Tetralogy Of Fallot Cases Research Articles

Whole-exome sequencing and homozygosity mapping identify variants in NCOR1 and MAP2K3 associated with non-syndromic congenital heart defects

BackgroundHomozygosity mapping is an efficient gene mapping method applicable to recessive disorders. It can detect homozygous segments of identical haplotype structures shared at a higher frequency among ventricular septal defect (VSD) and tetralogy of Fallot (TOF) cases. This study aims to identify the recessive genes involved in congenital heart disease (CHD) cases by homozygosity mapping. A total of 36 CHD cases of Indian origin were recruited based on inclusion and exclusion criteria, disease severity, and hole size. Of these, ten prediagnosed VSD and TOF cases were selected for homozygosity mapping. For in silico validation of variations, overlapping gene variants were analyzed from 26 cases based on pathogenecity and haploinsufficiency scores.ResultsGenome-wide homozygosity mapping identified 34 homozygous regions with a maximum block length of 80 bp marked for the CHD samples under study. A total of 4863 genes were identified in these 34 homozygous regions, which were present across almost all chromosomes except chromosomes 4, 8, 12, and 13. The homozygosity region found in chromosome 17 revealed genes for CHD manifestation. This homozygous region contained VSD- and TOF-related genes—Nuclear Corepressor 1 (NCOR1) and Mitogen-Activated Protein Kinase Kinase 3 (MAP2K3). In silico validation identified damaging variants for NCOR1 and MAP2K3. Three variants, G207C, C241T, and G244A, were found on exon 2 in the transcript NM_001190438 for NCOR1. Three variants were also found for MAP2K3, namely G194T and C199T in exon 5 and C578T in exon 8 in the transcript NM_002756. All these variants were present in the protein kinase domain.ConclusionPresence of homozygous regions identifies recessive genes leading to disease severity. Defects in recessive genes NCOR1 and MAP2K3 are responsible for abnormal myogenesis, resulting in CHD manifestation.

DNA methylation at CpG island shore and RXRα regulate NR2F2 in heart tissues of tetralogy of Fallot patients

The nuclear receptor subfamily 2 group F member 2 (NR2F2) gene encodes a ligand-inducible transcription factor involved in angiogenesis and heart development. This study aimed to elucidate the molecular mechanism of epigenetic regulation of NR2F2 in tetralogy of Fallot (TOF) development. In the present study, immunohistochemical staining showed that NR2F2 protein expression was significantly higher in the right ventricular outflow tract (RVOT) tissues of TOF cases compared with controls. The methylation status of the CpG island shore (CGIS) of the NR2F2 gene was decreased in TOF cases, and the CpG site 3 in the CGIS region of NR2F2 promoter was a differential methylation site. Furthermore, the methylation level of the CpG site 3 and the NR2F2 protein expression were significantly negatively correlated in TOF patients. In vitro functional analysis revealed that RXRα could upregulate the NR2F2 gene by directly binding to the CGIS in the NR2F2 promoter, while hypomethylation of the NR2F2 promoter via treatment with 5-azacytidine influenced the affinity of RXRα to its binding sites, as shown by ChIP-qPCR. These findings suggest that promoter hypomethylation activates NR2F2 by enhancing RXRα binding to NR2F2 CGIS in the development of TOF.

Rs4841587 in GATA4 and rs6999593 in DNMT1 gene associated with congenital heart diseases in the southeast of Iran

BackgroundDifferent genetic and epigenetic variations are implicated in congenital heart diseases (CHDs). GATA4 and DNMT1 genes play an important role in embryonic heart development. We aim to investigate the correlation between rs4841587 in GATA4 and rs6999593 in DNMT1 genes with susceptibility and severity of symptoms in ventricular septal defects (VSDs) and tetralogy of fallot (TF) diseases in the southeast of Iran. MaterialsThis case-control study was evaluated 200 children diagnosed with VSDs or TF as well as 200 healthy controls. SNPs genotyping were performed using T-ARMS-PCR. Odds ratio (OR) and 95% confidence interval (CI), as well as Chi-square, was used to assess the strength of the association. ResultsTT genotype at rs4841587 in GATA4 was associated with the susceptibility of CHDs (OR = 2.02, 95% CI = 1.06–3.83, P = .031). Rs4841587 was related with VSDs under the dominant model (GT + TT vs. GG: OR = 1.70, 95% CI = 1.08–2.65, P = .020). However, no significant differences were observed in genotype frequencies between TF cases and controls at this position. AG genotype at rs6999593 in DNMT1 was strongly correlated with the risk of CHDs (OR = 2.27, 95% CI = 1.43–3.60, P = .000). Significant differences also were found between AG genotype with VSDs (OR = 2.12, 95% CI = 1.19–3.77, P = .011) and TF (OR = 2.58, 95% CI = 1.19–5.57, P = .016). Conclusionsrs4841587 and rs6999593 can be proposed as a significant marker for CHDs. Rs4841587 T/G polymorphism correlated with the susceptibility and severity of symptoms in VSDs. Moreover, rs6999593 A/G affects the susceptibility of VSDs and TF, in the southeast of Iran. However, further investigations are necessary to confirm these results.

Tetralogy of Fallot and Outlet Ventricular Septal Defect with Anterior Malalignment Detected at Early Fetal Echocardiography

Objectives: To examine the evolution of tetralogy of Fallot (TOF) and outlet ventricular septal defect (VSD) with anterior malalignment (am) from the initial diagnosis at early fetal echocardiography through the gestation and to evaluate the impact of the first-trimester scan on the outcome. Methods: We identified cases of TOF or outlet VSD with am diagnosed before 16 weeks’ gestation. For all cases, prenatal data and pregnancy outcomes were evaluated. In continuing pregnancies, the evolution in severity of the disease was assessed. Results: Fifty-one fetuses with TOF or outlet VSD with am were diagnosed at early fetal echocardiography. Parents opted for termination of pregnancy in all 23 cases associated with additional anomalies. In 2 of 28 continuing pregnancies, there was an intrauterine death. In the remaining 26, there was progression in severity in 7 (by 20–22 weeks in 3 cases and during the third trimester in the remaining 4). Conclusions: TOF and outlet VSD with am diagnosed before 16 weeks’ gestation can progress in severity throughout pregnancy in over one-quarter of cases. In addition, a high proportion of cases diagnosed in the first trimester may have associated extracardiac anomalies, with a significant impact on clinical management and on the rate of early termination of pregnancy.

Placental DNA methylation changes in detection of tetralogy of Fallot.

To determine whether the methylation level of cytosine nucleotides in placental DNA can be used to predict tetralogy of Fallot (TOF) and provide insights into the developmental mechanism of this condition. Tissue sections were obtained from formalin-fixed paraffin-embedded specimens of placental tissue obtained at birth from eight cases with non-chromosomal, non-syndromic TOF and 10 unaffected newborns. The Illumina Infinium HumanMethylation450 BeadChip assay was used to measure cytosine ('CpG' or 'cg') methylation levels at loci throughout the placental genome. Differential methylation was assessed by comparing the β-values (a measure of the extent of cytosine methylation) for individual CpG loci in fetuses with TOF vs in controls. The most discriminating CpG sites were determined based on a preset cut-off of ≥ 2.0-fold change in the methylation level. The predictive accuracy of CpG loci with significant methylation changes for TOF was determined by the area under the receiver-operating-characteristics curve (AUC). A false-discovery-rate (FDR) P-value < 0.05 was used to define a statistically significant difference in the methylation level. Ingenuity Pathway Analysis (IPA) (Qiagen) was used to identify gene pathways that were significantly overexpressed, and thus altered, in TOF cases compared with controls. We found a total of 165 significantly differentially methylated CpG loci in TOF cases compared with controls, in 165 separate genes. These biomarkers demonstrated from fair to excellent individual predictive accuracy for TOF detection, with AUCs ≥ 0.75 (FDR P-value < 0.001 for all). The following CpG loci (gene) had the highest predictive accuracy: cg05273049 (ARHGAP22; AUC = 1.00; 95% CI, 1.00-1.00), cg02540011 (CDK5; AUC = 0.96; 95% CI, 0.87-1.00), cg08404201 (TRIM27; AUC = 0.95; 95% CI, 0.84-1.00) and cg00687252 (IER3; AUC = 0.95; 95% CI, 0.84-1.00). IPA revealed over-representation (dysregulation) of 14 gene pathways involved in normal cardiac development, including cardiomyocyte differentiation via bone morphogenetic protein receptors, cardiac hypertrophy signaling and role of nuclear factor of activated T cells in cardiac hypertrophy. Cardiac hypertrophy is an important feature of TOF. Analysis of placental DNA cytosine methylation changes yielded accurate markers for TOF detection and provided mechanistic information on TOF development. Our work appears to confirm the central role of epigenetic changes and of the placenta in the development of TOF. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Differential diagnosis of fetal large ventricular septal defect and tetralogy of Fallot based on big data analysis.

To analyze echocardiographic parameters of fetal large ventricular septal defect (VSD) and tetralogy of Fallot (TOF) in the context of multicenter data and big data analysis because these two diseases are often misdiagnosed in fetuses, and to find the key parameters for the differential diagnosis of these two diseases. A total of 305 cases of large VSD and 192 cases of TOF diagnosed by fetal echocardiography from August 2010 to July 2016 from the database of Beijing Key Laboratory of Fetal Heart Defects were analyzed. Quantile regression of the 48 echocardiographic parameters of the 6272 normal fetuses from seven Chinese medical institutions was performed to determine the Q-score. The forward selection method and the naive Bayesian classification method were used to analyze the core differential diagnostic variables of fetal TOF and VSD. The Q-score of the internal diameter of the aorta (AO Q-score), the ratio of the diameter of the pulmonary artery to the internal diameter of the aorta (PA/AO), and the Q-score of the ratio of the diameter of the pulmonary artery to the internal diameter of the aorta (PA/AO Q-score) were key parameters for the differential diagnosis of fetal large VSD and TOF. PA/AO was the primary parameter, with an area under the receiver operating characteristic curve of 0.951. These findings provide a new method for the prenatal diagnosis of large VSD and TOF and a theoretical basis for the intelligent diagnosis of large VSD and TOF.

22q11.2 Deletion Status Influences Resource Utilization in Infants Requiring Repair of Tetralogy of Fallot and Common Arterial Trunk.

22q11.2 deletion syndrome leads to both cardiac and non-cardiac developmental defects. We aimed to study the impact of 22q11.2 deletion syndrome on in-hospital outcomes in children undergoing surgical repair for tetralogy of Fallot (TOF) and truncus arteriosus (TA). Using the nationally representative Kids Inpatient Database (KID), we analyzed data from in-hospital pediatric patients for the years 2003, 2006, 2009, and 2012. We compared the in-hospital outcomes between those with and those without 22q11.2 deletion syndrome. There were 6126 cases of TOF and 968 cases of TA. 22q11.2 deletion syndrome were documented in 7.2% (n=441) of the TOF and 27.4% (n=265) of the TA group. 22q11.2 deletion did not significantly increase the risk of mortality in either group: [OR=1.98 (95% CI 0.99-3.94), adjusted p=0.053] for TOF and OR=1.07 (95% CI 0.57-1.99), adjusted p=0.82 for TA. However, the length of hospitalization was longer in the 22q11.2 deletion group by 8.6 days (95% CI 5.2-12), adjusted p<0.001 for TOF and by 8.15 days (95% CI 1.05-15.25), adjusted p=0.025 for the TA group. Acute respiratory failure [10.6% vs 5.5%, p<0.001] and acute renal failure [6.3% vs 2.6%, p<0.001] were higher in 22q11.2 deletion cohort within the TOF group but not in the TA group. Though survival is not affected, children with 22q11.2 deletion syndrome who undergo surgical repair for TOF and TA use significantly more hospital resources-specifically longer hospital stay and higher hospitalization cost-than those without 22q11.2 deletion syndrome. Prenatal or preoperative testing for 22q11deletion is indicated to make appropriate adjustments in parental, caregiver, and administrative expectations.

Tetralogy of Fallot in a child with VACTERL association - A case report of uncommon occurrence

Tetralogy of Fallot (TOF) is the most common cause of cyanotic congenital heart disease in ventricular septal defect and pulmonary stenosis physiology. TOF is associated with many syndromes, the most common being Down Syndrome, Velocardiofacial syndrome, Holt Oram Syndrome, and Poland's syndrome. VACTERL association is rare in incidence compared to the above mentioned. 1 We report a case of TOF with the VACTERL association.

Comparison of In-Hospital Outcomes When Repair of Tetralogy of Fallot Is in the Neonatal Period Versus in the Post-Neonatal Period

Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (CHD) and optimal timing for total repair of TOF is controversial. We hypothesize that TOF repair in the neonatal period is associated with worse outcomes compared with those who undergo repair later in infancy. We analyzed data using the Kids' Inpatient Database (KID) from 2003 to 2012. We used multivariable logistic regression analyses to compare the in-hospital outcomes between those who underwent total repair of TOF during the neonatal period vs the postneonatal period. There were 6,856 cases of TOF and 7.83% (n = 537) of those underwent repair during the neonatal period. The average mortality in all TOF repair was 2.1% (n = 147). In multiple regression model, compared with repair in postneonatal period, neonatal repair was associated with increased mortality, with adjusted odds ratio of 2.2 (95% confidence interval [CI]: 1.1 to 4.3, p = 0.023). Regarding complications, the neonatal group was associated with higher risk of acute renal failure (8.9% vs 2.3%, p <0.001), need for cardiac catheterization (18.6% vs 8.3%, p <0.001), and ECMO use (4.4% vs1.6%, p <0.001). There was no difference in the rates of arrhythmia, respiratory failure, pulmonary hypertension, or sudden cardiac arrest. Children who underwent repair in the neonatal period had longer hospital stay compared with the postneonatal group (45.5 days [95% CI: 39.3 to 51.7] vs 12.6 days [95% CI: 11.7 to 13.4], p <0.001). Hospital charges were higher for children who underwent repair in the neonatal period compared with those in the postneonatal period. In conclusion, TOF repair in the neonatal period is associated with higher rates of mortality, more postoperative complications, longer hospital stays, and higher hospitalization cost.

DNA methylation status of TBX20 in patients with tetralogy of Fallot

BackgroundTBX20 plays an important role in heart development; however, its epigenetic regulation in the pathogenesis of tetralogy of Fallot (TOF) remains unclear.MethodsThe methylation levels of the TBX20 promoter region in the right ventricular myocardial tissues of TOF and control samples were measured by the Sequenom MassARRAY platform. Bisulphite-sequencing PCR (BSP) was used to confirm the TBX20 methylation of CpG sites in cells. Dual-luciferase reporter assays were performed to detect the influence of TBX20 methylation and Sp1 transcription factors on gene activity. An electrophoretic mobility shift assay (EMSA) was used to explore the binding of the Sp1 transcription factor to the TBX20 promoter.ResultsTOF cases had a significantly lower TBX20_M1 methylation level than controls (median methylation: 20.40% vs. 38.73%; p = 0.0047). The Sp1 transcription factor, which binds to Sp1 binding sites in the TBX20_M1 region and promotes TBX20 gene activity, was blocked by the methylation of Sp1 binding sites in normal controls. With decreasing methylation in the TOF cases, the Sp1 transcription factor can bind to its binding site within the TBX20 promoter M1 region and promote TBX20 gene expression.ConclusionsHypomethylation of the TBX20 promoter region was observed in the TOF cases, and the high expression of the TBX20 gene may be caused by activated Sp1 transcription factor binding because of the decreasing methylation at the Sp1 transcription factor binding sites within TBX20_M1.

Case report discussion of management of pink tetralogy of Fallot in VACTERL association

Tetralogy of Fallot (TOF) and VACTERL are considered rare entities requiring medical attention with regards to diagnosis and management. When TOF is associated with VACTERL association, case management might differ from a simple case of TOF.&#x0D; Tetralogy of Fallot (TOF) is defined as a complex congenital cardiac abnormality characterized by ventricular septal defect, right outflow tract obstruction, right ventricular hypertrophy, and overriding aorta.1 The term was coined in 1888 by Fallot of Marseilles, even though the defect had been described in 1673 by Steno of Denmark. The entity was then studied extensively to deliver better care management through medical and surgical approaches.2

Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot

Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date. We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date. Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10-8) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1. The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.

Primary Results of Late Surgical Treatment in Children with Tetralogy of Fallot from a Developing Country

Objectives: The purpose was to show how important is to operate on the Senegalese African children presenting with Tetralogy of Fallot (TOF) regardless of their age. Methods: It is a retrospective, descriptive analysis of data from the Department of Pediatric Cardiology, University Hospital of Tuebingen’s data base which was searched for all cases of TOF in foreign patients younger than 15 years between 05/2004-10/2016. Results: 16 children from Senegal with TOF were referred for treatment. Mean age of patients was 7.0 years (range 0.9 - 14.8 years). Primary corrective surgery was performed in 13/16 patients. A primary shunt procedure was required in 3/16 patients. All patients were discharged in good condition with a median 13 postoperative days. We did not register any deaths. All became asymptomatic with pulse oximetry oxygen saturations greater than 95%. The right ventricular outflow tract (RVOT) gradient was less than 30 mmHg in all patients and 2 patients had moderate pulmonary valvular insufficiency. Conclusions: It was still necessary to operate Senegalese children presenting with TOF irrespective of their age.

Genetic variants of HIF1\u03b1 are associated with right ventricular fibrotic load in repaired tetralogy of Fallot patients: a cardiovascular magnetic resonance study

BackgroundStudies suggest that right ventricular (RV) fibrosis is associated with RV remodeling and long-term outcomes in patients with tetralogy of Fallot (TOF). Pre-operative hypoxia may increase expression of hypoxia inducible factor-1-alpha (HIF1α) and promote transforming growth factor β1 (TGFβ1)-mediated fibrosis. We hypothesized that there would be associations between: (1) RV fibrosis and RV function, (2) HIF1α variants and RV fibrosis, and (3) HIF1α variants and RV function among post-surgical TOF cases.MethodsWe retrospectively measured post-surgical fibrotic load (indexed volume and fibrotic score) from 237 TOF cases who had existing cardiovascular magnetic resonance imaging using late gadolinium enhancement (LGE), and indicators of RV remodeling (i.e., ejection fraction [RVEF] and end-diastolic volume indexed [RVEDVI]). Genetic data were available in 125 cases. Analyses were conducted using multivariable linear mixed-effects regression with a random intercept and multivariable generalized Poisson regression with a random intercept.ResultsIndexed fibrotic volume and fibrotic score significantly decreased RVEF by 1.6% (p = 0.04) and 0.9% (p = 0.03), respectively. Indexed fibrotic volume and score were not associated with RVEDVI. After adjusting for multiple comparisons, 6 of the 48 HIF1α polymorphisms (representing two unique signals) were associated with fibrotic score. None of the HIF1α polymorphisms were associated with indexed fibrotic volume, RVEDVI, or RVEF.ConclusionThe association of some HIF1α polymorphisms and fibrotic score suggests that HIF1α may modulate the fibrotic response in TOF.

Exercise testing and spirometry as predictors of mortality in congenital heart disease: Contrasting Fontan physiology with repaired tetralogy of Fallot.

Risk prediction using cardiopulmonary exercise testing (CPET) in complex congenital heart disease tends to either focus on single diagnoses or complete cohorts. We aimed to evaluate patients with two distinct anatomies cared for at a single institution over the same time period to determine CPET variables associated with mortality. All Fontan and tetralogy of Fallot (TOF) subjects with CPET between November 1, 2002 and December 31, 2014 and subsequently died were identified (cases). Cases were matched 1:3 to controls with similar age, underlying anatomy and timing of exercise test. Of the 42 cases, 27 had a Fontan circulation and 15 with TOF. All Fontan patients had a low peak VO2 but there was no significant difference between cases and controls (52.5±14.7 v. 57.4%±13.5% predicted, P=.11). Spirometry values were significantly lower in Fontan cases than controls (eg, FVC 67.4±19.1 v 77.6%±14.9% predicted, P=.007). Spirometry values were also lower in TOF cases than controls (% predicted FVC 62.8±16.7 v 75±14, P=.006). In contrast to the Fontan analysis, both %peak predicted VO2 and VE/VCO2 slope were worse in TOF cases than controls (50.1±13.5 v. 68.5%±15.0% predicted VO2 , P=.0004; 33.9±12.9 v 26.6±4.4, P=.002). Multivariable analysis also identified different predictors of mortality among the anatomic subgroups. Spirometric data (FVC) correlated most strongly with mortality in Fontan patients while the VE/VCO2 slope was most associated with outcome in TOF patients. Variables most predictive of mortality in Fontan and TOF patients diverge but spirometry was abnormal and associated with mortality in both groups. When compared with age-matched controls, reduced FEV1 and FVC correlated most strongly with mortality in Fontan patients while VE/VCO2 slope correlated with mortality for TOF patients. These findings further support the importance of lung health in patients with complex congenital heart disease.

Newborn blood DNA epigenetic variations and signaling pathway genes associated with Tetralogy of Fallot (TOF).

Tetralogy of Fallot (TOF) is the most common Critical Congenital Heart Defect (CCHD). The etiology of TOF is unknown in most cases. Preliminary data from our group and others suggest that epigenetic changes may play an important role in CHD. Epidemiologically, a significant percentage of CHD including TOF fail to be diagnosed in the prenatal and early newborn period which can negatively affect health outcomes. We performed genome-wide methylation assay in newborn blood in 24 non-syndromic TOF cases and 24 unaffected matched controls using Illumina Infinium HumanMethylation450 BeadChips. We identified 64 significantly differentially methylated CpG sites in TOF cases, of which 25 CpG sites had high predictive accuracy for TOF, based on the area under the receiver operating characteristics curve (AUC ROC) ≥ 0.90). The CpG methylation difference between TOF and controls was ≥10% in 51 CpG targets suggesting biological significance. Gene ontology analysis identified significant biological processes and functions related to these differentially methylated genes, including: CHD development, cardiomyopathy, diabetes, immunological, inflammation and other plausible pathways in CHD development. Multiple genes known or plausibly linked to heart development and post-natal heart disease were found to be differentially methylated in the blood DNA of newborns with TOF including: ABCB1, PPP2R5C, TLR1, SELL, SCN3A, CREM, RUNX and LHX9. We generated novel and highly accurate putative molecular markers for TOF detection using leucocyte DNA and thus provided information on pathogenesis of TOF.

Association between the promoter methylation of the TBX20 gene and tetralogy of fallot

Objectives. To investigate the association between promoter methylation of the TBX20 gene and tetralogy of Fallot (TOF)． Methods. The methylation level of TBX20 promoter regions in 23 patients with TOF and five controls were analyzed through bisulfite sequencing polymerase chain reaction. Meanwhile, the expression of TBX20 mRNA was measured using real time fluorescence quantitative polymerase chain reaction. Results. The region −400 to −48 in the TBX20 promoter consisting of 42 CpG sites was predicted to contain multiple transcription factor binding sites. In this study, the overall methylation level in this region was lower in patients with TOF than in the controls (P = .035). Among the 42 CpG sites, the methylation percentages of the CpG 26 site in the TOF cases were lower than those in the controls (P = .016). The mRNA expression of TBX20 in the right ventricular outflow tract myocardium was increased in TOF cases in contrast to those in the controls (P < .001). The methylation levels in TOF cases were correlated with mRNA expression values (r = −0.81, P < .001). Conclusion. The downregulated methylation level at TBX20 promoter may be responsible for the elevated mRNA expression levels in patients with TOF. The abnormal methylation status of the TBX20 promoter may contribute to the pathogenesis of TOF.

Tetralogy of Fallot Repair in Developing Countries: International Quality Improvement Collaborative

Isolated reports from low- and middle-income countries (LMICs) for surgical results in tetralogy of Fallot (TOF) are available. The International Quality Improvement Collaborative for Congenital Heart Disease (IQIC) seeks to improve surgical results promoting reductions in infection and mortality in LMICs. All cases of TOF in the IQIC database performed between 2010 and 2014 at 32 centers in 20 LMICs were included. Excluded from the analysis were TOF with any associated lesions. A logistic regression analysis was performed to identify risk factors for in-hospital mortality after surgery for TOF. A total of 2,164 patients were identified. There were 1,839 initial primary repairs, 200 with initial systemic-to-pulmonary artery shunt, and 125 underwent secondary repair after initial palliation. Overall mortality was 3.6% (78 of 2,164), initial primary repair was 3.3% (60 of 1,839), initial systemic-to-pulmonary artery shunt was 8.0% (16 of 200), and secondary repair was 1.6% (2 of 125; p= 0.003). Major infections occurred in 5.9% (128 of 2,164) of the entire cohort. Risk factors for death after the initial primary repair were oxygen saturation less than 90% and weight/body mass index for age below the fifth percentile (p < 0.001). The initial primary repair occurredafter age 1 year in 54% (991 of 1,839). Older age at initial primary repair was not a risk factor for death (p= 0.21). TOF patients are often operated on after age 1 year in LMICs. Unlike in developed countries, older age is not a risk factor for death. Nutritional and hypoxemic status were associated with higher mortality and infection. This information fills a critical knowledge gap for surgery in LMIC.

Tetralogy of Fallot with absent pulmonary valve syndrome: A 34-year African single centre experience

Background: Absent pulmonary valve syndrome (APVS) is most commonly associated with Tetralogy of Fallot (TOF). TOF with APVS is characterised by features of TOF with either rudimentary ridges or complete absence of pulmonary valve tissue. This is often associated with varying degrees of pulmonary stenosis and severe pulmonary regurgitation with massive dilatation of the proximal branch pulmonary arteries, causing compression of the tracheobronchial tree. Hence, respiratory symptoms are a common presenting feature. Methods: Cases of TOF with APVS were extracted from the paediatric cardiology database at Chris Hani Baragwanath Academic Hospital (CHBAH) for January 1981 - April 2016. Results: A total of 15 patients with TOF and APVS were seen at CHBAH over the 34-year study period. TOF with APVS comprised 3% of all TOF patients. Ten (67%) patients presented before 1 year of age. The majority of patients (67%) had respiratory symptoms as their cause of presentation, of which 6 (40%) were infants. Fourteen (93%) patients were described to have the characteristic to-and-fro murmur at presentation. Five patients (33%) were suspected of having 22q11.2 deletion syndrome, but only 4 were tested and 2 were found to be positive. A third of patients underwent surgical intervention and 4 of the 15 patients (27%) were known to be alive at 10 years of age. Conclusions: TOF with APVS compromised 3% of all TOF patients, correlating with the literature. It is associated with the 22q11.2 deletion syndrome and was suspected in 33% of patients. TOF with APVS should be strongly considered in a child less than 1 year presenting with respiratory symptoms and a characteristic to-andfro murmur.

Sex differences for major congenital heart defects in Down Syndrome: A population based study

BackgroundDown syndrome (DS) is the most common autosomal chromosomal anomaly in liveborn infants. About 40% of infants with DS have a major congenital heart defect (CHD). Among them, atrioventricular septal defects (AVSD), atrial septal defects (ASD), ventricular septal defect (VSD) and Tetralogy of Fallot (ToF) are the most common. The aim of this study was to estimate the sex difference in the occurrence of CHD in infants with DS comparing it with non-DS infants. MethodLive birth cases of DS diagnosed by the first year of life were extracted from the Registry of Congenital Anomalies of Tuscany (2003–2015 period). CHDs associated with DS were detected both from the registry and the hospital discharge data. Sex differences in total CHDs and ASD, VSD, AVSD, severe CHDs, ToF subgroups were investigated. Relative Risks between males and females (RRMF) with p-values and 95% confidence interval (95% CI) were estimated. RRMF of CHD in infants with DS was compared to RRMF in infants without DS. The ratio between relative risks (RRR) was estimated. ResultsA total of 230 live birth cases of DS were analyzed, with a prevalence of 5.70 per 10,000 births. Sex ratioMF was 1.3. One hundred and one DS cases (43.9%) were associated with at least one CHD. Among them, CHDs are more frequent in females (total CHD: RRMF = 0.62; 95% CI: 0.46–0.83, ASD: RRMF = 0.40; 95% CI: 0.21–0.77, severe CHD: RRMF = 0.58; 95% CI: 0.35–0.95, AVSD: RRMF = 0.57; 95% CI: 0.32–1.00, VSD: RRMF = 0.59; 95% CI: 0.35–1.00). Four cases of ToF were observed (all males). Sex difference was more evident in DS than in non-DS infants (RRR = 0.63; 95% CI: 0.52–0.77), in particular for severe CHDs (RRR = 0.38; 95% CI: 0.25–0.57). ConclusionThe increased sex difference for CHDs in DS suggests a possible role of sex as effect modifier in the association between DS and CHD. The results enforce the evidence on sex differences for CHDs in DS and can stimulate future genetic research activities.