCNQ1 founder population- origin and clinical phenotype: phenotypic variability partly explained by gender-specific effects of sequence variants in the NOS1AP geneManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Background: Genetic modifiers have been proposed to explain phenotypic variability in the long QT syndrome (LQTS). We investigate the origin and phenotype of the worldwide common R518X/KCNQ1 mutation in Sweden, as well as possible associations between p.R518X-LQTS phenotype and previously reported modifying sequence variants in the NOS1AP, KCNH2, KCNE1, SCN5A and KCNQ1(3’UTR) genes.

    Methods and Results: We identified 19 p.R518X families (101 mutation-carriers, whereof 15 Jervell and Lange-Nielsen (JLNS) cases and 86 LQTS cases). Analyses of microsatellite markers, genealogy and mutation age (ESTIAGE) identified a common northern origin ~700 years ago for 17/19 families and a high prevalence of Swedish p.R518X heterozygotes was suggested (DMLE). 

    Clinical phenotype ranged from severe in JLNS to relatively benign in LQTS (QTc 576±61 ms vs. 462±34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%).

    In p.R518X-LQTS males, two NOS1AP variants rs12143842 and rs16847548 were associated with a 29 ms QT prolongation (p=0.004), explaining 27% of QTc variability.

    Three derived 3’UTR-KCNQ1 variants, previously shown to suppress gene expression in an allele-specific manner, were found to segregate with the founder mutation.

    Conclusion: The R518X/KCNQ1 mutation is a Swedish founder mutation presenting with an expectedly severe phenotype in JLNS and an unusually mild phenotype in LQTS, although intra-familial variability remained. Gender-specific effects of NOS1AP sequence variants explained over a fourth of QTc variance in p.R518X-LQTS males, warranting further studies. Repressive 3’UTR-KCNQ1 sequence variants segregating within the founder haplotype could possibly contribute to its relative benignancy.

  • 22.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Stattin, Eva-Lena
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nordin, Charlotte
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Diamant, Ulla-Britt
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Persson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jensen, Steen M.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: a clinical, genealogical and molecular genetics study including Swedish R518X/KCNQ1 families2014Ingår i: BMC Cardiovascular Disorders, ISSN 1471-2261, E-ISSN 1471-2261, Vol. 14, s. 22-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: The R518X/KCNQ1 mutation is a common cause of autosomal recessive (Jervell and Lange Nielsen Syndrome-JLNS) and autosomal dominant long QT syndrome (LQTS) worldwide. In Sweden p.R518X accounts for the majority of JLNS cases and is the second most common cause of LQTS. Here we investigate the clinical phenotype and origin of Swedish carriers of the p. R518X mutation. Methods: The study included 19 Swedish p. R518X index families, ascertained by molecular genetics methods (101 mutation-carriers, whereof 15 JLNS cases and 86 LQTS cases). In all families analyses included assessment of clinical data (symptoms, medications and manually measured electrocardiograms), genealogy (census records), haplotype (microsatellite markers) as well as assessment of mutation age and associated prevalence (ESTIAGE and DMLE computer software). Results: Clinical phenotype ranged from expectedly severe in JLNS to surprisingly benign in LQTS (QTc 576 +/- 61 ms vs. 462 +/- 34 ms, cumulative incidence of (aborted) cardiac arrest 47% vs. 1%, annual non-medicated incidence rate (aborted) cardiac arrest 4% vs. 0.04%). A common northern origin was found for 1701/1929 ancestors born 1650-1950. Historical geographical clustering in the coastal area of the Pite River valley was shown. A shared haplotype spanning the KCNQ1 gene was seen in 17/19 families. Mutation age was estimated to 28 generations (95% CI 19;41). A high prevalence of Swedish p. R518X heterozygotes was suggested (similar to 1: 2000-4000). Conclusions: R518X/KCNQ1 occurs as a common founder mutation in Sweden and is associated with an unexpectedly benign phenotype in heterozygous carriers.

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  • 23.
    Winbo, Annika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik. Department of Physiology, University of Auckland, Auckland, New Zealand.
    Stattin, Eva-Lena
    Westin, Ida Maria
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Persson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Jensen, Steen M.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Kardiologi.
    Rydberg, Annika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Sex is a moderator of the association between NOS1AP sequence variants and QTc in two long QT syndrome founder populations: a pedigree-based measured genotype association analysis2017Ingår i: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 18, artikel-id 74Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    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 QTc in females (both p = 0.16) while in males, a prolongation of +19 ms and +8 ms (p = 0.002 and p = 0.02) was seen in multivariable analysis, explaining up to 23% of QTc variance in all males.

    Conclusions: Sex was identified as a moderator of the association between NOS1AP sequence variants and QTc in two LQT1 founder populations. This finding may contribute to QTc sex differences and affect the usefulness of NOS1AP as a marker for clinical risk stratification in LQTS.

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