Novel mutations in the TBX5 gene in patients with Holt-Oram Syndrome

The Holt-Oram syndrome (HOS) is an autosomal dominant condition characterized by upper limb and cardiac malformations. Mutations in the TBX5 gene cause HOS and have also been associated with isolated heart and arm defects. Interactions between the TBX5, GATA4 and NKX2.5 proteins have been reported in humans. We screened the TBX5, GATA4, and NKX2.5 genes for mutations, by direct sequencing, in 32 unrelated patients presenting classical (8) or atypical HOS (1), isolated congenital heart defects (16) or isolated upper-limb malformations (7). Pathogenic mutations in the TBX5 gene were found in four HOS patients, including two new mutations (c.374delG; c.678G > T) in typical patients, and the hotspot mutation c.835C > T in two patients, one of them with an atypical HOS phenotype involving lower-limb malformations. Two new mutations in the GATA4 gene were found in association with isolated upper-limb malformations, but their clinical significance remains to be established. A previously described possibly pathogenic mutation in the NKX2.5 gene (c.73C > 7) was detected in a patient with isolated heart malformations and also in his clinically normal father.     

Identification of cardiac malformations in mice lacking <Emphasis Type="Italic">Ptdsr</Emphasis>using a novel high-throughput magnetic resonance imaging technique

Background  

Congenital heart defects are the leading non-infectious cause of death in children. Genetic studies in the mouse have been crucial to uncover new genes and signaling pathways associated with heart development and congenital heart disease. The identification of murine models of congenital cardiac malformations in high-throughput mutagenesis screens and in gene-targeted models is hindered by the opacity of the mouse embryo.     

Pulmonary Artery Stenosis—A Frequent Part of the Congenital Rubella Syndrome

The case records, cardiac catheterization and angiographic findings in 32 patients were reviewed to illustrate the high incidence of pulmonary artery stenosis in congenital rubella syndrome. These interesting lesions often are of equivocal or unknown clinical significance compared with the other malformations that beset these patients, but to know of them explains certain physical findings and to study their incidence is an unusual opportunity to pinpoint a definite cause for a congenital cardiac lesion.     

Measuring hemodynamic changes during mammalian development

The pathogenesis of many congenital cardiovascular diseases involves abnormal flow within the embryonic vasculature that results either from malformations of the heart or defects in the vasculature itself. Extensive genetic and genomic analysis in mice has led to the identification of an array of mutations that result in cardiovascular defects during embryogenesis. Many of these mutations cause secondary effects within the vasculature that are thought to arise because of altered fluid dynamics. Presumably, cardiac defects disturb or reduce flow and thereby lead to the disruption of the mechanical signals necessary for proper vascular development. Unfortunately, a precise understanding of how flow disruptions lead to secondary vasculature defects has been hampered by the inadequacy of existing analytical tools. Here, we used a fast line-scanning technique for the quantitative analysis of hemodynamics during early organogenesis in mouse embryos, and we present a model system for studying cellular responses during the formation and remodeling of the mammalian cardiovascular system. Flow velocity profiles can be measured as soon as a heart begins to beat even in newly formed vessels. These studies establish a link between the pattern of blood flow within the vasculature and the stage of heart development and also enable analysis of the influence of mechanical forces during development.     

Heparan sulfate expression in the neural crest is essential for mouse cardiogenesis

Impaired heparan sulfate (HS) synthesis in vertebrate development causes complex malformations due to the functional disruption of multiple HS-binding growth factors and morphogens. Here, we report developmental heart defects in mice bearing a targeted disruption of the HS-generating enzyme GlcNAc N-deacetylase/GlcN N-sulfotransferase 1 (NDST1), including ventricular septal defects (VSD), persistent truncus arteriosus (PTA), double outlet right ventricle (DORV), and retroesophageal right subclavian artery (RERSC). These defects closely resemble cardiac anomalies observed in mice made deficient in the cardiogenic regulator fibroblast growth factor 8 (FGF8). Consistent with this, we show that HS-dependent FGF8/FGF-receptor2C assembly and FGF8-dependent ERK-phosphorylation are strongly reduced in NDST1^−/− embryonic cells and tissues. Moreover, WNT1-Cre/LoxP-mediated conditional targeting of NDST function in neural crest cells (NCCs) revealed that their impaired HS-dependent development contributes strongly to the observed cardiac defects. These findings raise the possibility that defects in HS biosynthesis may contribute to congenital heart defects in humans that represent the most common type of birth defect.     

Oculo-facio-cardio-dental syndrome in a girl and her mother

Congenital heart defects are known to be associated with facial dysmorphism and other congenital anomalies. Oculo-facio-cardio-dental (OFCD) syndrome is one such rare multiple congenital anomaly syndrome inherited as an X-linked dominant condition characterized by congenital cataracts, multiple minor facial dysmorphic features, congenital heart defects and dental anomalies. It is unrecognized by many medical and dental professionals. Only 21 cases have been reported so far. This syndrome is often misrecognized as rubella embryopathy because of association of congenital cataract with cardiac anomalies. It is usually the orthodontists who diagnose the syndrome based on typical findings on dental panoramic radiographs. But we suspected our patient to be having OFCD syndrome based on typical facial dysmorphism, ocular and cardiac defects, and finally it was confirmed after noticing typical dental radiographic findings.     

Left-right asymmetry and congenital cardiac defects: getting to the heart of the matter in vertebrate left-right axis determination

Cellular and molecular left-right differences that are present in the mesodermal heart fields suggest that the heart is lateralized from its inception. Left-right asymmetry persists as the heart fields coalesce to form the primary heart tube, and overt, morphological asymmetry first becomes evident when the heart tube undergoes looping morphogenesis. Thereafter, chamber formation, differentiation of the inflow and outflow tracts, and position of the heart relative to the midline are additional features of heart development that exhibit left-right differences. Observations made in human clinical studies and in animal models of laterality disease suggest that all of these features of cardiac development are influenced by the embryonic left-right body axis. When errors in left-right axis determination happen, they almost always are associated with complex congenital heart malformations. The purpose of this review is to highlight what is presently known about cardiac development and upstream processes of left-right axis determination, and to consider how perturbation of the left-right body plan might ultimately result in particular types of congenital heart defects.     

BMP signaling in congenital heart disease: new developments and future directions

Congenital heart malformations are the most common of all congenital human birth anomalies. During the past decade, research with zebrafish, chick, and mouse models have elucidated many fundamental genetic pathways that govern early cardiac patterning and differentiation. This review highlights the roles of the bone morphogenetic protein (BMP) signaling pathway in cardiogenesis and how defective BMP signals can disrupt the intricate steps of cardiac formation and cause congenital heart defects.     

Partitioning the heart: mechanisms of cardiac septation and valve development

Heart malformations are common congenital defects in humans. Many congenital heart defects involve anomalies in cardiac septation or valve development, and understanding the developmental mechanisms that underlie the formation of cardiac septal and valvular tissues thus has important implications for the diagnosis, prevention and treatment of congenital heart disease. The development of heart septa and valves involves multiple types of progenitor cells that arise either within or outside the heart. Here, we review the morphogenetic events and genetic networks that regulate spatiotemporal interactions between the cells that give rise to septal and valvular tissues and hence partition the heart.     

Anti-SSA/Ro antibodies and the heart: more than complete congenital heart block? A review of electrocardiographic and myocardial abnormalities and of treatment options

Apart from complete and incomplete congenital heart block (CHB), new cardiac manifestations related to anti-SSA/Ro antibodies have been reported in children born to mothers bearing these antibodies. These manifestations include transient fetal first-degree heart block, prolongation of corrected QT (QTc) interval, sinus bradycardia, late-onset cardiomyopathy, endocardial fibroelastosis and cardiac malformations. Anti-SSA/Ro antibodies are not considered pathogenic to the adult heart, but a prolongation of the QTc interval has recently been reported in adult patients and is still a matter of debate. Treatment of CHB is not well established and needs to be assessed carefully. The risks and benefits of prenatal fluorinated steroids are discussed.     

Etiologic heterogeneity in the familial aggregation of congenital cardiovascular malformations.

Recent data indicate that there is increased risk of congenital cardiovascular malformations (CCVM) within families of probands diagnosed with congenital cardiovascular malformations that are due to altered embryonic blood flow (flow lesions). In the present study, regressive models recently developed by Bonney were used to compare specific models of inheritance and to test for etiologic heterogeneity among three subgroups of 375 flow-lesion families identified by the Baltimore-Washington Infant Study. When all families were analyzed as a single group, the best-fitting model was a simple recessive model with Mendelian transmission; race did not have a significant effect on estimated risk. Separate analyses of families of probands with left heart defects, right heart defects, and ventricular septal defects (VSD) confirmed this simple Mendelian recessive model as the model of choice. However, when race was included as a covariate in these genetic models, there was evidence for significant heterogeneity among the three subgroups. There was an increased risk to relatives of white probands with right heart defects and to relatives of black probands with VSD, while there was no effect of race among relatives of probands with left heart defects. These results strongly suggest that there is etiologic heterogeneity in the control of CCVM among flow-lesion families and that the patterns of familial aggregation differ among the races.     

The genetics of cardiac birth defects

Congenital heart disease likely results from a complex mixture of environmental and genetic factors. Recent work has elucidated rare single gene mutations that cause a variety of cardiac defects, but the etiologies of more common disease remains unknown. Here, we review the known genetic causes of cardiac malformations and discuss future approaches for addressing sporadic congenital heart disease as a complex trait.     

Model systems for the study of heart development and disease. Cardiac neural crest and conotruncal malformations

Neural crest cells are multipotential cells that delaminate from the dorsal neural tube and migrate widely throughout the body. A subregion of the cranial neural crest originating between the otocyst and somite 3 has been called "cardiac neural crest" because of the importance of these cells in heart development. Much of what we know about the contribution and function of the cardiac neural crest in cardiovascular development has been learned in the chick embryo using quail-chick chimeras to study neural crest migration and derivatives as well as using ablation of premigratory neural crest cells to study their function. These studies show that cardiac neural crest cells are absolutely required to form the aorticopulmonary septum dividing the cardiac arterial pole into systemic and pulmonary circulations. They support the normal development and patterning of derivatives of the caudal pharyngeal arches and pouches, including the great arteries and the thymus, thyroid and parathyroids. Recently, cardiac neural crest cells have been shown to modulate signaling in the pharynx during the lengthening of the outflow tract by the secondary heart field. Most of the genes associated with cardiac neural crest function have been identified using mouse models. These studies show that the neural crest cells may not be the direct cause of abnormal cardiovascular development but they are a major component in the complex tissue interactions in the caudal pharynx and outflow tract. Since, cardiac neural crest cells span from the caudal pharynx into the outflow tract, they are especially susceptible to any perturbation in or by other cells in these regions. Thus, understanding congenital cardiac outflow malformations in human sequences of malformations as represented by the DiGeorge syndrome will necessarily require understanding development of the cardiac neural crest.     

Are selective serotonin reuptake inhibitors cardiac teratogens? Echocardiographic screening of newborns with persistent heart murmur

BACKGROUND : Selective serotonin reuptake inhibitors (SSRIs) have been suspected of cardiac teratogenicity, but reports have been inconsistent. Our aim was to investigate the rate of nonsyndromic congenital heart defects in newborns exposed in utero to SSRIs compared with unexposed controls. METHODS : This prospective study of women who gave birth at our tertiary center from 2000 to 2007 yielded 235 women who reported first‐trimester SSRI use during pregnancy. All newborns born during the study period and found to have a persistent cardiac murmur on day 2 or 3 of life were referred for examination by a pediatric cardiologist and by echocardiography. The findings were compared between the newborns who were exposed to SSRIs and those who were not. RESULTS : Nonsyndromic congenital heart defects were identified by echocardiography in 8 of 235 (3.40%) newborns exposed in utero to SSRIs and in 1083 of 67,636 (1.60%) non‐exposed newborns. The difference in prevalence between the two groups was significant (relative risk, 2.17; 95% confidence interval, 1.07–4.39). The prevalence rates for paroxetine and fluoxetine exposure were 4.3% and 3.0%, respectively. All cardiac defects in the study group were mild: ventricular septal defect (6), bicuspid aortic valve (1) and right superior vena cava to coronary sinus (1). CONCLUSIONS : Newborns exposed in utero to SSRIs, have a twofold higher risk of mild nonsyndromic heart defects than unexposed infants. The data suggest that women who require SSRI treatment during pregnancy can be reassured that the fetal risk is low and possible cardiac malformations will probably be mild. Late‐targeted ultrasound and fetal echocardiography at 22 to 23 weeks' gestation are recommended in this patient group. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.     

Combinatorial signaling in the heart orchestrates cardiac induction, lineage specification and chamber formation

The complexity of mammalian cardiogenesis is compounded, as the heart must function in the embryo whilst it is still being formed. Great advances have been made recently as additional cardiac progenitor cell populations have been identified. The induction and maintenance of these progenitors, and their deployment to the developing heart relies on combinatorial molecular signalling, a feature also of cardiac chamber formation. Many forms of congenital heart disease in humans are likely to arise from defects in the early stages of heart development; therefore it is important to understand the molecular pathways that underlie some of the key events that shape the heart during the early stages of it development.     

Diagnosis of congenital heart malformations--possibilities for the employment of telepathology.

GOAL: In a study of 10 autopsy cases with congenital cardiac malformations we investigated whether obtaining a second opinion by means of telepathology could satisfy quality standards for the diagnosis of cardiac malformations and what the advantages and disadvantages of such a procedure might be. MATERIAL: The investigatory samples were 10 formalin-fixed hearts with complex malformations from 9 fetuses and one newborn on which autopsies had been performed at the Pathological Institute of the Charité Hospital. The requests for a second opinion, which included text and image data, were sent in the form of Microsoft PowerPoint presentations to 5 experts in 4 countries. Per case the number of images that were sent was between 3 and 7. The size of the files was between 439 and 942 kb. The time required for preparation of the cases for sending them to the specialists was between 1 and 2 hours: this encompassed the time for putting the notation on the images, compressing them, creating a file that included both the images and the clinical data and then sending the case file. RESULTS: All 10 cardiac malformations were correctly identified. In 8 of the 10 cases at least one expert had questions. After these questions had been answered and further images had been sent final correct diagnoses were made in all cases. All experts said that the quality of the images was very good. Use of a standardized findings questionnaire, which also included the marking of anatomic structures and of pathological findings in the images, proved useful. Standardized findings forms facilitate orientation during interpretation of the cases and should be used generally to avoid misunderstandings in telepathological communication. CONCLUSIONS: In general it is possible to obtain an effective and reliable diagnosis of congenital heart malformations by means of telepathology. It is far quicker to get a second opinion by this means than by conventional means.     

Genetic Screening of the Canine Connexin 40 Gene in Dogs with Inherited Cardiac Conduction Defects

Connexin 40 (Cx40) is a gap-junction protein expressed in the heart where it mediates the coordinated electrical activation of the atria and ventricular conduction tissues, facilitates cell-to-cell adhesion, and provides pathways for direct intercellular communication. Recent studies have shown that Cx40 null mice have cardiac conduction abnormalities with a very high incidence of cardiac malformations in heterozygous (18%) and homozygous (33%) animals, indicating that Cx40 plays a vital role in cardiomorphogenesis. Since several inherited cardiac conduction defects have also been found in dogs, we hypothesized that the clinical findings are genetically linked to a tissue-specific mutation or mutations in the canine Cx40 gene. We therefore screened the Cx40 gene in dogs with inherited cardiac conduction defects for mutations. In this study, we have identified three heterozygous base changes (C384G, C402T, C837T) in the dogs screened and determined them to be synonymous mutations. These mutations, however, have recently been found in an unrelated group of normal dogs.     

Congenital cardiology: recent advances emphasise the need for collaboration

The population of adult patients with congenital heart disease is steadily growing, due to the developments in cardiac surgery and thereby decreased mortality. However, morbidity in these patients is substantial. Patients with repaired lesions often need reoperations later in life. Most congenital heart defects, operated or not, have the potential to lead to clinical heart failure. Arrhythmias affect up to 50% of patients with congenital heart disease. The prevalence of pulmonary hypertension due to a left-to-right shunt among patients with a congenital heart defect is estimated at 4 to 10%. Advances in diagnostics, interventional and surgical therapy will result in new populations of adult survivors with even more complex disease. Collaboration of cardiologists with expertise in different areas of modern cardiology, such as electrophysiology, imaging and percutaneous interventions, is necessary for optimal care and management of these patients.     

Essential role for ADAM19 in cardiovascular morphogenesis

Congenital heart disease is the most common form of human birth defects, yet much remains to be learned about its underlying causes. Here we report that mice lacking functional ADAM19 (mnemonic for a disintegrin and metalloprotease 19) exhibit severe defects in cardiac morphogenesis, including a ventricular septal defect (VSD), abnormal formation of the aortic and pulmonic valves, leading to valvular stenosis, and abnormalities of the cardiac vasculature. During mouse development, ADAM19 is highly expressed in the conotruncus and the endocardial cushion, structures that give rise to the affected heart valves and the membranous ventricular septum. ADAM19 is also highly expressed in osteoblast-like cells in the bone, yet it does not appear to be essential for bone growth and skeletal development. Most adam19(-/-) animals die perinatally, likely as a result of their cardiac defects. These findings raise the possibility that mutations in ADAM19 may contribute to human congenital heart valve and septal defects.