How does genetics affect the development of congenital heart defects?
About 400 genes have been implicated in CHD, encompassing transcription factors, cell signaling molecules, and structural proteins that are important for heart development. Recent studies have shown genes encoding chromatin modifiers, cilia related proteins, and cilia-transduced cell signaling pathways play important roles in CHD pathogenesis. Elucidating the genetic etiology …
What's new in congenital heart disease research?
INTRODUCTION. Congenital heart disease (CHD) is the leading cause of birth defects, and accounts for more deaths in the first year of life than any other condition when infectious etiologies are excluded [].With an incidence ranging from 19 to 75 per one thousand live births and present in an even greater proportion of miscarriages, CHD is an important cause of childhood …
How many congenital heart disease genes are there?
The contribution of genetic variants to the pathogenesis of congenital heart disease (CHD) has been long suspected and, more recently, well established. The accepted model for the roles of genetic variation causing CHD has evolved over time, with the pendulum swinging between complex, summative polygenic models and simplistic, high-impact ...
Can single-gene defects lead to isolated congenital heart disease?
Abstract. In isolated congenital heart disease genetic factors have been shown from family studies, individual pedigree analyses, the frequency of consanguinity, examination of data from twins, and possibly from cytogenetics. In defects of the atrial septum, where data are most complete, genetic factors appear to be important, particularly in secundum atrial septal defect.
How many genes are associated with heart valve development?
In a less biased approach, another study used a cost-cognizant method of combinatorial pooling and targeted multigene sequencing of 97 genes associated with heart valve development in 78 unrelated patients with a mix of sporadic and inherited BAV with and without coarctation of the aorta [6]. After filtering in silicoand confirmation with Sanger sequencing, 31 putatively pathogenic variants from 28 genes in 16 patients were identified. Only two of these variants were de novo(affecting APCand GATA5), and both were found in the same patient with a family history of aortic coarctation. Pathway analysis of the 28 genes was performed using the Database for Annotation, Visualization and Integrated Discovery, revealing overrepresentation of WNT signaling pathway genes (WNT4, PPP3CA, NFATC1, APC, AXIN1,and AXIN2). Eleven of the remaining 15 patients had no family history of CHD, suggesting that these inherited variants were not sufficient to impact aortic valve development alone but interacted with other genetic or environmental factors in the pathogenesis of BAV.
What is the most common congenital heart malformation?
Conclusively outlining the molecular mechanisms that determine genotype–phenotype correlations is often not straightforward, even in smaller studies that focus on a single CHD phenotype and candidate gene [4]. Bicuspid aortic valve (BAV) is the most common congenital heart malformation but is often clinically silent until late adulthood. Variants affecting the only two genes strongly linked to BAV, NOTCH1and GATA5, account for a small fraction of cases [5]. A nonsense mutation affecting NKX2-5(p. K192X) was identified in a patient with inherited BAV and demonstrated in vitroto negate synergistic transcriptional activation with GATA5. Sequencing of available family members identified the mutation in the proband’s sister and father, both of whom had BAV as part of a more complex phenotype, including atrial septal defect, paroxysmal atrial fibrillation, and atrioventricular conduction delay.
What are CNVs in CHD?
CNVs are increasingly recognized as a major contributor to the pathogenesis of CHD. Estimates for the portion of CHD attributable to CNVs have been limited by the resolution of CNV detection methods and small study sizes. In a study of sporadic cases of complex CHD, high-density single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing were used to identify CNVs with a limit of detection of 0.1 KB [11]. A de novoputative CNV was identified in approximately 10% of cases for whom a pathogenic genetic lesion was not already identified, including recurrently affected regions 1q21.1, 7q11.23, 8p23.1, 11q25, 15q11.2, and 22q11.2. In another study, hypoplastic left heart syndrome or conotruncal defect (CTD) patient/parent trios were prospectively recruited from a single institution without first screening for family history but incorporating echocardiographic data on all available parents [12]. Using array competitive genomic hybridization, a presumed causative CNV was identified in 5.6% of probands. They, too, identified recurrent de novoCNVs affecting 1q21.1 and 22q11.2 regions, as well as 19p13.3 and many recurrent rare inherited CNVs. Interestingly, an association between rare inherited CNVs and underdiagnosed parental CHD was not observed, and, specifically for those parents found to have BAV, there was no association with their child having hypoplastic left heart syndrome. It was also worth noting that the two classes of CHD did not differ in their CNV incidence or the specific genes affected.
What is the leading contributor to the observed clinical overlap of CHD with developmental delay?
The shared genetic regulation of heart and brain development is a leading contributor to the observed clinical overlap of CHD with developmental delay.
What causes CHD in mice?
From multiple different study designs, the genetic lesions that cause CHD are increasingly being elucidated. Of the more novel findings, a forward genetic screen in mice has implicated recessive inheritance and the ciliome broadly in CHD pathogenesis. The developmental delays frequently observed in patients with CHD appear to result from mutations affecting genes that overlap heart and brain developmental regulation. A meta-analysis has provided clarity, discriminating pathologic from incidental copy number variations and defining a critical region or gene.
What are the environmental factors that affect CHD?
An expanding list of environmental risk factors for CHD, including infectious, autoimmune, and toxic ones , have been proposed, most with only modest relative risk (RR) [14]. The phenotypic heterogeneity and incomplete penetrance characteristic of CHD genetics may remain esoteric unless modifying factors, such as environmental exposures, additional genetic variants, or epigenetic imprinting are evaluated. Folate supplementation during pregnancy, initiated to reduce risk of neural tube defects, unexpectedly reduced CHD incidence. Efforts to identify folate metabolic genetic variants associated with CHD risk have yielded inconsistent results. It is possible that this inconsistency may be a result of environmental confounders.
Is CHD a multifactorial disease?
Though significant gaps remain, genetic lesions remain the primary explanation for CHD pathogenesis, although the precise mechanism is likely multifactorial.
What are the genes that cause CHD?
Remarkable insights into Mendelian and inherited forms of CHD have emerged from classic linkage analyses, positional cloning and targeted sequencing of CHD candidate genes . Many of the genes first implicated in inherited CHD are members of a core group of cardiac transcription factors that includes NKX2.5, the GATA family of zinc-finger proteins, T-box factors including TBX5 and TBX1 and MEF2 factors. 49 – 51 Mutations in NKX2.5 were one of the first inherited point mutations clearly shown to cause human CHD. NKX2.5 is a transcriptional regulator that interacts with GATA4 to specify cardiac mesoderm, first identified in Drosophila mutants that had complete failure to form a heart tube. 52 Evaluation of large pedigrees that included individuals with isolated ASDs, and individuals with ASDs along with abnormalities of the conduction system subsequently identified NKX2.5 mutation underlying both the ASD and conduction system defects. Notably, some affected individuals had the ASD alone, others had the conduction defect alone, and some had both the ASD and the conduction defect. 53 The phenotypic heterogeneity associated with NKX2.5 mutations is remarkable, encompassing a wide range of CHD beyond ASDs, including heterotaxy and TOF. 54 It is interesting to speculate whether the wide spectrum of CHD results from differences in genetic background, or interaction between an at-risk genotype and environmental influences that may include subtle variation in hemodynamics in utero during critical times in cardiac development. GATA4 is a zinc-finger transcription factor essential for cardiogenesis that directly associate with NKX2.5. 55 GATA4 mutations were implicated in two families with CHD with cardiac septal defects. 56
What are the causes of CHD?
Aneuploidies were the earliest identified genetic causes of CHD. Estimates of the proportion of CHD associated with cytogenetic abnormalities range from 9% to 18%. 26 The large number of genes that are dysregulated in the setting of aneuploidy results in effects on development that are often pleiotropic and severe, and 98% of fetuses with CHD and cytogenetic abnormalities have at least one extracardiac abnormality. 27 CHD is observed in 35% to 50% of liveborns with trisomy 21, 60% to 80% of liveborns with trisomy 13 and trisomy 18, and 33% with monosomy X. Furthermore, there is a large effect on overall viability, as evidenced by the 33% to 42% incidence of aneuploidy among fetuses with prenatally diagnosed CHD, compared with 9% to 18% among neonates with CHD. 27 The types of CHD associated with specific aneuploidies covers a broad range of CHD phenotypes, although there are lesions that are more prominently associated with specific chromosomal abnormalities, such as atrioventricular septal defects in trisomy 21. The large numbers of genes with dosage disturbance in aneuploidy make it more challenging to pinpoint the underlying genetic and developmental mechanisms. However, insights have been gleaned from studies of patients with rare segmental trisomies affecting chromosome 21 suggesting that DSCAM and COL6A contribute to Down Syndrome–associated CHD. 28 Interestingly, overexpression of both DSCAM and COL6A in mice leads to heart abnormalities, while overexpression of either gene alone does not affect heart development. 29
How long do people with CHD live?
The natural history of severe congenital heart disease (CHD) was altered dramatically by the performance of the first systemic to pulmonary artery shunt procedure by Helen Taussig, Vivien Thomas, and Alfred Blalock. 6 Since then, an almost universally lethal condition has become progressively more approachable through a combination of surgical, catheter-based, and medical interventions. In the modern era, patients in developed countries undergoing CHD surgery, including those with complex CHD, have 10-year survival exceeding 80%. 1 This has resulted in an ever-increasing population of adults who are living with CHD, and there are now more people over the age of 18 years with CHD than children with CHD. 7
What is ZIC3 mutation?
19, 60, 61 ZIC3 is a zinc-finger transcription factor that is required to form a functional left–right organizer 62 and is required to direct the directionality of heart looping. As the absence of left–right organizer function leads to random heart looping, these pedigrees show striking incomplete penetrance: some affected family members will have normal heart looping and appear phenotypically normal and transmit the disease allele, while others will have situs inversus or heterotaxy and complex CHD.
How many de novo mutations are there in CHD?
Analysis of de novo mutations has illuminated the immense genetic heterogeneity underlying CHD pathogenesis. Recent work analyzing de novo mutations in 1213 CHD subjects showed that ≈392 genes, albeit with wide confidence intervals, collectively contribute to CHD. This estimation of the number of risk genes was performed using a maximum likelihood function, details of the simulation and derivation are noted in the studies by Homsy et al 75 and Iossifov et al. 113 On the basis of this function in 1213 CHD cases, 392 genes were estimated to contribute to CHD. 75 An approach to identify a greater fraction of the CHD risk genes is to identify additional genes with more than one de novo mutation in patients with CHD. In a cohort double the size (2426 trios), power simulations approximate 61 genes with more than one damaging mutation (≈40 new genes in the additional 1213 trios and 21 previously identified in the original 1213 trios). To identify all 392 CHD genes would require a significant increase in the number of CHD trios analyzed. Furthermore, recent work suggests that WES of 10 000 trios would permit ≈80% saturation for detecting genes contributing to haploinsufficient syndromic CHD alone 80; it is likely that a significantly larger number of trios will have to be analyzed to approach a complete gene set for all CHD. As sequencing continues to become faster and less expensive, it is anticipated that large-scale collaboration of CHD genetics programs, such as the Pediatric Cardiac Genomics Consortium, 114 Pediatric Heart Network, 115 and the UK10K consortium, 116 could allow for capture of the estimated ≈392 CHD risk genes and make a previously daunting task achievable.
What are chromatin-regulating genes?
Chromatin-regulating genes encompass ≈600 genes that orchestrate dynamic gene expression during development by addition or removal of chemical marks on chromatin or by catalyzing changes in chromatin structure. The biological state of chromatin is controlled by ATP-dependent chromatin modifiers, including the Baf complex and Chd8, and by histone modifiers. Both have been linked to heart development; Baf60c regulates early heart development through cooperation with the GATA4 transcription factor. 83 H3K4me and H3K27me constitute “bivalent” marks that are found on the promoters and enhancers of key cardiac developmental genes poised for activation. 84 A significant burden of haploinsufficient (dominant) de novo mutations within these elements, therefore, indicate dosage sensitivity of the chromatin pathway in heart development. Although relatively rare, chromatin modifiers have been linked to isolated CHD such as the histone methyl transferase PRDM6 which has been associated with nonsyndromic Patent Ductus Arteriosus. 85
What are the biological pathways involved in CHD?
The genetics underlying CHD have identified critical biological pathways involved in CHD, including chromatin remodeling, Notch signaling, cilia function, sarcomere structure and function, and RAS signaling. These pathways are anticipated to provide direct insights into the mechanism of heart development and to provide insights into potential CHD comorbidities, such as ventricular dysfunction observed in the setting of sarcomere and RAS pathway mutations. Furthermore, identification of common developmental pathways shared between cardiac development and other systems, such as the nervous system in the setting of chromatin modifier mutations and the respiratory system in the setting of cilia mutations, is anticipated to directly inform outcomes and prognosis for patients with CHD. We will outline studies linking three of these pathways to CHD: chromatin remodeling, Notch signaling, and cilia genes.
What are the genes that cause congenital HD?
In summary, in recent years, NGS approaches in isolated congenital HD have revealed the following: 1 There are several hundred genes that either cause or contribute to congenital HD. 275 2 Sequence variants in congenital HD genes can cause both sporadic and inherited congenital HD. 3 Sequence variants in congenital HD genes can cause both syndromic and nonsyndromic congenital HD, with strong association of de novo variants with syndromic CHD 274 and of inherited variants with nonsyndromic congenital HD. 411 4 There is phenotypic heterogeneity, with sequence variants in the same genes often associated with different cardiac phenotypes, not only between families but also within families. This discordance in phenotype among family members was further highlighted in a Danish national study in which only 50% of siblings had the same type of congenital HD as the proband. 415 5 Family studies often show incomplete segregation even in familial congenital HD, with could be attributable in part to incomplete penetrance but could also be related to oligogenic origins of congenital HD. 413 The occurrence of multiple variants in some patients might explain why some affected individuals have a more severe phenotype. 414
Why is the mouse model used for heart development?
Because of the high degree of conservation between mouse and human cardiac development and the availability of well-established techniques for genetic manipulation, the mouse model has been used to study heart development for >25 years, resulting in an extensive knowledge base with bountiful reagents and resources.
What are the most common cardiovascular defects associated with 22q11.2 deletion?
Conotruncal malformations account for 70% of the heart defects associated with a 22q11.2 deletion. 52 The most common cardiovascular defects include tetralogy of Fallot (20%), truncus arteriosus (6%), conoventricular VSD (14%), type B interruption of the aortic arch (IAA), and other aortic arch anomalies (13%). 53–56 ASDs, pulmonary valve stenosis (PVS), HLHS, double-outlet right ventricle, transposition of the great arteries (TGA), vascular rings, and heterotaxy syndrome are less common but have also been reported.
How common is congenital HD?
Current research indicates that congenital HD is the most common birth defect, affecting nearly 10 to 12 per 1000 liveborn infants (1%–1.2%). 6–8 Not all individuals with congenital HD are diagnosed early, so the actual prevalence has been difficult to determine, but one estimate from Canada suggested that the overall prevalence is 13.1 per 1000 children and 6.1 per 1000 adults. 9 Their data also suggested that congenital HD prevalence increased 11% in children and 57% in adults from 2000 to 2010. The impact of successful medical and surgical management of congenital HD on the survival of individuals with congenital HD is likely contributing to a large extent to its increased prevalence among older children and adults. More and more patients with severe types of congenital HD are surviving into their 30s and beyond. Of note, estimates of congenital HD incidence and prevalence have not included cases of isolated bicuspid aortic valve (BAV), unarguably a form of congenital HD. Because the population prevalence of BAV is 1% to 2% (based on studies at autopsy and of liveborn infants and healthy adolescents), the total prevalence of congenital HD is closer to 2% to 3%. 10–12
Is congenital HD pathogenic?
On average as a group, children with pathogenic C NVs associated with congenital HD have poorer outcomes than children without pathogenic CNVs. At least part of the explanation for the worse outcome could be an association with extracardiac manifestations that impact medical care. In one series of 58 patients with congenital HD and other dysmorphic features or other anomalies, 20.7% of the patients had potentially pathogenic CNVs that ranged in size from 240 kb to 9.6 Mb. 45 In another series of 422 children with nonsyndromic, isolated congenital HD followed up prospectively from before their first surgery, there was an increased frequency of potentially pathogenic CNVs in 12.1% of congenital HD subjects compared with 5% of control subjects, and in this series, the presence of a CNV was associated with significantly decreased transplant-free survival after surgery, with an adjusted 2.6-fold increased risk of death or transplantation. 46 Beyond survival, putatively pathogenic CNVs that were more frequent in congenital HD patients with single-ventricle physiology (13.9% of 223 affected individuals compared with 4.4% of control subjects) were associated with worse linear growth and worse neurocognitive outcomes. 47 There is undoubtedly heterogeneity in outcomes across CNVs, and future studies will require refined analyses specific to the individual CNV to determine which ones are associated with differential prognosis when controlling for the cardiac anatomy, as well as studying the other associated anomalies, ventricular function, and arrhythmias that could account for differential outcomes.
Is PCD inherited?
PCD is most commonly inherited as an autosomal recessive condition, although a rare association of X-linked PCD with retinitis pigmentosa has been described and a new X-linked form of PCD has recently been identified. 290 There are at least 39 genes known to cause PCD, with additional candidate genes identified in animal models. The number of PCD-causing genes that can also cause isolated congenital HD is unknown, but recent work shows that predicted damaging variants are found in genes required for ciliary motility and function in patients with congenital HD. 14
Is there a correlation between the size of the deletion and whether or not there is congenital HD?
There is no correlation between the size of the deletion and whether or not there is congenital HD or what the specific congenital HD is . Using FISH, Grossfeld and colleagues 91 found that the smallest terminal deletion associated with a congenital HD (HLHS) was ≈7 Mb (cardiac critical region).
About this Research Topic
Congenital heart diseases (CHDs) are the most common birth defects accounting for almost one-third of all birth defects. The cause of CHDs is largely unknown. It is widely accepted that the cause of CHDs is the interaction between genes (from parents or de novo mutations) and environmental factors, such as ...
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What is the most common CHD in DS?
The most common CHD in DS patients is the atrioventricular septal defect (AVSD), followed by atrial septal defect, ventricular septal defect (VSD) and tetralogy of Fallot (Tof) [ 23 ]. Recent studies show that genes mapping on chromosomes different from 21 can play an important role in the development of specific anatomic patterns of CHDs in DS [ [24], [25], [26] ]. More than 30 years ago, our group showed in children with AVSD a lower prevalence of left-sided obstructions in subjects with DS, compared with non-syndromic AVSD. The favourable anatomic pattern of AVSD ( Fig. 1, Fig. 2) explained the better results of cardiac surgery in this syndrome [ 27 ]. With the predictive medicine approach, specific perioperative protocols were adopted in these patients accordingly with their specific cardiac and extracardiac characteristics. For example, in DS it is necessary to evaluate in the perioperative period the presence of comorbidity, frequently associated with this genetic syndrome, such as upper airway obstructions and immune system disorders that predispose these patients to a greater risk of respiratory infections. These aspects deserve specific attention and treatment [ 28 ].
What is the most common type of birth defect?
Congenital heart diseases ( CHDs) are the most common and severe type of birth defects accounting for almost 1% of live births and causing significant morbidity and mortality in neonates, infants and adults [ 1 ]. In recent years, surgical results for CHDs have significantly improved, but post-operative complications and long-term mortality and morbidity are still important, particularly for the most severe forms of cardiac defects [ 2 ]. Underlying genetic variations have an increasingly recognized impact on anatomical and functional complexity of CHDs and could represent additional risk factors for cardiac surgery and long-term clinical outcomes including ventricular function, arrhythmias, comorbidities, neurodevelopment and survival [ 3, 4 ].
