Etiology Of Congenital Heart Disease Research Articles

Copy Number Variants and Exome Sequencing Analysis in Six Pairs of Chinese Monozygotic Twins Discordant for Congenital Heart Disease.

Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.

Early life environment and social determinants of cardiac health in children with congenital heart disease.

Congenital heart disease is a significant cause of infant mortality. Epidemiology and social context play a crucial role in conditioning disease burden and modulating outcomes, while diagnosis and treatment remain resource intensive. This review will address the role of social demographics, environmental exposure, epigenetics and nutrition in the aetiology of congenital heart disease. We then discuss the determinant effect of social factors on the provision and outcomes of care for congenital heart disease and implications for practice. It is our hope that enhanced knowledge of the intersection of social determinants of health and congenital heart disease will facilitate effective preventative strategies at the individual and population levels to optimize heart health outcomes across the life course.

Identification of intronic-splice site mutations in GATA4 gene in Indian patients with congenital heart disease

Congenital Heart Disease (CHD) is the most common birth defect among congenital anomalies that arise before birth. GATA4 transcription factor plays an important role in foetal heart development. Mutational analysis of GATA4 gene in CHD patients revealed five known heterozygous mutations (p.T355S, p.S377G, p.V380M, p.P394T and p.D425N) identified in exons 5 and 6 regions and fifteen intronic variants in the non-coding regions (g.76885T>C/Y,g.76937G>S, g.78343G>R, g.83073T>Y, g.83271C>A/M, g.83318G>K, g.83415G>R, g.83502A>C/M, g.84991G>R, g.85294C>Y, g.85342C>T/Y, g.86268A>R, g.87409G>A/R, g.87725T>Y, g.87813A>T/W). In silico analysis of these intronic variants identified two potential branch point mutations (g.83271C>A/M, g.86268A>R) and predicted effects of these on intronic splice sites as enhancer and silencer motifs. This study attempts to correlate the pattern of intronic variants of GATA4 gene which might provide new insights to unravel the possible molecular etiology of CHD.

177 Deciphering the mechanisms of developmental disorders (dmdd): a powerful new resource for studying congenital heart disease

Identifying the genetic components of heart disease remains challenging despite the transformation of clinical genetics by new DNA sequencing technologies. For congenital heart disease (CHD), animal models have provided a...

Exome sequencing reveals novel IRXI mutation in congenital heart disease.

Genetic variation in specific transcription factors during heart formation may lead to congenital heart disease (CHD) or even miscarriage. The aim of the present study was to identify CHD‑associated genes using next generation sequencing (NGS). The whole exome DNA sequence was obtained from a stillborn fetus diagnosed with tricuspid atresia and complete transposition of the great arteries using high‑throughput sequencing methods. Subsequently, genetic variants of CHD‑associated genes were selected and verified in 215 non‑syndromic CHD patients and 249 healthy control subjects using polymerase chain reaction combined with Sanger sequencing. Genetic variants of previously reported CHD‑inducing genes, such as cysteine rich with EGF like domains 1 and cbp/p300‑interacting transactivator with Glu/Asp rich carboxy‑terminal domain 2, were discovered through the NGS analysis. In addition, a novel non‑synonymous mutation of the iroquois homeobox 1 (IRX1) gene (p.Gln240Glu) was identified. A total of three non‑synonymous mutations (p.Gln240Glu, p.Ser298Asn and p.Ala381Glu) of the IRX1 gene were verified in 215 non‑syndromic CHD patients, but not in 249 healthy volunteers. The results demonstrated that NGS is a powerful tool to study the etiology of CHD. In addition, the results suggest that genetic variants of the IRX1 gene may contribute to the pathogenesis of CHD.

Appropriate Use of Genetic Testing in Congenital Heart Disease Patients

Congenital heart disease (CHD) remains the most common birth defect, occurring in 1% of all births. Although the exact etiology of CHD is still largely unknown, it is thought to be an interaction of genetic and non-genetic factors. The purposes of this review are to summarize recent advances in CHD genetics and testing and to present a suggested algorithm for appropriate use of genetic testing in patients with CHD. Advances in genetic testing technology are rapidly expanding the options for screening and are providing further insights into the genetic and molecular background of non-syndromic CHD. As the field advances, the role of the geneticist and genetic counselor will continue to expand as the testing becomes more complex and interpretation of results becomes increasingly challenging. Coordination of practice between cardiologists and geneticists using a shared clinical structure is essential and will help improve cost utilization and facilitate individualized patient care.

MESP1 Mutations in Patients with Congenital Heart Defects.

Identifying the genetic etiology of congenital heart disease (CHD) has been challenging despite being one of the most common congenital malformations in humans. We previously identified a microdeletion in a patient with a ventricular septal defect containing over 40 genes including MESP1 (mesoderm posterior basic helix-loop-helix transcription factor 1). Because of the importance of MESP1 as an early regulator of cardiac development in both in vivo and in vitro studies, we tested for MESP1 mutations in 647 patients with congenital conotruncal and related heart defects. We identified six rare, nonsynonymous variants not seen in ethnically matched controls and one likely race-specific nonsynonymous variant. Functional analyses revealed that three of these variants altered activation of transcription by MESP1. Two of the deleterious variants are located within the conserved HLH domain and thus impair the protein-protein interaction of MESP1 and E47. The third deleterious variant was a loss-of-function frameshift mutation. Our results suggest that pathologic variants in MESP1 may contribute to the development of CHD and that additional protein partners and downstream targets could likewise contribute to the wide range of causes for CHD.

Prevalence of Extra-Cardiac Malformations with Congenital Heart Disease among Hospital Admitted Children- A Study in a Tertiary Level Hospital of Bangladesh

Introduction: Congenital anomalies are a major cause of stillbirths and infant mortality. In this post genomic era, congenital heart diseases (CHDs) are still the most common and lethal of all birth defects in children. Although most of the CHD occur as a sporadic event many of them have a well-defined genetic basis. This genetic basis is expressed in the form of concomitant occurrence of extra-cardiac malformations (ECM) which may occur alone or as a part of a syndrome.Objective: The present study was designed to find out the burden of CHDs in the hospital admitted children and to find out the prevalence of occurrence of clinically recognizable ECM associated with CHDs.Methods: This is a cross-sectional hospital based study. Total patients admitted during the study period were 5264. Of these 335 patients were found suffering from different types of congenital heart diseases. This gives the hospital admission rate for CHD, as 63.6 per 1000 admission (6.36%). Out of total 335 cases of CHD, 273 (81.5%) were acyanotic and 62 (18.5%) were cyanotic. Among the CHD patients 68 (20.3%) had a significant ECM. Out of the 68 patients with a significant ECM 53 (77.9%) had a clinically recognizable genetic syndrome, whereas 15 cases (22.1%) had a major ECM which was not a part of a syndrome.Conclusion: A high rate of hospital admission is found for CHDs in the pediatric setting, signifying the need for improvement of pediatric cardiology infrastructure in Bangladesh, which should help in providing better medical and surgical care for the patients with CHD. A significant proportion of patients with CHD have associated ECM, implicating a genetic background for the etiology of CHD. It also emphasizes the need for thorough evaluation of patient with CHD for ECM.Journal of Armed Forces Medical College Bangladesh Vol.10(2) 2014

Environmental Factors And Risk For Congenital Heart Disease

BACKGROUND: The prevalence of congenital heart disease (CHD) is increasing globally, but the role of environmental factors in the etiology of CHD remains unclear. METHODS: In this case–control stud...

Genetics of congenital heart disease: the contribution of the noncoding regulatory genome.

Congenital heart disease (CHD) is the most common type of birth defect. The advent of corrective cardiac surgery and the increase in knowledge concerning the longitudinal care of patients with CHD has led to a spectacular increase in life expectancy. Therefore, >90% of children with CHD, who survive the first year of life, will live into adulthood. The etiology of CHD is complex and is associated with both environmental and genetic causes. CHD is a genetically heterogeneous disease that is associated with long-recognized chromosomal abnormalities, as well as with mutation in numerous (developmental) genes. Nevertheless, the genetic factors underlying CHD have remained largely elusive, and it is important to realize that in the far majority of CHD patients no causal mutation or chromosomal abnormality is identified. However, new insights (alternative inheritance paradigms) and technology (next-generation sequencing) have become available that can greatly advance our understanding of the genetic factors that contribute to CHD; these will be discussed in this review. Moreover, we will focus on the discovery of regulatory regions of key (heart) developmental genes and the occurrence of variations and mutations within, in the setting of CHD.

Cilia: Organelles at the Heart of Heart Disease

Genetic disorders, such as heterotaxy, first provided a link between cilia and developmental heart defects. Now, a genetic screen in mice shows that ciliary dysfunction may indeed be the major contributing factor in the etiology of congenital heart disease.

Gene network analysis: from heart development to cardiac therapy.

Networks offer a flexible framework to represent and analyse the complex interactions between components of cellular systems. In particular gene networks inferred from expression data can support the identification of novel hypotheses on regulatory processes. In this review we focus on the use of gene network analysis in the study of heart development. Understanding heart development will promote the elucidation of the aetiology of congenital heart disease and thus possibly improve diagnostics. Moreover, it will help to establish cardiac therapies. For example, understanding cardiac differentiation during development will help to guide stem cell differentiation required for cardiac tissue engineering or to enhance endogenous repair mechanisms. We introduce different methodological frameworks to infer networks from expression data such as Boolean and Bayesian networks. Then we present currently available temporal expression data in heart development and discuss the use of network-based approaches in published studies. Collectively, our literature-based analysis indicates that gene network analysis constitutes a promising opportunity to infer therapy-relevant regulatory processes in heart development. However, the use of network-based approaches has so far been limited by the small amount of samples in available datasets. Thus, we propose to acquire high-resolution temporal expression data to improve the mathematical descriptions of regulatory processes obtained with gene network inference methodologies. Especially probabilistic methods that accommodate the intrinsic variability of biological systems have the potential to contribute to a deeper understanding of heart development.

0390 : Vascular emergencies revealing a coarctation of the aorta in pregnant women

Coarctation of the aorta is defined as a circular narrowing at the junction of the aortic arch and descending aorta, opposite the start of the ducts arteriosus. It represents 6-8% of congenital heart disease. It represents the first etiology of congenital heart disease in pregnant women. We report in this paper, two cases of coarctation of the aorta complicated in pregnant women, collected within the maternal resuscitation Lalla Meryem in Ibn Rochd UH center of Casablanca. The complications occurring during this condition makes the poor prognosis. Thus, the incidence of hypertension and pre-eclampsia is higher, putting them at risk of aortic dissection and rupture, rupture of cerebral aneurysm and heart failure. Infective endocarditis is rare but it is a serious complication. Preterm delivery is not common in coarctation of the aorta as well as Fetal growth retardation. While the incidence of miscarriages and abortions is much higher. The management of these patients is based on a good understanding of the specific risks to the coarctation of the aorta, pregnancy planning and a multidisciplinary approach involving the cardiologist, the anesthesiologist, the intensivist, the Gynecologic obstétrien, the neonatologist and pediatrician. Research factor for cardiovascular risk is an essential part of monitoring of pregnancies. A preconception assessment and appropriate care throughout pregnancy are necessary to avoid a late diagnosis of this disease and an acute decompensation whose prognosis remains severe for mother and fetus. The cure reference coarctation of the aorta is surgical treatment to take place before the pregnancy. The angioplasty finds its place in the restenosis. Above all through, preventing the coarctations of the aorta complicated must be systematically and repeatedly search in the young age, raising the problematic of congenital cardiopathies detection in Morocco.

Cytogenomic Evaluation of Subjects with Syndromic and Nonsyndromic Conotruncal Heart Defects.

Despite considerable advances in the detection of genomic abnormalities in congenital heart disease (CHD), the etiology of CHD remains largely unknown. CHD is the most common birth defect and is a major cause of infant morbidity and mortality, and conotruncal defects constitute 20% of all CHD cases. We used array comparative genomic hybridization (array-CGH) to retrospectively study 60 subjects with conotruncal defects and identify genomic imbalances. The DNA copy number variations (CNVs) detected were matched with data from genomic databases, and their clinical significance was evaluated. We found that 38.3% (23/60) of CHD cases possessed genomic imbalances. In 8.3% (5/60) of these cases, the imbalances were causal or potentially causal CNVs; in 8.3% (5/60), unclassified CNVs were identified; and in 21.6% (13/60), common variants were detected. Although the interpretation of the results must be refined and there is not yet a consensus regarding the types of CHD cases in which array-CGH should be used as a first-line test, the identification of these CNVs can assist in the evaluation and management of CHD. The results of such studies emphasize the growing importance of the use of genome-wide assays in subjects with CHD to increase the number of genomic data sets associated with this condition.

Copy number variation of GATA4 and NKX2-5 in Chinese fetuses with congenital heart disease.

Congenital heart disease (CHD) is one of the most common birth defects in newborns. The etiology of CHD has remained largely unknown, but it is assumed to result from the combined effects of genetic and environmental factors. Recent investigations have detected potentially pathogenic copy number variations (CNV) in a proportion of patients with CHD. The present case-control study evaluated whether CNV in the GATA4 and NKX2-5 genes contribute to the pathogenesis of CHD in Chinese fetuses (n = 117), by comparing them with non-CHD control subjects (n = 100). Multiplex ligation-dependent probe amplification with the P311A probe mixture was used to detect CNV. The normalized signals were within the normal range for all exons in all CHD patients and non-CHD control subjects. Of the 117 CHD patients, three had a deletion of 22q11, and two had a duplication of 22q11. There was no evidence of a role for NKX2-5 and GATA4 CNV in fetal CHD; therefore, these CNV may not be common in fetal CHD in China.

Abstract 19285: Notch1 Haploinsufficiency Increases Risk of Congenital Heart Defects in the Setting of Maternal Diabetes by an Epigenetic Mechanism

Congenital heart disease (CHD) is the most common type of birth defect. Epidemiologic studies have shown the importance of genetic and environmental factors in the multifactorial etiology of CHD. Maternal diabetes mellitus (DM) is one of the non-genetic risk factors that predisposes to CHD predominantly cardiac septation and cardiac outflow tract defects. DM is known to be associated with endothelial cell dysfunction and we recently demonstrated a genetic interaction between endothelial nitric oxide synthase and Notch1, which encodes a receptor that functions in an important cardiac developmental signaling pathway. We hypothesized that maternal DM in the setting of Notch1 heterozygosity of the developing embryo will predispose to CHD. Notch1 +/- embryos (E13.5) exposed to maternal DM demonstrated an increased incidence (86%) of ventricular septal defects compared to wildtype littermates (22%) (Table). Gene expression studies in non-diabetic wildtype, diabetic wildtype and Notch1 +/- embryos showed DM was associated with decreased Notch1 mRNA levels and upregulation in Jarid2, a histone H3K9 demethylase known to regulate Notch1. In H9C2 and endocardial-derived cells and chick embryos, we showed that hyperglycemia led to decreased expression of Notch1 and its downstream targets in a dose-dependent manner. Similarly, Jarid2 mRNA levels increased with high glucose. Furthermore, we found reduced luciferase reporter activity in cells transfected with a constitutively active Notch1 intracellular domain with hyperglycemia. Studies demonstrating the relative enrichment of Jarid2 on Notch1 locus with hyperglycemia by ChIP-qPCR will also be presented. Our findings reveal that maternal DM disrupts cardiac development by deregulating the Notch1 signaling pathway and suggest that this gene-environment interaction is mediated by an epigenetic mechanism involving Jarid2 providing the first mechanistic insights for this association.

Spatial patterns of the congenital heart disease prevalence among 0- to 14-year-old children in Sichuan Basin, P. R China, from 2004 to 2009.

BackgroundCongenital heart disease (CHD) is the most common type of major birth defects in Sichuan, the most populous province in China. The detailed etiology of CHD is unknown but some environmental factors are suspected as the cause of this disease. However, the geographical variations in CHD prevalence would be highly valuable in providing a clue on the role of the environment in CHD etiology. Here, we investigate the spatial patterns and geographic differences in CHD prevalence among 0- to 14-year-old children, discuss the possible environmental risk factors that might be associated with CHD prevalence in Sichuan Basin from 2004 to 2009.MethodsThe hierarchical Bayesian model was used to estimate CHD prevalence at the township level. Spatial autocorrelation statistics were performed, and a hot-spot analysis with different distance thresholds was used to identify the spatial pattern of CHD prevalence. Distribution and clustering maps were drawn using geographic information system tools.ResultsCHD prevalence was significantly clustered in Sichuan Basin in different spatial scale. Typical hot/cold clusters were identified, and possible CHD causes were discussed. The association between selected hypothetical environmental factors of maternal exposure and CHD prevalence was evaluated.ConclusionsThe largest hot-spot clustering phenomena and the CHD prevalence clustering trend among 0- to 14-year-old children in the study area showed a plausibly close similarity with those observed in the Tuojiang River Basin. The high ecological risk of heavy metal(Cd, As, and Pb)sediments in the middle and lower streams of the Tuojiang River watershed and ammonia–nitrogen pollution may have contribution to the high prevalence of CHD in this area.

ĮGIMTOS ŠIRDIES YDOS: GENETINĖ ETIOLOGIJA IR DIAGNOSTIKA

Congenital heart disease (CHD) is the most common type of birth defect. It is leading cause of death in the first of year of live. The etiology of CHD is still not completely understood. Recent scientific investigations have focused on discovering of molecular mechanisms of cardiac development. New knowledges about genes participating in cardiac morphogenesis have led to the identification of genetic etiologies of CHD. In this article, genetic factors causing CHD, from large genome rearangements to single nucleotide polymorphisms are rewieved, and new genetic techniques, allowing to reveal the genetic causes and providing new understanding about molecular etiology of CHD are described.

Genetic variations of ISL1 associated with human congenital heart disease in Chinese Han people

Congenital heart disease (CHD) is the most common birth abnormality, but the etiology of CHD is unknown. ISL1 may play a fundamental role in cardiac morphogenesis, and mutations of this gene could cause CHD. To evaluate whether genetic variations of ISL1 are associated with CHD in Chinese Han people, polymerase chain reaction restriction fragment-length polymorphism and SNaPshot were used to examine 9 polymorphisms of ISL1 in 233 patients with CHD as well as 288 healthy controls. We found that one SNP (rs1017) in ISL1 was significantly associated with simple CHD. Genetic variation of ISL1 was confirmed to be associated with the risk of CHD. ISL1 is related to the atrial septal defect group and the ventricular septal defect group, and the genotypes were associated with the occurrence of CHD in the dominant mode of inheritance. We concluded that rs1017 contributed to the risk of CHD in Chinese Han people, and ISL1 may be involved in the formation and development of the heart.

Cardiovascular Developmental Biology Research— Elucidating Mechanisms Underlying Congenital and Acquired Heart Diseases

Cardiovascular diseases (CVDs) are the number one cause of death worldwide. According to a recent report from the World Health Organization, an estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Despite significant advances in surgical approaches and increased survival rate, congenital heart disease (CHD) is still the primary cause of birth defect-related deaths in the western world. More than half of all babies born with a cardiac abnormality will require at least one invasive surgery in their lifetime. As a result of improvement in surgical procedures, many babies who once would have died of CHD now survive into adulthood. In fact, the number of adults with CHD in the USA is now greater than the number of babies born with CHD. However, many adults with congenital heart disease are suffering from functional abnormalities, including arrhythmias and heart failure [1,2] and require lifelong care. The cardiovascular problems can be either intrinsic to the perturbation of developmental events that led to the structural malformations in the first place, or can result from acquired conditions related to scar tissues resulting from the surgical procedures. The primary goals of cardiovascular developmental research are to elucidate the mechanisms that govern normal cardiac development and to determine the molecular and cellular mechanisms involved in the etiology of CHD. In addition, as it becomes increasingly clear that many so-called acquired heart diseases may also have developmental origins, an additional goal of cardiovascular developmental biologists is to identify the early events that may play a role in the pathogenesis of acquired diseases, such as mitral valve prolapse. [...]