title: Third trimester fetal heart rate predicts phenotype and mutation burden in the type 1 long QT syndrome.
abstract: 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.
  
  
  RESULTS
  This retrospective study includes 184 fetuses from 2 LQT1 founder populations segregating p.Y111C and p.R518X (74 noncarriers and 110 KCNQ1 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.
authors.affiliation: From the Department of Clinical Sciences, Pediatrics (A.W., M.L., J.P., A.R.) and Department of Public Health and Clinical Medicine, Heart Centre (U.-B.D.), Umeå University, Umeå, Sweden; Pediatric Clinic, Visby Hospital, Visby, Sweden (I.F.); Department of Pediatrics and Pediatric Cardiology, University of Lund, Lund, Sweden (G.W.); and Department of Physiology, University of Auckland, Auckland, New Zealand (A.W.). Annika.Winbo@umu.se.
authors.forename: Annika
authors.initials: A
authors.lastname: Winbo
authors.affiliation: From the Department of Clinical Sciences, Pediatrics (A.W., M.L., J.P., A.R.) and Department of Public Health and Clinical Medicine, Heart Centre (U.-B.D.), Umeå University, Umeå, Sweden; Pediatric Clinic, Visby Hospital, Visby, Sweden (I.F.); Department of Pediatrics and Pediatric Cardiology, University of Lund, Lund, Sweden (G.W.); and Department of Physiology, University of Auckland, Auckland, New Zealand (A.W.).
authors.forename: Inger
authors.initials: I
authors.lastname: Fosdal
authors.affiliation: From the Department of Clinical Sciences, Pediatrics (A.W., M.L., J.P., A.R.) and Department of Public Health and Clinical Medicine, Heart Centre (U.-B.D.), Umeå University, Umeå, Sweden; Pediatric Clinic, Visby Hospital, Visby, Sweden (I.F.); Department of Pediatrics and Pediatric Cardiology, University of Lund, Lund, Sweden (G.W.); and Department of Physiology, University of Auckland, Auckland, New Zealand (A.W.).
authors.forename: Maria
authors.initials: M
authors.lastname: Lindh
authors.affiliation: From the Department of Clinical Sciences, Pediatrics (A.W., M.L., J.P., A.R.) and Department of Public Health and Clinical Medicine, Heart Centre (U.-B.D.), Umeå University, Umeå, Sweden; Pediatric Clinic, Visby Hospital, Visby, Sweden (I.F.); Department of Pediatrics and Pediatric Cardiology, University of Lund, Lund, Sweden (G.W.); and Department of Physiology, University of Auckland, Auckland, New Zealand (A.W.).
authors.forename: Ulla-Britt
authors.initials: UB
authors.lastname: Diamant
authors.affiliation: From the Department of Clinical Sciences, Pediatrics (A.W., M.L., J.P., A.R.) and Department of Public Health and Clinical Medicine, Heart Centre (U.-B.D.), Umeå University, Umeå, Sweden; Pediatric Clinic, Visby Hospital, Visby, Sweden (I.F.); Department of Pediatrics and Pediatric Cardiology, University of Lund, Lund, Sweden (G.W.); and Department of Physiology, University of Auckland, Auckland, New Zealand (A.W.).
authors.forename: Johan
authors.initials: J
authors.lastname: Persson
authors.affiliation: From the Department of Clinical Sciences, Pediatrics (A.W., M.L., J.P., A.R.) and Department of Public Health and Clinical Medicine, Heart Centre (U.-B.D.), Umeå University, Umeå, Sweden; Pediatric Clinic, Visby Hospital, Visby, Sweden (I.F.); Department of Pediatrics and Pediatric Cardiology, University of Lund, Lund, Sweden (G.W.); and Department of Physiology, University of Auckland, Auckland, New Zealand (A.W.).
authors.forename: Göran
authors.initials: G
authors.lastname: Wettrell
authors.affiliation: From the Department of Clinical Sciences, Pediatrics (A.W., M.L., J.P., A.R.) and Department of Public Health and Clinical Medicine, Heart Centre (U.-B.D.), Umeå University, Umeå, Sweden; Pediatric Clinic, Visby Hospital, Visby, Sweden (I.F.); Department of Pediatrics and Pediatric Cardiology, University of Lund, Lund, Sweden (G.W.); and Department of Physiology, University of Auckland, Auckland, New Zealand (A.W.).
authors.forename: Annika
authors.initials: A
authors.lastname: Rydberg
mesh_terms: D000328:Adult; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D042241:Early Diagnosis; D004562:Electrocardiography; D005260:Female; D005315:Fetal Diseases / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006340:Heart Rate, Fetal / Q000235:genetics*; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D011296:Prenatal Diagnosis; D012189:Retrospective Studies; D029597:Romano-Ward Syndrome / Q000196:embryology / Q000235:genetics* / Q000378:metabolism
chemical_list: D051657:KCNQ1 Potassium Channel; D004247:DNA
keywords: arrhythmias; cardiac; genetic association studies; genotype; heart rate; long QT syndrome