Congenital Heart Defects In Down Syndrome Research Articles

Maternal Blood Group Is a Possible Predictor for Developing Congenital Heart Disease in Turkish Children with Down's Syndrome

AbstractWe aimed to evaluate the clinical characteristics and the risk factors for the anomalies of Down's syndrome (DS) patients and reviewed the relation of blood groups of the patients and the mothers with these anomalies. Pediatric patients who were diagnosed with trisomy 21 between 2010 and 2022 were enrolled in this study. The medical records of the DS patients and their parents were retrospectively reviewed. A total of 48 patients applied to our clinic. 24 (50%) patients were diagnosed with congenital heart disease. 21 (43.75%) patients had hypothyroidism. The distribution of individual congenital heart defects (CHDs) was as follows: ventricular septal defect in eight (33.3%) patients, one of which also had patent ductus arteriosus (PDA); atrioventricular septal defects in seven (29.1%) patients; atrial septal defects in four (16.6%) patients, one of which also had patent ducus arteriosus; and PDA in five (20.8%) patients. One (4.2%) patient had tetralogy of Fallot. The incidence of CHD in patients with maternal blood group A was significantly higher than those without CHD, with a prevalence of 63.6 and 21.1%, respectively (p = 0.020). Binary logistic regression analysis showed that maternal blood group A was a risk factor for CHDs (odds ratio = 6.563; 95% confidence interval: 1.259–34.204; p = 0.025). Although we found that the rate of advanced father age was high in hypothyroidism type, the regression analysis showed that it was not a risk factor. We found that maternal blood group A increased the likelihood of being born with CHDs in DS.

Abstract P1161: Interferon Hyperactivity Impairs Cardiogenesis In Down Syndrome Via Downregulation Of Canonical Wnt Signaling

Congenital heart defects (CHDs) are very frequent in children with Down syndrome (DS), the genetic condition caused by trisomy of chromosome 21 (T21). Despite significant efforts, the mechanisms by which T21 causes susceptibility to CHDs remain largely unknown. Here, using a combination of a human induced pluripotent stem cell (iPSC)-based model and the Dp(16)1Yey/+ (Dp16) mouse model of DS, we identified downregulation of canonical Wnt signaling downstream of increased dosage of interferon (IFN) receptors (IFNRs) genes on chromosome 21 as a causative factor of CHDs in DS. We differentiated human iPSCs derived from individuals with DS and CHDs (DS/CHD iPSCs), and euploid controls into cardiac cells. We observed that T21 upregulates IFN signaling, downregulates the canonical WNT pathway, and impairs cardiac differentiation. Furthermore, genetic and pharmacological normalization of IFN signaling restored canonical WNT signaling and rescued defects in cardiac differentiation of DS/CHD iPSCs. To define the role of IFN signaling in CHDs in vivo , we genetically and pharmacologically normalized the activity of IFN signaling in the Dp16 mouse model of DS. Normalization of the activity of IFN signaling prevented heart malformations in Dp16 embryos. In addition, treatment with an inhibitor of Janus kinases, which act downstream of IFNRs, normalized canonical Wnt signaling and ameliorated CHDs in Dp16 embryos. Our findings provide new insights into mechanisms underlying CHDs in DS, ultimately aiding the development of novel therapeutic strategies.

Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation.

Down syndrome (DS), a complex disorder that is caused by the trisomy of chromosome 21 (Hsa21), is a major cause of congenital heart defects (CHD). Interestingly, only about 50% of individuals with Hsa21 trisomy manifest CHD. Here we review the genetic basis of CHD in DS, focusing on genes that regulate extracellular matrix (ECM) organization. The overexpression of Hsa21 genes likely underlies the molecular mechanisms that contribute to CHD, even though the genes responsible for CHD could only be located in a critical region of Hsa21. A role in causing CHD has been attributed not only to protein-coding Hsa21 genes, but also to genes on other chromosomes, as well as miRNAs and lncRNAs. It is likely that the contribution of more than one gene is required, and that the overexpression of Hsa21 genes acts in combination with other genetic events, such as specific mutations or polymorphisms, amplifying their effect. Moreover, a key function in determining alterations in cardiac morphogenesis might be played by ECM. A large number of genes encoding ECM proteins are overexpressed in trisomic human fetal hearts, and many of them appear to be under the control of a Hsa21 gene, the RUNX1 transcription factor.

Neonatal mortality and morbidity in Down syndrome in the time of prenatal aneuploidy testing: a retrospective cohort study

The total uptake of prenatal aneuploidy screening for Down syndrome (DS) is increasing worldwide. As a result of increasing prenatal diagnosis of DS and subsequent termination of pregnancy, livebirth prevalence of DS is decreasing. The aim of this study is to explore the impact of an increasing uptake of prenatal aneuploidy screening on the neonatal mortality and morbidity in DS. This is a retrospective cohort study of 253 neonates with DS born between 2012 and 2018 that were seen at the outpatient clinic of five hospitals in the Netherlands. The medical files were reviewed for maternal and neonatal characteristics and neonatal morbidities. The Dutch national birth registry (Perined) provided mortality numbers of neonates with DS. The results were interpreted in the context of other published studies. Neonatal mortality in DS remained stable, ranging from 1.4 to 3.6%. A congenital heart defect (CHD) was found in 138 of the 251 neonates (55.0%) with atrial septal defect, atrioventricular septal defect, and ventricular septal defect being the most common. The type of CHD in DS did not change over time. Gastro-intestinal defects were present in 22 of the 252 neonates with DS (8.7%), with duodenal atresia as the most reported anomaly. Persistent pulmonary hypertension of the neonate (PPHN) was found in 31 of the 251 infants (12.4%). Conclusions: Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in DS appears to be stable. An increased incidence of PPHN was found.What is Known:• The total uptake of prenatal aneuploidy screening for Down syndrome is increasing worldwide.• As a result of increasing prenatal diagnosis of Down syndrome and subsequent termination of pregnancy, the livebirth prevalence of Down syndrome is decreasing.What is New:• Although uptake of prenatal aneuploidy screening increased, neonatal mortality and morbidity in Down syndrome appears to be stable.• An increased incidence of persistent pulmonary hypertension of the neonate was found.

Abstract P515: Dynamics Of Cardiomyocyte Differentiation In Isogenic Induced Pluripotent Stem Cells Derived From Trisomy21 Patients Hints Molecular Pathology Of Congenital Heart Defects In Down Syndrome

Down syndrome (DS) is the most frequently occurring human chromosomal disorder and is responsible for a range of both congenital defects and progressive, degenerative conditions. For instance, an estimated 50% DS neonates are born with congenital heart defects (CHD) and more than 50% of DS adults develop early onset Alzheimer’s. Using induced pluripotent stem cells (iPSCs) derived from DS patients and isogenic controls we previously demonstrated the presence of a hyper-metabolic, hyper-fused mitochondrial network in trisomic iPSCs (3S-iPSCs) compared to disomic (2S-iPSCs) controls. Furthermore, mitochondrial function was normalized by siRNA depletion of RCAN1, an inhibitor of the protein phosphatase calcineurin (CN). Both CN signaling and mitochondrial metabolism have been implicated in a variety of steps during the progression from embryonic stem cells to cardiac progenitors, including self-renewal, exit from pluripotency, and commitment to cardiac verses hematopoietic lineages. Based on this, we hypothesized that the dynamics of many of these processes will be altered over the course of differentiation of 3S-iPSCs to cardiomyocytes when compared to 2S-iPSCs. Here, we investigate the temporal expression of pluripotency associated genes and lineage associated genes as well as cardiac mesoderm and mature cardiomyocyte specific genes. We also define and compare changes in CN activity, expression of specific CN isoforms, mitochondrial expansion, ROS generation, and activation of stress responses. Our study identifies early developmental and metabolic sequelae capable of contributing to CHD in DS that may result from a disruption in the normal balance in crosstalk between CN and RCAN1.

Methyltetrahydrofolate-homocysteine methyltransferase reductase gene and congenital heart defects in Down syndrome

Congenital heart defects (CHD) are the most common abnormalities occurring in 40% -60% of Down syndrome (DS) patients. The 5-methyltetrahydrofolate homocysteine methyl transferase reductase (MTRR) is one of the key regulatory enzymes involved in folate pathway. Disrupted folate pathway due to MTRR polymorphism could be a risk factor for CHD in DS. The aim of the study was to determine the association between polymorphism MTRR 66A> G and CHD in DS. Additionally, the impact of maternal endogenous factors on CHD was analyzed, intake of folate through diet, periconceptional folic acid supplementation, smoking and alcohol drinking. A total of 155 children with DS and 148 their mothers have been enrolled in this study. Genotyping was performed by PCR-RFLP. The frequency of alleles and genotypes of MTRR 66A> G polymorphisms was not significantly different between a group with CHD compared to a group without CHD among DS subjects as well as in their mothers. The mothers with mutated homozygous genotypes who have taken folic acid preparations from the fourth week before pregnancy to eight weeks of pregnancy were more likely to have DS-CHD+ child. The study results suggested that maternal MTRR 66A> G polymorphisms associated with their lifestyle habits such as folic acid intake could altered individual risk for CHD in DS child.

Differences in morbidity and mortality in Down syndrome are related to the type of congenital heart defect.

Morbidity and mortality in Down syndrome (DS) are mainly related to congenital heart defects (CHDs). While CHDs with high prevalence in DS (typical CHDs), such as endocardial cushion defects, have been extensively described, little is known about the impact of less common CHDs (atypical CHDs), such as aortic coarctation and univentricular hearts. In our single-center study, we analyzed, in observational, retrospective manner, data regarding cardiac features, surgical management, and outcomes of a cohort of DS patients. Literature review was performed to investigate previously reported studies on atypical CHDs in DS. Patients with CHDs were subclassified as having typical or atypical CHDs. Statistical analysis was performed for comparison between the groups. The study population encompassed 859 DS patients, 72.2% with CHDs, of which 4.7% were atypical. Statistical analysis showed a significant excess in multiple surgeries, all-cause mortality and cardiac mortality in patients with atypical CHDs (p = .0067, p = .0038, p = .0001, respectively). According to the Kaplan-Meier method, survival at 10 and 40 years was significantly higher in typical CHDs (99 and 98% vs. 91 and 84%, log rank <0.05). Among atypical CHDs, it seems that particularly multiple complex defects in univentricular physiology associate with a worse outcome. This may be due to the surgical difficulty in managing univentricular hearts with multiple defects concurring to the clinical picture or to the severity of associated defects themselves. Further studies need to address this specific issue, also considering the higher pulmonary pressures, infective complications, and potential comorbidities in DS patients.

The Combined Use of Ultrasound and Fetal Magnetic Resonance Imaging for a Comprehensive Fetal Neurological Assessment in Fetal Congenital Cardiac Defects: Scientific Impact Paper No. 60.

Heart problems are common in newborn babies, affecting approximately 5-10 in 1000 babies. Some are more serious than others, but most babies born with heart problems do not have other health issues. Of those babies who have a serious heart problem, almost 1 in 4 will have heart surgery in their first year. In the UK, pregnant women are offered a scan at around 20weeks to try and spot any heart problems. In most cases there is not a clear reason for the problem, but sometimes other issues, such as genetic conditions, are discovered. In recent years the care given to these babies after they are born has improved their chances of surviving. However, it is recognised that babies born with heart problems have a risk of delays in their learning and development. This may be due to their medical condition, or as a result of surgery and complications after birth. In babies with heart problems, there is a need for more research on ultrasound and magnetic resonance imaging (MRI) to understand how the brain develops and why these babies are more likely to have delays in learning and development. This paper discusses the way ultrasound and MRI are used in assessing the baby's brain. Ultrasound is often used to spot any problems, looking at how the baby's brain develops in pregnancy. Advances in ultrasound technologies have made this easier. MRI is well-established and safe in pregnancy, and if problems in the brain have been seen on ultrasound, MRI may be used to look at these problems in more detail. While it is not always clear what unusual MRI findings can mean for the baby in the long term, increased understanding may mean parents can be given more information about possible outcomes for the baby and may help to improve the counselling they are offered before their baby's birth.

Systematic Tracking of Disrupted Modules Identifies Altered Pathways Associated with Congenital Heart Defects in Down Syndrome.

BackgroundThis work aimed to identify altered pathways in congenital heart defects (CHD) in Down syndrome (DS) by systematically tracking the dysregulated modules of reweighted protein-protein interaction (PPI) networks.Material/MethodsWe performed systematic identification and comparison of modules across normal and disease conditions by integrating PPI and gene-expression data. Based on Pearson correlation coefficient (PCC), normal and disease PPI networks were inferred and reweighted. Then, modules in the PPI network were explored by clique-merging algorithm; altered modules were identified via maximum weight bipartite matching and ranked in non-increasing order. Finally, pathways enrichment analysis of genes in altered modules was carried out based on Database for Annotation, Visualization, and Integrated Discovery (DAVID) to study the biological pathways in CHD in DS.ResultsOur analyses revealed that 348 altered modules were identified by comparing modules in normal and disease PPI networks. Pathway functional enrichment analysis of disrupted module genes showed that the 4 most significantly altered pathways were: ECM-receptor interaction, purine metabolism, focal adhesion, and dilated cardiomyopathy.ConclusionsWe successfully identified 4 altered pathways and we predicted that these pathways would be good indicators for CHD in DS.

Angiogenic Gene Expression in Down Syndrome Fetal Hearts

Introduction: Forty percent of Down syndrome (DS) fetuses have congenital heart defects (CHD). An abnormal angiogenic environment has been described in euploid fetuses with CHD. However, the underlying pathophysiologic pathway that contributes to CHD in DS remains unknown. The objective was to compare the expression of angiogenic factors and chronic hypoxia genes in heart tissue from DS and euploid fetuses with and without CHD. Methods: The gene expression profile was determined by real-time PCR quantification in heart tissue from 33 fetuses with DS, 23 euploid fetuses with CHD and 23 control fetuses. Results: Angiogenic factors mRNA expression was significantly increased in the DS group compared to the controls (soluble fms-like tyrosine kinase-1, 81%, p = 0.007; vascular endothelial growth factor A, 57%, p = 0.006, and placental growth factor, 32%, p = 0.0227). Significant increases in the transcript level of hypoxia-inducible factor-2α and heme oxygenase 1 were also observed in the DS group compared to the controls. The expression of angiogenic factors was similar in DS fetuses and CHD euploid fetuses with CHD. Conclusion: Abnormal angiogenesis was detected in the hearts of DS fetuses with and without CHD. Our results suggest that DS determines an intrinsically angiogenic impairment that may be present in the fetal heart.

Down Syndrome in Moderate Altitude Residents: Are There Unique Features?

REFER TO THE PAGE 72-77 Acute exposure to high altitude, which is defined as > 2500 m above sea level, is well-known to be associated with significant alterations to the cardiovascular system, with reductions in atmospheric pressure, oxygen pressure resulting in acute hypoxia, increased myocardial work, increased epinephrine release, and increased pulmonary artery pressures.1) However, the effects of moderate altitude chronic hypoxia on the cardiovascular system have not been much studied. In general, clinically significant changes are difficult to demonstrate at elevations lower than 2500 m. High-altitude residents have successfully evolved adaptive regulatory mechanisms to survive in a chronic hypoxic environment.2) Moreover, it has been suggested that exposure to mild to moderate chronic hypoxia may induce cardio-protective properties against various disease states such as hypertension or coronary heart disease and result in favorable outcomes.2),3) In contrast, a few studies reported important physiological and anatomic features of pulmonary vasculature resulting in pulmonary hypertension even in healthy subjects living at moderate to high altitude.4),5) In this issue of the Journal, Espinola-Zavaleta et al.6) report the results of their study of one-hundred twenty-seven patients with Down syndrome (DS) living in Mexico City to assess the prevalence of congenital heart disease and pulmonary hypertension. Mexico City is a capital of Mexico and located in the Valley of Mexico, a large valley in the high plateaus at the center of Mexico, at an altitude of 2240 m. Moderate altitude is defined as 1500-2500 m above sea level. Therefore, Halla Mountain (1950 m) in Korea is corresponding to moderate altitude but Paektu Mountain (2744 m) is at high altitude. In this study, the investigators demonstrated somewhat interesting features of DS in moderate altitude residents although this study could not provide conclusive causal relationship. First, the most prevalent congenital anomaly in DS in this study was patent ductus arteriosus, probably related with the moderate altitude of Mexico City as interpreted by the authors. Since patent ductus arteriosus closes with high oxygen tension, it is possible that a hypoxic environment and postnatal persistence of pulmonary hypertension delay closure of ductus arteriosus resulting in the high prevalence of patent ductus arteriosus in this population. Bialkowski et al.7) also reported supportive evidences of this first unique feature in this study. Larger ductal diameter and higher pulmonary artery pressure were observed in patients living at moderate to high altitudes (1500-4200 m) than in those at low altitudes (340-700 m).7) Second, pulmonary hypertension is not rare (46%) even in DS patients without congenital heart defects. People native living in a chronic hypoxic environment develop alveolar hypoxia, hypoxemia, and polycythemia.4) In the heart and pulmonary circulation, a delayed postnatal remodeling of the distal pulmonary arterial branches, increased amount of smooth muscle cells and increased pulmonary vascular resistance resulting in pulmonary hypertension, right ventricular hypertrophy have been reported.4),5) The magnitude of pulmonary hypertension has been known to increase with the altitude level and the degree of exercise.4) Interestingly, this structural change in the pulmonary vasculature becomes normal after 2 years of residence at sea level.8) In the interpretation of the present study, it is needed to understand the limitations of this study. In fact, this study was not a comparison study not only between DS patients living in moderate altitude and those living in sea level but also between DS patients and healthy subjects without DS. Therefore, further observation and comparison should be needed to confirm the higher prevalence of patent ductus arteriosus or pulmonary hypertension in DS patients at moderate altitude. In addition, the pathophysiology of pulmonary hypertension without congenital heart defects in DS or at moderate altitude should be studied in the future. Comprehensive cardiopulmonary hemodynamic evaluation using an exercise stress echocardiogram or cardiac magnetic resonance imaging is warranted in order to detect early changes of exercise-induced pulmonary hypertension or to clarify the clinical impact on exercise capacity, right ventricular function, or clinical outcomes.9),10)

Prevalence of congenital heart defects associated with Down syndrome in Korea.

Congenital heart defect (CHD) is common in infants with Down syndrome (DS), which is the principle cause of mortality. However, there is no data available for the frequency and types of CHD in infants with DS in Korea. We investigated the frequency of CHD in infants with DS in Korea. After the survey on birth defects was conducted throughout the country, the prevalence of CHD in DS in 2005-2006 was calculated. This study was conducted based on the medical insurance claims database of the National Health Insurance Corporation. The number of total births in Korea was 888,263 in 2005-2006; of them, 25,975 cases of birth defects were identified. The prevalence of DS was 4.4 per 10,000 total births, accounting for 1.5% of all birth defects. Of the 394 infants with DS, 224 (56.9%) had a CHD. Atrial septal defect was the most common defect accounting for 30.5% of DS followed by ventricular septal defect (19.3%), patent duct arteriosus (17.5%), and atrioventricular septal defect (9.4%). Our study will be helpful to demonstrate the current status of DS and to identify the distribution of CHD in infants with DS in Korea.

The complex SNP and CNV genetic architecture of the increased risk of congenital heart defects in Down syndrome

Congenital heart defect (CHD) occurs in 40% of Down syndrome (DS) cases. While carrying three copies of chromosome 21 increases the risk for CHD, trisomy 21 itself is not sufficient to cause CHD. Thus, additional genetic variation and/or environmental factors could contribute to the CHD risk. Here we report genomic variations that in concert with trisomy 21, determine the risk for CHD in DS. This case-control GWAS includes 187 DS with CHD (AVSD = 69, ASD = 53, VSD = 65) as cases, and 151 DS without CHD as controls. Chromosome 21–specific association studies revealed rs2832616 and rs1943950 as CHD risk alleles (adjusted genotypic P-values <0.05). These signals were confirmed in a replication cohort of 92 DS-CHD cases and 80 DS-without CHD (nominal P-value 0.0022). Furthermore, CNV analyses using a customized chromosome 21 aCGH of 135K probes in 55 DS-AVSD and 53 DS-without CHD revealed three CNV regions associated with AVSD risk (FDR ≤ 0.05). Two of these regions that are located within the previously identified CHD region on chromosome 21 were further confirmed in a replication study of 49 DS-AVSD and 45 DS- without CHD (FDR ≤ 0.05). One of these CNVs maps near the RIPK4 gene, and the second includes the ZBTB21 (previously ZNF295) gene, highlighting the potential role of these genes in the pathogenesis of CHD in DS. We propose that the genetic architecture of the CHD risk of DS is complex and includes trisomy 21, and SNP and CNV variations in chromosome 21. In addition, a yet-unidentified genetic variation in the rest of the genome may contribute to this complex genetic architecture.

MTHFR C677T and A1298C polymorphisms as a risk factor for congenital heart defects in Down syndrome

Congenital heart defects (CHD) are present in most, but not all, cases of Down syndrome (DS). The presence of methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms has been reported as a risk factor for CHD in DS. The aims of the present study were to assess (i) the frequency of MTHFR C677T and A1298C polymorphisms in DS individuals in the Croatian population; (ii) the relationship between the two maternal MTHFR polymorphisms and CHD-affected DS children; and (iii) the transmission frequencies of the variant alleles of the two MTHFR polymorphisms in CHD-affected DS. The study population included 112 DS subjects and 221 controls. CHD were present in 48% of the DS subjects (54/112). The mothers of 107 DS individuals were available for the study; none was a periconceptional folic acid user. Allele transmission was analyzed in 34 complete parent-offspring triads. The frequencies of the allele, individual, and combined genotypes of MTHFR C677T and A1298C in DS subjects were not statistically different compared to the normal healthy Croatian controls. The maternal MTHFR polymorphisms were not found to be a risk factor for DS-related CHD. The allele transmission of the two MTHFR polymorphisms showed no deviations from random segregation. Because the fetus is lost in a great proportion of trisomy 21 pregnancies, both maternal and fetal, not only live-born MTHFR C677T and A1298C, as well as maternal nutrition and lifestyle during pregnancy, should be analyzed to asses the impact on CHD in DS.

Population-based study of congenital heart defects in Down syndrome

Mental retardation and hypotonia are found in virtually all Down syndrome (DS) individuals, whereas congenital heart defects (CHDs) are only present in a subset of cases. Although there have been numerous reports of the frequency of CHDs in DS, few of the studies have had complete ascertainment of DS in a defined geographic area. The Atlanta Down Syndrome Project, a population-based study of infants born with trisomy 21, provides such a resource. In the first 6.5 years of the study, 243 trisomy 21 livebirths were identified in the five-county Atlanta area (birth prevalence: 9.6/10,000). Cardiac diagnoses were available on 227 (93%) of the cases and 89% of these evaluations were made by echocardiography, cardiac catheterization, surgery, or autopsy. Of the 227 DS infants, 44% had CHDs including 45% atrioventricular septal defect (with or without other CHDs), 35% ventricular septal defect (with or without other CHDs), 8% isolated secundum atrial septal defect, 7%, isolated persistent patent ductus arteriosus, 4% isolated tetralogy of Fallot, and 1% other. This report is unique in that it contains the largest number of trisomy 21 infants ascertained in a population-based study where modern techniques for diagnosing cardiac abnormalities predominate.