Pediatric Cardiology

Parental Electrocardiographic Screening Identifies a High
Degree of Inheritance for Congenital and Childhood
Nonimmune Isolated Atrioventricular Block
Alban-Elouen Baruteau, MD; Albin Behaghel, MD; Swanny Fouchard, PhD; Philippe Mabo, MD;
Jean-Jacques Schott, PhD; Christian Dina, MS; Ste´phanie Chatel, PhD; Elisabeth Villain, MD;
Jean-Benoit Thambo, MD, PhD; Franc¸ois Marc¸on, MD; Ve´ronique Gournay, MD, PhD;
Francis Rouault, MD; Alain Chantepie, MD; Sophie Guillaumont, MD; Franc¸ois Godart, MD, PhD;
Raphae¨l P. Martins, MD; Be´atrice Delasalle, MS; Caroline Bonnet, MD; Alain Fraisse, MD, PhD;
Jean-Marc Schleich, MD, PhD; Jean-Rene´ Lusson, MD; Yves Dulac, MD; Jean-Claude Daubert, MD;
Herve´ Le Marec, MD, PhD; Vincent Probst, MD, PhD

Background—The origin of congenital or childhood nonimmune isolated atrioventricular (AV) block remains unknown.
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We hypothesized that this conduction abnormality in the young may be a heritable disease.
Methods and Results—A multicenter retrospective study (13 French referral centers, from 1980 –2009) included 141
children with AV block diagnosed in utero, at birth, or before 15 years of age without structural heart abnormalities and
without maternal antibodies. Parents and matched control subjects were investigated for family history and for ECG
screening. In parents, a family history of sudden death or progressive cardiac conduction defect was found in 1.4% and
11.1%, respectively. Screening ECGs from 130 parents (mean age 42.0⫾6.8 years, 57 couples) were compared with
those of 130 matched healthy control subjects. All parents were asymptomatic and in sinus rhythm, except for 1 with
undetected complete AV block. Conduction abnormalities were more frequent in parents than in control subjects, found in
50.8% versus 4.6%, respectively (P⬍0.001). A long PR interval was found in 18.5% of the parents but never in control
subjects (P⬍0.0001). Complete or incomplete right bundle-branch block was observed in 39.2% of the parents and 1.5% of
the control subjects (P⬍0.0001). Complete or incomplete left bundle-branch block was found in 15.4% of the parents and
3.1% of the control subjects (P⬍0.0006). Estimated heritability for isolated conduction disturbances was 91% (95%
confidence interval, 80%–100%). SCN5A mutation screening identified 2 mutations in 2 patients among 97 children.
Conclusions—ECG screening in parents of children affected by idiopathic AV block revealed a high prevalence of
conduction abnormalities. These results support the hypothesis of an inheritable trait in congenital and childhood
nonimmune isolated AV block. (Circulation. 2012;126:1469-1477.)
Key Words: atrioventricular block 䡲 conduction 䡲 ECG screening 䡲 genetics 䡲 pediatrics

A trioventricular (AV) block is a rare electrocardiographic
finding in neonates and children who are at risk of
sudden death in the absence of cardiac pacing. It can be
some cases, no obvious cause of AV conduction disorder can be
identified. Familial clustering of progressive cardiac conduction
defect (PCCD) of unknown cause, including congenital AV
caused by various conditions such as transplacental passage block, has been reported. Published pedigrees have shown an
of maternal anti-Ro/SSA or anti-La/SSB antibodies, structural autosomal dominant inheritance with incomplete penetrance and
congenital heart disease, postoperative complications, myocar- variable expressivity.1–3 Given that a limited number of genes
ditis, neuromuscular disorder, or metabolic disease. However, in have been found to be responsible for hereditary PCCD in

Received October 18, 2011; accepted June 26, 2012.
From the Department de Chirurgie cardiaque des cardiopathies conge´nitales, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson (A.-E.B.);
Faculte´ de Me´decine, Universite´ Paris-Sud, Le Kremlin-Biceˆtre (A.E.-B.); INSERM UMR1087, CNRS UMR 6291, L’Institut du thorax, Universite´ de
Nantes, Nantes (A.-E.B., S.F., J.-J.S., C.D., S.C., B.D., H.L.M., V.P.); INSERM, CIC-IT 804, Rennes (A.B., P.M., R.P.M., J.-M.S., J.-C.D.); INSERM,
U642, Rennes (A.B., P.M., R.P.M., J.-M.S., J.-C.D.); Cardiologie, CHU Rennes, Rennes (A.B., P.M., R.P.M., J.-M.S., J.-C.D.); Cardiologie, L’Institut
du thorax, Nantes (S.F., J.-J.S., S.C., B.D., H.L.M., V.P.); APHP, Hoˆpital Necker Enfants Malades, Paris (E.V.); Cardiologie pe´diatrique, CHU Bordeaux,
Bordeaux (J.-B.T.); Cardiologie pe´diatrique CHU Nancy, Nancy (F.M.); Cardiologie pe´diatrique, CHU Nantes, Nantes (V.G.); Cabinet de Cardiologie
pe´diatrique, Marseille (F.R.); Cardiologie pe´diatrique, CHU Tours, Tours (A.C.); Cardiologie Pe´diatrique, CHU Montpellier, Montepellier (S.G.);
Cardiologie Pe´diatrique, CHU Lille, Lille (F.G.); Cardiologie Pe´diatrique, CHU Dijon, Dijon (C.B.); Cardiologie Pe´diatrique, CHU Marseille, Marseille
(A.F.); Cardiologie, CHU Clermont-Ferrand, Clermont-Ferrand (J.-R.L.); and Cardiologie Pe´diatrique, CHU Toulouse, Toulouse (Y.D.); all in France.
Correspondence to Vincent Probst, MD, PhD, Service de cardiologie, CHU de Nantes, 44093 Nantes CEDEX 01, France. E-mail
© 2012 American Heart Association, Inc.
Circulation is available at DOI: 10.1161/CIRCULATIONAHA.111.069161


adults4 – 6 and that it has been recently shown that several block at a young age and invited to consult a cardiologist to undergo common variants modulate heart rate. France.10 and once they are detected. QRS-complex acteristics of apparently healthy parents. and QRS physical examination and a screening 12-lead ECG. Categorical variables were expressed as numbers and percent- were contacted by the genetic research unit of l’Institut du Thorax. the antibodies permanently remain bundle-branch block (LBBB) and left anterior or posterior fascicular in the maternal serum. ECG readers were blinded between control spective cohort of children with idiopathic pediatric AV subjects and family by guest on February 25.10 The parents of the 141 children studied Inc). history. second-. the mothers of all patients included in the block were defined according to American Heart Association/ present study systematically underwent.15 PR-interval duration ⬍200 ms was consid- and 60-kd SSA/Ro by use of previously described high-sensitivity. 1470 Circulation September 18. 52-kd SSA/Ro. or during the first month was defined as a sinus rhythm ⬍60 bpm. 25 mm/s. of life and as childhood AV block if diagnosed between the first month and the fifteenth year of life. Left-axis deviation was defined as utero or in early childhood. Parents and were asked about family histories of sudden death. and QT interval were measured at rest with DatInf Measure dedicated software (DatInf GmbH). was considered to be children presenting with nonimmune isolated AV block diagnosed in normal within ⫺30° and ⫹90°.16 Sinus bradycardia genital if it was diagnosed in utero. 2012 Downloaded from http://circ. seronegative at the time of fetal diagnosis later become seroposi. on inclusion. Time variables were presented with median (25th– screening for asymptomatic cardiac conduction disorders. The 3 ECG readers all analyzed each block. PR interval. usually V2 or Clinical Investigation V3. All participants gave their informed written consent. 2017 Figure 1.11 AV block was classified as con. This hypothesis was tested in a nationwide (France) retro. ECGs were centralized at l’Institut du Thorax and analyzed by 3 medical investigators. Continuous variables with normal distribution were expressed Nantes. and informed about the possibility of parental as mean⫾SD. or heart control subjects were matched 1-to-1 for sex and age on ECG . and QT rate correction was performed with Bazett’s formula. at birth. duration. and a screening 12-lead ECG. Relatives 75th percentiles) or median (minimum-maximum). physical examination.13 The mean frontal plane electric axis. Paper speed was disorders or sudden death and the electrocardiographic char.12 The methodology and Statistical Analysis available data on the clinical characteristics of these patients have Analyses were performed with PASW Statistics 18 software (SPSS been reported previously. and measurements were then averaged.ahajournals. P-wave duration. a screening for American College of Cardiology Foundation/Heart Rhythm Society antibodies to soluble nuclear antigens 48-kd SSB/La. Screening ECG of a 56-year-old father showing third-degree atrioventricular block and a wide QRS complex escape rhythm. matched for age and sex. recommendations. with examination of family histories of conduction ECG. QRS axis.7–9 we hypothesized that idiopathic AV block enrolled at l’Institut du Thorax and subjected to review of family in the young may be a heritable disease. classified according to consensual definition. All included values were averaged from 3 to 5 interval measurements. and third-degree AV blocks were quantitative radioligand assays. PCCD. determined by tertiary hospitals provided the basis for a clinical database of 141 the vector of the maximal QRS deflection. Heart rate. The study was conducted according to the French guidelines for genetic research Editorial see p 1434 and was approved by the Ethics Committee of Nantes University Clinical Perspective on p 1477 Hospital. QT interval Methods was measured in the lead that showed the longest QT. were also complex durations. as A retrospective study conducted from 1980 to 2009 at 13 French recommended. First-. PR interval. Complete or incomplete right bundle-branch block (RBBB) and left tive. Healthy control subjects from the general population.14. Because 9% of mothers who are ⫺30° and beyond and right-axis deviation as ⫹90° and beyond. ages. ered normal.

maximum) PR interval. children’s median (minimum- A cohort of 141 white children affected by a nonimmune maximum) age was 15 (2–34) years. respectively. Corrected QT interval. The McNemar test was performed for categorical Matched Control Subjects variables and Wilcoxon signed rank tests for continuous variables. including 57 couples and 16 isolated maximum) parents.88 0. Baruteau et al Inherited Isolated Heart Block in Children 1471 recording.4%) Family History None of the parents or control subjects had a personal history and complete in 100 (70. Tp and Median (minimum.0⫾7 42. The likelihood of observing 66 Mean⫾SD 408⫾69 372⫾30 affected children of 130 given children polygenic value was esti. Median (minimum. Applied Biosystems). ms 0. 97 parents gave their written consent for a blood Median (minimum.001 s2p) and environmental E (variance s2e) components.4%).8 sequencing of abnormal profiles or directly by sequencing (ABI Median (minimum. The Kaplan-Meier method was used to estimate time to complete Parents Control Subjects block and pacemaker implantation. and 130 matched control subjects were analyzed.6 years. assuming a Median (minimum. PCCD history was found in 8 parents (11. Incomplete AV block pro- of unexplained syncope. or childhood AV block was found in the 2 groups.5) rhythm except for 1 asymptomatic parent in whom previously .2%) of 26 patients with congenital AV no control subjects (P⫽0. 105 (55–247) 74 (41–110) To.8 and 42. a Kruskal-Wallis test was performed. Both components follow a normal distribution.88 parents. A Median (minimum. Mutation screening of SCN5A was performed by high-resolution melting assay P wave. ␮⫽␮p. which reflect the different severity of status in parents and maximum) offspring: L⫽G⫹E. in Children At the time of last follow-up. a 1-way ANOVA was performed for continuous variables Age at ECG. with s2g⫹s2e⫽1. and a Pearson ␹2 test was used Mean⫾SD 42. y with a Tukey post hoc test if needed. 392 (245–587) 370 (317–451) mated for each heritability value i as follows: Li(A/ maximum) pg)⫽66⫻loge(␲)⫹64⫻loge(1⫺␲). Genomic DNA was extracted from periph.6⫾12. (n⫽130) (n⫽130) P Value To compare children’s data from groups with 0. during consanguineous marriages were known in the families of the first year of life in 18 (16.001 (L⬎To) to estimate mean Li in parents (␮p).4%) and no control subjects incomplete block was 81. Narrow QRS complexes (P⫽1. 69 (48–100) 65 (47–92) sample from their child. we used the biometric model. Nonparametric tests for paired data were used to compare Table 1.1%) and were present in 18 (69. ° 0.4%). or 2 affected Male/female sex ratio 0.9%). 157 (97–313) 160 (110–200) quantitative liability normalized (mean 0 and variance 1) trait L and a threshold T above which an individual is declared affected maximum) (Falconer).0⫾6.002 Mean⫾SD 423⫾36 408⫾25 Results Median (minimum. bpm 0.2⫾22.88 in the 2 groups. 41 (24–65) 40 (25–62) 2-sided P value ⬍0.0 68⫾10.0⫾7 for categorical variables. ms ⬍0.ahajournals. known conduction disorders.001 on the Light Cycler 480 System (Roche) followed by bidirectional Mean⫾SD 98. s2e).0 (0 – 8. No complications isolated AV block was compiled.5) years. s2g⫹s2e) heritability is the proportion of Mean⫾SD 38⫾47 46⫾29 genetic variance: h2⫽s2g/(s2g⫹s2e)⫽s2g. No Pacemakers were implanted in 112 children (79. AV block was asymptomatic in 119 patients (84. ␴2⫽1).10 Briefly.6%.2%) of 115 with childhood AV block. Median (minimum. The median (25th–75th percentile) time to pacemaker implantation was 2. compared. L⬃N(0. 1.0).5%).org/ by guest on February 25. No family history of congenital block and 106 (92. A family history of sudden death block. s2g)⫹N(0. Characteristics of ECG Parameters in Parents and the 2 groups. ms ⬍0. 2017 Heritability Estimate Mean⫾SD 165⫾39 156⫾19 To estimate heritability. Sex All conduction intervals were significantly longer in parents than in control ratio was 0. or gressed to complete in 29 patients (70.15 of the 2 components L N(0. During a All parents and control subjects were asymptomatic and in sinus median (25th–75th percentile) follow-up of 11 (6 –16. no patient died or developed dilated cardiomyopathy. and mean age at the time of ECG subjects. The variance of L is divided into polygenic G (variance QRS complex. ms 0. To compare continuous variables with nonnormal distribution. 417 (350–549) 405 (360–462) A total of 130 parents.05 was considered statistically significant. Because of independence QRS axis.0 For 141 children. At 10 years’ time.7%) with incomplete pacemaker implantation. Their characteristics and occurred during long-term follow-up in 127 children (90. conditioned on the children being severely affected. 98 (47–188) 87 (56–125) PRISM 3730 DNA Sequencer. Characteristics of Nonimmune Isolated AV Block years. ms ⬍0. No difference appeared when heart rates in the 2 groups were recording was 42.0⫾6. maximum) Heart rate. long-term outcomes have been published elsewhere. 60 (⫺140 to 140) 60 (⫺60 to 100) We simulated trios (1 child and 2 parents) for a grid of heritability maximum) values i and retained trios in which the children were affected QT interval.1%) and before 10 years of age affected children. This classic Mean⫾SD 109⫾29 73⫾13 model was modified slightly to allow 2 different thresholds. The pacing Screening ECG Analysis indication was prophylactic in 70 children (62.69 Genetic Analysis Mean⫾SD 69⫾12. the proportion of children with was found in 1 parent (1. maximum) eral blood lymphocytes by use of standard protocols.33 Downloaded from http://circ. in 90 (80.1%).3 88.1%⫾3.01). ␲⫽⌽⫺1 (Tp.

1%. (18. QRS incomplete RBBB was observed in 51 parents (39. and corrected QT-interval durations were control subjects (1.3%) versus 2 (1. . respectively found in 66 (50.5%) cases. PR interval (D). LBBB.0006). corrected QT interval (QTc) (B) durations were longer in parents than in control subjects. P⬍0. P⬍0. (P⬍0.0001). 1472 Circulation September 18. respectively PR interval.0001). ECG character. P wave (C). Comparison of heart rate (A).6%) Intraventricular conduction defect of any type (RBBB. (Table 2).001). significant difference was found when we compared heart rate.5%) but in no control subjects (P⬍0.001). Complete or incomplete LBBB was found in 20 malities were more frequent in parents than in control subjects parents (15. QRS axis (F). 2012 Downloaded from http://circ. PR interval was prolonged in 24 parents complex escape rhythm was found (Figure 1). No significantly more frequent in parents than in control subjects. P wave.8%) and 6 (4. undetected permanent complete AV block with broad QRS individuals (P⬍0.2%) and 2 complex. No differences appeared when heart rate and QRS axis were compared in the 2 groups.4%) and 4 control subjects (3.ahajournals. QRS complex (E). and QRS axis in the 2 groups. found in 16 (12.5%. and different conduction intervals between parents and matched control subjects. 2017 Figure 2. Incomplete RBBB was significantly longer in parents than in control by guest on February 25. Complete or istics are presented in Table 1 and Figure 2. QT interval. Conduction abnor.

Arg367His). of having This is the first relatively large-scale study looking for 0. Parental ECG screening performed in a large cohort First-degree AVB⫹complete 5 (3. Moreover.16.02 RBBB⫹LAFB of children with pediatric idiopathic heart block provided First-degree AVB⫹LAFB 3 (2.08 strong evidence for a genetic origin in congenital and child- hood nonimmune isolated AV block. complete RBBB. the mutation was also found in her father.001 was affected by a cardiac conduction defect (first-degree AV conduction block.4) 0 (0) 0.004 second mutation. Baruteau et al Inherited Isolated Heart Block in Children 1473 Table 2. 95% of variation in the presence of the trait was attributed to heritable factors. . 1.8) 0 (0) 0. however. their ECG phenotype differed from the propositus cases in the present study because they presented with intraventricular Phenotype of Children According to Parents conduction impairment. Severity of conduction disorders in children.7) 12 (9.32 Downloaded from http://circ. in this age group.17–19 Isolated complete LBBB 0 (0.6%. pacemakers Complete RBBB⫹LAFB 4 (3. did not differ pediatric heart block may be inherited or not. right-axis deviation) was observed in 59 reporting ECG findings in the general population.8) 4 (3.23 interval. The p.8. P⬍0.5) 0 (0) ⬍0.Thr1806SerfsX27 and p.1.4) 4 (3.3) 0 (0) 0. majority of index cases had no known family history.22.8) 0 (0) 0.5) 0. atrioventricular block. calculated at h2⫽91% (95% confidence gation. the child was diagnosed at 12 months with a Incomplete RBBB⫹LAFB 2 (1.1) ⬍0. Heritability Estimate A genetic contribution has been suggested for a long time The heritability estimate for isolated conduction disturbances by reports of familial clusters of isolated heart block segre- was very high.4. which included some rare pediatric cases.4) ⬍0. cardiac In addition. evaluated congenital and childhood nonimmune isolated AV block. Third-degree AVB 1 (0. complete or incomplete RBBB. The very low rate of conduction abnormalities observed in control subjects was comparable with that of historical studies left-axis deviation. some affected children have been described in presenting with asymptomatic conduction impairment had a large families in whom SCN5A and TRPM4 have been 6-fold increased relative risk of presenting with isolated identified as the genes causing the conduction defect. left posterior parents than control subjects. but nonimmune AV block. and left-axis devia- tion.Arg367His has been Isolated LPFB 0 (0. RBBB. AV.0001 did not present with any conduction block.0) 0 (0) Isolated first-degree AVB 7 (5. who Normal AV and intraventricular 64 (49. abnormalities (Table 3).8%). AV block.5) ⬍0. or 2 parents presenting with subclinical conduction heritability in a cohort with pediatric idiopathic heart block.16 drome cases and failed to generate any current. 1. Individuals with at least 1 parent Similarly.67 degree AV block. (p.008 disease.2) 2 (1. bances was not relevant to determine whether an isolated related symptoms. indicative of intra-atrial. by age at diagnosis. and left anterior hemiblock).5) 0 (0) 0. For the Isolated incomplete RBBB 13 (10. well- characterized conduction disturbances were more frequent in AV indicates atrioventricular. No difference was found to be The present findings demonstrate a high degree of inheritance significant when the 3 groups were compared one to each and a strong genetic contribution in the pathogenesis of other. time of progression from incomplete to A family history of sudden death or conduction distur- complete heart block.8) 0 (0) 0.4%) and 6 control subjects (4. and age at cardiac pacing.3) 124 (95. This mutant p.0006 the LBBB intraventricular conduction abnormalities.0) 2 (1. baseline heart by guest on February 25. who Isolated complete RBBB 16 (12.16 2/1 AV block.1) 0. LBBB. 80%–100%).05 had been implanted in his maternal aunt and grandmother (no Isolated LAFB 5 (3. because the vast significantly in these groups. LAFB. we found that congenital and childhood isolated conduction impairment was found in at least 1 parent of 39 nonimmune AV block is a highly heritable trait.ahajournals.74 ECG or DNA available). The mutation was inherited from his mother. and Impaired conduction in 20 (15.0) 0 (0) described in Brugada syndrome and early repolarization syn- Isolated incomplete LBBB 2 (1.4%) and in both parents of 17 children (29. and AVB. right bundle-branch block. left anterior fascicular block. because almost children (68. and complete LBBB was reported to be in the 2 groups (Figure 3).0001).21 child and his or her 2 parents) with available ECGs.0001 by idiopathic AV block revealed a high prevalence of impaired Impaired conduction in 51 (39. complete RBBB.32 ECG screening in asymptomatic parents of children affected PR prolongation 24 (18.3. presence of block.0001 the RBBB cardiac conduction characterized by a long P wave and pro- longed PR and QRS intervals. Among the 57 trios (made up of a 6. In a series of parents (45. To date. Sinus 122 043 asymptomatic adults. respectively.008 Discussion The aim of the present study was to evaluate the hypothesis First-degree AVB⫹incomplete RBBB 1 (0.20. Children were classified in 3 groups. and 0. Subclinical Characterized Conduction Disturbances in Genetic Study in Children Parents and Matched Control Subjects SCN5A gene screening was performed in 97 children and led to Control the identification of 2 different mutations in 2 children Parents.Thr1806SerfsX27 n (%) n (%) P Value mutation carrier was diagnosed at 7 years of age with first- Sinus bradycardia 14 (10.4) 0 (0) 0. 2017 that idiopathic AV block in the young may be a heritable First-degree AVB⫹complete RBBB 7 (5.2) 0. the prevalence of first-degree AV bradycardia was not found in a statistically different proportion block.13 per 1000. LPFB. mainly consisting of first-degree fascicular block. Subjects.5) 0 (0) 0.1) 0 (0) 0.5. left bundle-branch block.3) 0 (0) ⬍0. respectively.

the gene rhythm. These former segregation of cardiac conduction disorders. variants may cause more QRS escape rhythm can lead to syncope or sudden death.22–25 Our findings from degree AV block. The role of consanguinity has reported in the literature.28 –34: SCN5A. which phenotype associates RBBB esize that parents may carry 1 or more allelic variant with a possibly with right.28 This is the most frequently reported type of Surprisingly. syndromes. This PCCD is an isolated conduction disorder. interval.26 Since then. incomplete penetrance.27 Progression to complete heart block with a wide Once inherited from both parents. complete right bundle-branch block. progressed to a permanent.2– 6. To date. possibly associated with first- effect of the causative mutation. Morquio first called attention to a familial that reported to date in large affected families. a . Children were mainly diagnosed with affected families has led to the identification of several causal permanent. 2012 Downloaded from http://circ. particularly inheritance in familial pedigrees.1 Both a ge- may also be carriers of a variant with an incomplete pen. the gene encoding the function-modifying sodium time and also had a narrow QRS complex.23. (2) both parents were found to have subclinical conduction progressive familial heart block type II2. They can be classified into 3 distinct been discussed because this condition has been reported in clinical entities: (1) PCCD or hereditary Lene`gre disease. We hypoth. and left-axis deviation. heart block with a narrow QRS complex. complete AV block and narrow QRS escape mutations in 3 main genes4 – 6. data suggest that pediatric isolated AV block may have a several cases of familial heart block segregation have been distinct genetic background.0%) channel ␤1-subunit. An isolated PR-interval prolongation with- parental screening make this transmission mode less probable out evidence of infrahisian conduction impairment was found here.ahajournals. all published cases of inherited congenital or childhood conduction abnormalities. In contrast.26 However. netic background and congenital cases have been published etrance. the children. Screening ECG of a 48-year-old father showing sinus rhythm. parental ECG screen- isolated heart block have revealed an autosomal dominant ing revealed mainly bundle-branch defects. also some families with AV conduction defect. the gene encoding the of the 141 children were diagnosed with intraventricular transient receptor potential subfamily M member 4. but no evidence of designated by some authors as progressive familial heart consanguineous marriages in families was found. linkage analysis of large dren and their parents. 2017 Figure 3. we found different ECG phenotypes in chil. Nonaffected parents progressive atrioventricular conduction defect. which differs from In 1901. severe cardiac conduction disturbances in their progeny. block type I or hereditary bundle-branch defect2. and (3) hereditary abnormalities in nearly 30% of the cases. The phenotype of our propositus associates complete in only 5% of the by guest on February 25. complete block in a short mean SCN1B. mainly with diffuse conduction impairment but PCCD is an autosomal dominant inherited disorder with without complete heart block. 1474 Circulation September 18.4.or left-axis deviation or a prolonged PR mild effect. but some cases of kind of transmission should correspond to a polygenic model dilated cardiomyopathy have been described in overlapping of inheritance. hereditary heart block. which suggests a major RBBB and left-axis deviation. except in 1 case. Only 17 (12. and TRPM4. Those initially presenting with incomplete AV block encoding the ␣-subunit of the cardiac sodium channel.22. Parental phenotype appeared less severe than that of for PCCD and progressive familial heart block type II. which would explain the less severe phenotype.

the ECG phenotype of affected an unknown nature could also explain the difference in the parents was close to that described in PCCD with RBBB.7 0. The pattern of 57 trios made up of an affected child and his or her 2 may present with associated isolated conduction disturbances.4⫾6.* mo Median (minimum-maximum) 6 (0–132) 0 (0–300) 13 (0–122) 0. mean⫾SD 56⫾15 55⫾16 62⫾24 0. 1. cQT.37 QRS complex. related hereditary Lene`gre disease results from haploinsuffi- but a locus has been mapped to chromosome 1q32. or 2 Affected Parents No Affected Parent 1 Affected Parent 2 Affected Parents (n⫽18) (n⫽22) (n⫽17) P Value Male/female sex ratio 1. n (%) 4 (22.0) 3. and PM.2-q32.6) 3 (17.5 deviation. atrioventricular. and its branches.0 Sudden death 0 1 0 0. but a of their children was similar to that described in hereditary conduction defect is most often associated with a secundum progressive atrioventricular conduction defect.8⫾4.4) 0. n (%) 4 (22. n (%) 13 (72. calcium-activated nonselective cation channel.6) 10 (58. phenotype between a child and his or her parents.8) 0.27 Family history. human does not need all of the Na⫹ channels for proper impulse tricular conduction defect. which exacerbates Hereditary progressive atrioventricular conduction defect physiological age-related progressive conduction slowing is a rare condition.25 At last follow-up Follow-up time. transmitted in an autosomal dominant caused by fibrosis or an alternative process.45 At diagnosis Age at diagnosis.35 ciency of the cardiac Na⫹ channel gene. 2017 Heart rate. y Mean⫾SD 5. n PCCD 1 3 3 0.34 Mortality.39.2) 3 (13. has Lev-Lene`gre disease.0 PCCD indicates progressive cardiac conduction defect.57 0.9 0.0) 0 (0. Why the ECG phenotype differs between a child and isolated dilated cardiomyopathy.8⫾4.0 Childhood AV block 0 0 0 1.0) 1.46 Congenital AV block 0 0 0 1.8⫾8.0) 1.5 3. *Time between AV block diagnosis and first pacemaker implantation. n (%) 0 (0.0⫾6.ahajournals. No gene has been identified yet.51 Downloaded from http://circ. the same family is highly unusual.95 PM implantation. including congenital cases of may have a high safety factor that leads to sufficient impulse AV block. ms. despite the strong effect of inherited variants.78 Childhood AV block. although we found it in 39 somal dominant cardiac disorder of adult onset. ms.6⫾6. 1.1 propagation has been proposed.7⫾3. y 11.6) 0.2) 16 ( by guest on February 25.0) 0 (0. n (%) 14 (77. y Mean⫾SD 3.33 ences appeared when we compared children from 0.30 Compensatory mechanisms of In the present study. We have pairment is characterized by sinus bradycardia and AV block previously shown that the pathophysiology of the SCN5A- with a narrow QRS complex. from first.1) 3 (17.8) 14 (63. ECG possibly associated with PR prolongation or left.7 3.32.or right-axis follow-up of these children until adulthood would be of interest .2) 2 (9. The NKX2.78 cQT interval. with no associated intraven.0) 0.96 Median (minimum-maximum) 4 (0–22) 5 (0–25) 3 (0–15) 0. the ECG phenotype also been identified in isolated pediatric AV blocks.7) 12 (70.0 (0–12.68 P wave.1 5.6) 0.3.6 11.99 Median (minimum-maximum) 2. Baruteau et al Inherited Isolated Heart Block in Children 1475 Table 3. which encodes a homeobox transcription factor. The hypothesis that the heart in the young degree to complete AV block.57 0.9 0. or 2 Progressive familial heart block type II has been described affected parents.1.1⫾6.30 We hypothesize manner with incomplete penetrance. a limited number of families.99 Time. mean⫾SD 82⫾23 81⫾36 89⫾35 0. bpm.7 10.5 (0–19. Comparison of Children’s Characteristics in Groups With 0.40 Interestingly. his or her parents remains to be clearly elucidated. mean⫾SD 96⫾66 70⫾18 80⫾19 0.9 0. n (%) 14 (77. ms.36 –38 ECG features were characterized by a propagation for almost normal conduction in the His bundle progressive increase in AV conduction delay. or both.3 (0–15. as in the historical descriptions of the idiopathic gene. parents.4) 14 (82.78 Complete AV block.71 Congenital AV block. corrected QT. It has been described in that children.4 6. mean⫾SD 456⫾100 450⫾47 403⫾64 0.53 Age at first PM.4⫾4.8) 19 (86. AV.29 Wide QRS complex.34 Conduction im. The mixing of these 2 distinct phenotypes in in a South African family of European descent as an auto.6) 0. pacemaker. No differ- atrial septal defect or tetralogy of Fallot.

Acknowledgment Pramstaller PP. 1999. Gasparini M. Løchen ethically justify offering ECG screening to these families. van Herpen G. Proposal for a new definition of congenital complete atrioventricular block. Johnson T. and health insurance refusal or complaint) that Li M. Rudan I. Vo¨lker U. Sotoodehnia N.32:32–34. Mabo by guest on February 25. van Gilst WH. Jeronimo AL. Taber E. ECG screening in parents of children affected by idiopathic Magnani JW. Johannet C. and interpretation of the electrocardiogram: part IV: the ST segment. Yang T. Yamamoto AM. Wang TJ. Heckbert SR. Jamshidi Y. Kors JA. Stricker BHC.ahajournals. Carter S. Le Scouarnec S. 1. or 2 affected parents are compared. Godart F. Bis AV block revealed diffuse subclinical impairment of cardiac JC. Brucato A. Lusson J-R. van Herpen G. the Daubert J-C. Caulfield MJ. Nat Genet. Launer LJ. Gharib SA. Gournay V. Vignati G. 2010. At the time we designed 7. Wichmann H-E. Isaacs A. the American College of Car- Wilde AA. . Pongs O. Alonso A. Campbell of transmission. Wichmann HE. J Clin Invest. AHA/ACCF/HRS recommendations for the standardization Med J. Lynch HT. Larson MG. van Veldhuisen DJ. Witteman JC. 2. Agence Nationale de la Recherche grant 05-MRAR-028. Harris TB. Franke L. Escande D. te Meerman G. this context. would subsequently appear with aging. Kors JA. Teumer A. Ka¨a¨b S. Fuchsberger C. Pfeufer A. Runco V. Macfarlane P. Okin P. Given our results. Holm H. Snieder H. and the QT interval: a scientific statement from the conduction defects. Several common because the chances of identifying clinically relevant findings variants modulate heart rate. Amoura Z. Montella S. Gudbjartsson DF. Folsom AR. Wilson JF. Cardiac conduction diology Foundation. Bailey JJ. Schulze-Bahr E. seemed smaller than the possible side effects (such as 8. Dominiczak AF. dation pour la Recherche Me´dicale. Brink P. This study was supported in part by grants from PHRC 2004 R20/07 Bonnet C. despite Newton-Cheh C. Childers R. 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