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Citations
... The severity of congenital heart disease varies but up to one-quarter of cases have been classified as critical [3,4], and 30% of infant deaths from birth defects are associated with a heart defect [2]. However, peripartum ultrasound [5], postnatal pulse-oximetry and advances in surgical treatment have improved early detection and survival [6][7][8][9][10] and 250,000 adults are currently living with congenital heart disease in the United Kingdom [11], as are two million Americans [3]. ...
Background
Nine in every thousand children born in the United Kingdom have congenital heart disease, and 250,000 adults are living with the condition. This study aims to investigate the associations between congenital heart disease and educational outcomes among school-aged children in Scotland.
Methods
Routine health and education databases were linked to produce a cohort of all singleton children born in Scotland and attending a local authority run primary, secondary, or special school in Scotland at some point between 2009 and 2013. Children with congenital heart disease within this cohort were compared with children unaffected by congenital conditions. Outcomes investigated were special educational need (SEN), absenteeism, exclusion, academic attainment, and unemployment. All analyses were adjusted for sociodemographic and maternity confounders. Absenteeism was investigated as a mediating factor in the associations with attainment and unemployment.
Results
Of the 715,850 children, 6,295 (0.9%) had congenital heart disease and 4,412 (6.1%) had isolated congenital heart disease. Congenital heart disease and isolated congenital heart disease were both significantly associated with subsequent special educational need (OR 3.45, 95% CI 3.26–3.65, p < 0.001 and OR 1.98, 95% CI 1.84–2.13, p < 0.001 respectively), absenteeism (IRR 1.13, 95% CI 1.10–1.16, p < 0.001 and IRR 1.10, 95% CI 1.06–1.13, p < 0.001 respectively), and low academic attainment (OR 1.69, 95% CI 1.39–2.07, p < 0.001 and OR 1.35, 95% CI 1.07–1.69, p = 0.011 respectively). Neither congenital heart disease nor isolated congenital heart disease were associated with school exclusion. Only congenital heart disease (OR 1.21, 95% CI 1.03–1.42, p = 0.022) but not isolated congenital heart disease was associated with unemployment. When days absent were included in the analyses investigating attainment and unemployment, the conclusions were not altered.
Conclusion
Children with congenital heart disease have greater special educational need, lower school attendance, attain lower examination grades and have greater unemployment compared to peers. In addition to healthcare support, affected children need educational support to avoid additional impact on their long-term wellbeing.
... These aforesaid factors are contributed to the complex patterns of inheritance for CHDs than the traditionally considered monogenic autosomal dominant (AD), autosomal recessive (AR), X-linked or mitochondrial inheritance patterns [8]. Thus, while information gathered from clinical genetic studies as well as animal models strongly suggests genetic factors as the predominant cause of CHDs, epidemiological studies plead that environmental exposures are also relevant [9]. At the same time, a good number of epigenetic modifiers are being identified. ...
... Recently, CNVs > 300 kb are detected in iCHD [38]. Many pathogenic CNVs are associated with iCHD with a diverse set of genes, which are dispersed throughout the genome [9]. ...
Purpose of Review
Congenital heart disease (CHD) is the most frequently occurring birth defect. Majority of the earlier reviews focussed on the association of genetic factors with CHD. A few epidemiological studies provide convincing evidence for environmental factors in the causation of CHD. Although the multifactorial theory of gene-environment interaction is the prevailing explanation, explicit understanding of the biological mechanism(s) involved, remains obscure. Nonetheless, integration of all the information into one platform would enable us to better understand the collective risk implicated in CHD development.
Recent Findings
Great strides in novel genomic technologies namely, massive parallel sequencing, whole exome sequencing, multiomics studies supported by system-biology have greatly improved our understanding of the aetiology of CHD. Molecular genetic studies reveal that cardiac specific gene variants in transcription factors or signalling molecules, or structural proteins could cause CHD. Additionally, non-hereditary contributors such as exposure to teratogens, maternal nutrition, parental age and lifestyle factors also contribute to induce CHD. Moreover, DNA methylation and non-coding RNA are also correlated with CHD.
Summary
Here, we inform that a complex combination of genetic, environmental and epigenetic factors interact to interfere with morphogenetic processes of cardiac development leading to CHD. It is important, not only to identify individual genetic and non-inherited risk factors but also to recognize which factors interact mutually, causing cardiac defects.
... Approximately 13% of syndromic children with CHD show chromosomal aneuploidy, thus accounting for a significant proportion of CHD [8,12]. Aneuploidies, detected by karyotyping, are the first genetic anomaly associated with CHD [13]. Common examples of aneuploidy with CHD include trisomy 21 and TS (45, X) and others are listed in Table 1. ...
... Turner syndrome is a common sex chromosomal anomaly caused due to either partial or complete loss of the X chromosome in females [13]. Patients with Turner syndrome have characteristic features of short stature, loss of ovarian function manifesting as delayed puberty, menarche and in adult women, unovulation and infertility. ...
Purpose of Review
Approximately 30% of syndromic cases diagnosed with CHD, which lure us to further investigate the molecular and clinical challenges behind syndromic CHD (sCHD). The aetiology of sCHD in a majority of cases remains enigmatic due to involvement of multiple factors, namely genetic, epigenetic and environmental modifiable risk factors for the development of the disease. Here, we aim to update the role of genetic contributors including chromosomal abnormalities, copy number variations (CNVs) and single gene mutations in cardiac specific genes, maternal lifestyle conditions, environmental exposures and epigenetic modifiers in causing CHD in different genetic syndromes.
Recent Findings
The exact aetiology of sCHD is still unknown. With the advancement of next-generation technologies including WGS, WES, transcriptome, proteome and methylome study, numerous novel genes and pathways have been identified. Moreover, our recent knowledge regarding epigenetic and environmental regulation during cardiogenesis is still evolving and may solve some of the mystery behind complex sCHD.
Summary
Here, we focus to understand how the complex combination of genetic, environmental and epigenetic factors interact to interfere with developmental pathways, culminating into cardiac and extracardiac defects in sCHD.
... Identification of the genetic background of CHDs has great clinical importance, because it allows for an early specific diagnosis and a more comprehensive care for patients with syndromic CHDs, and it helps in the assessment of recurrence risk and helps evaluate the prognosis and the outcomes of different therapeutic measures for the patient [31,32]. For example, patients with 22q11.2 ...
... For example, patients with 22q11.2 deletion have affected survival and complication rates in the case of CHD repair, requiring longer cardiopulmonary bypass times and longer postoperative stay in the intensive care unit, with globally worse surgical outcomes [32]. The presence of potentially pathogenic CNVs is equally important in isolated cases of CHDs, their association increasing the risk of death and heart transplant by 2.6 times after heart surgery [12]. ...
... Most of the studies that reported the detection of CNVs identified variations in the 22q11.2 region [25,[29][30][31][32][33], both deletions and duplications, demonstrating once again the high mutagenicity of this genetic locus, as described previously [20,21]. There is a complex network of morphogens and transcription factors that orchestrates the development of the cardiovascular system, in which GATA4, NXK2-5, and TBX5 act as early regulators [13]. ...
Congenital heart defects (CHDs) have had an increasing prevalence over the last decades, being one of the most common congenital defects. Their etiopathogenesis is multifactorial in origin. About 10–15% of all CHD can be attributed to copy number variations (CNVs), a type of submicroscopic structural genetic alterations. The aim of this study was to evaluate the involvement of CNVs in the development of congenital heart defects. We performed a cohort study investigating the presence of CNVs in the 22q11.2 region and GATA4, TBX5, NKX2-5, BMP4, and CRELD1 genes in patients with syndromic and isolated CHDs. A total of 56 patients were included in the study, half of them (28 subjects) being classified as syndromic. The most common heart defect in our study population was ventricular septal defect (VSD) at 39.28%. There were no statistically significant differences between the two groups in terms of CHD-type distribution, demographical, and clinical features, with the exceptions of birth length, weight, and length at the time of blood sampling, that were significantly lower in the syndromic group. Through multiplex ligation-dependent probe amplification (MLPA) analysis, we found two heterozygous deletions in the 22q11.2 region, both in patients from the syndromic group. No CNVs involving GATA4, NKX2-5, TBX5, BMP4, and CRELD1 genes were identified in our study. We conclude that the MLPA assay may be used as a first genetic test in patients with syndromic CHD and that the 22q11.2 region may be included in the panels used for screening these patients.
... Por otra parte, cabe mencionar que desde las variables explicativas, un aspecto relevantes es el hecho de que muchas de ellas no presentan una sintomatología asociada y por lo tanto no reciben un tratamiento integral adecuado (55). Sólo en aquellos casos, donde la presencia de los sintomas es exacerbado y requieren de correcciones desde las intervenciones quirúrgicas, se ha hecho un estudio en el cual se requiere un proceso de seguimiento y acompañamiento desde el área de cardiología, siendo importante resaltar que las posibles complicaciones a mediano y largo plazo pueden alcanzar al 90 % de los infantes que son sometidos a estos tratamientos; por lo que en la vida adulta continuan las secuelas y la esperanza de vida es media, no comparable con la población general (56). ...
... 50 It is now known that causative genetic mutations significantly impact the anatomical and functional complexity of CHD and could represent additional risk factors for cardiac surgery or for clinical outcomes. 51,52 Furthermore, identifying specific genoty-peÀphenotype correlations is necessary to identify a tailored approach for patients with CHD improving quality of life and long-term outcomes. 53 Future research aimed at better understanding the genotypeÀphenotype correlation in CHD will also lead to the implementation of new preventive strategies and therapies targeted to the needs of everyone, improving clinical and surgical management, long-term outcome, and quality of life for these patients (Table 1). ...
... [1][2][3] Despite advances in diagnostics and surgery, a high neonatal mortality rate prevails due to congenital heart defect. 4) Multiple later complications, such as heart failure, endocarditis, and arrhythmias, are the leading causes of neonatal death. 3) Ventricular septal defect (VSD) is the most common type of CHD. 5) Similar to other types of congenital heart defects, the major pathogenesis of ventricular septal defect is cardiac dysplasia. ...
Ventricular septal defect (VSD), the most common type of congenital heart disease (CHD), is primarily caused by cardiac dysplasia. Heart and neural crest derivatives expressed 2 (HAND2) participates in developing the right heart. The loss of HAND2 expression in humans is closely connected with ventricular septal defects. We used a case-control study to analyze the genetic variations in the HAND2 promoter region in VSD patients and controls. Some statistical analysis methods were used to analyze the association of single nucleotide polymorphisms (SNPs) with VSD. The dual-luciferase reporter assay and electrophoretic mobility shift assay (EMSA) were used to conduct functional analysis and molecular mechanism study of genetic variations. Through sequencing, we identified nine genetic variants in patients with VSD. The SNP rs2276940 G>T and rs2276941 G>A were associated with an increased risk of VSD. The dual-luciferase reporter assay showed that SNP rs2276940 G>T and rs138531627 C>G decreased the transcriptional activity of the HAND2 promoter. Transcription factors (TFs) predicting suggested that all three SNPs may change the binding of TFs. The result of EMSA showed that rs138531627 C>G may create a new binding site for TFs while rs2276940 G>T enhanced the binding affinity for TFs. These results indicated that genetic variants of the HAND2 promoter may increase the risk of VSD, and the molecular mechanism may be the change of the binding affinity of TFs.
... 9 It is known that underlying genetic conditions have an increasingly recognized impact on the anatomical and functional complexity of CHDs and could represent additional risk factors or even protective factors for cardiac surgery and clinical outcomes. [10][11][12][13][14] It is even more clear that early identification of the genetic causes of CHDs is expected to allow our understanding of the underlying pathogenetic mechanisms that influence the clinical and surgical outcome of a specific subtype of CHD. 15 Similarly, the identification of genotype-phenotype correlations is predicted to guide a more effective personalized management of patients with cardiac defects, improving quality of life and long-term outcome. 14 Recent studies showed that precision medicine using genotype-phenotype correlation data is able to guide not only risk stratification, but also identification of treatments that can modify the molecular mechanism of the disease. ...
... [10][11][12][13][14] It is even more clear that early identification of the genetic causes of CHDs is expected to allow our understanding of the underlying pathogenetic mechanisms that influence the clinical and surgical outcome of a specific subtype of CHD. 15 Similarly, the identification of genotype-phenotype correlations is predicted to guide a more effective personalized management of patients with cardiac defects, improving quality of life and long-term outcome. 14 Recent studies showed that precision medicine using genotype-phenotype correlation data is able to guide not only risk stratification, but also identification of treatments that can modify the molecular mechanism of the disease. [16][17][18] In our case series, we have described different cardiac anomalies along with the extracardiac findings in fetus which has helped us in suspecting the underlying genetic abnormality in fetus which was later confirmed by definitive genetic testing. ...
: Recent advances in molecular genetic techniques have found evidence of the role of genetic factors in the development of CHD. Approximately 30% of CHD is thought to be related to genetic syndromes accompanied by extra-cardiac anomalies. We describe the cases of cardiac anomalies detected on prenatal ultrasound, which helped us in suspecting the genetic abnormality in fetus which were later confirmed by definitive testing.
: Prospective evaluation and follow up of 10 cases done which showed cardiac and extracardiac findings suspicious of chromosomal disorder.
: Definitive testing showed genetic abnormality in (N = 10) cases. We could detect Trisomy 21 in (N = 3), Trisomy 18 in (N=2), Trisomy 13 in (N=2), Triploidy in (N=1) and Monosomy X (Turners) in (N=2) cases in our series. Detection of abnormal cardiac findings can definitely improve the detection rate of genetic disorders and positive yield of genetic testing.
... Despite improvements in standardized care, neurodevelopmental and growth outcomes vary substantially in children with SV-CHD 2 . Identifiable syndromes and chromosomal abnormalities are associated with worse outcomes for multiple forms of complex CHD [3][4][5][6] . Predicted damaging genetic variants in genes related to CHD may contribute to poor outcomes, irrespective of whether the patient has syndromic CHD. ...
Background
Recent large-scale sequencing efforts have shed light on the genetic contribution to the etiology of congenital heart defects (CHD); however, the relative impact of genetics on clinical outcomes remains less understood. Outcomes analyses using genetics are complicated by the intrinsic severity of the CHD lesion and interactions with conditionally dependent clinical variables.
Methods
Bayesian Networks were applied to describe the intertwined relationships between clinical variables, demography, and genetics in a cohort of children with single ventricle CHD.
Results
As isolated variables, a damaging genetic variant in a gene related to abnormal heart morphology and prolonged ventilator support following stage I palliative surgery increase the probability of having a low Mental Developmental Index (MDI) score at 14 months of age by 1.9- and 5.8-fold, respectively. However, in combination, these variables act synergistically to further increase the probability of a low MDI score by 10-fold. The absence of a damaging variant in a known syndromic CHD gene and a shorter post-operative ventilator support increase the probability of a normal MDI score 1.7- and 2.4-fold, respectively, but in combination increase the probability of a good outcome by 59-fold.
Conclusions
Our analyses suggest a modest genetic contribution to neurodevelopmental outcomes as isolated variables, similar to known clinical predictors. By contrast, genetic, demographic, and clinical variables interact synergistically to markedly impact clinical outcomes. These findings underscore the importance of capturing and quantifying the impact of damaging genomic variants in the context of multiple, conditionally dependent variables, such as pre- and post-operative factors, and demography.
... These syndromes, known to disrupt valvular microenvironmental homeostasis due to genetic impairments, exhibit a prevalence of BAV exceeding 10 times that of the general population (21% vs. 2%). This recurrent presence of BAV in such syndromes underscores its intricate association with conditions involving compromised neural crest migration and gene abnormalities that potentially disrupt the valvular microenvironment [19][20][21][22][23][24][25][26][27][28][29][30][31]. [28] * Bicuspid aortic valve prevalence in general is 0.5-2%. ...
Objective:
bicuspid aortic valve (BAV) stands as the most prevalent congenital heart condition intricately linked to aortic pathologies encompassing aortic regurgitation (AR), aortic stenosis, aortic root dilation, and aortic dissection. The aetiology of BAV is notably intricate, involving a spectrum of genes and polymorphisms. Moreover, BAV lays the groundwork for an array of structural heart and aortic disorders, presenting varying degrees of severity. Establishing a tailored clinical approach amid this diverse range of BAV-related conditions is of utmost significance. In this comprehensive review, we delve into the epidemiology, aetiology, associated ailments, and clinical management of BAV, encompassing imaging to aortic surgery. Our exploration is guided by the perspectives of the aortic team, spanning six distinct guidelines.
Methods:
We conducted an exhaustive search across databases like PubMed, Ovid, Scopus, and Embase to extract relevant studies. Our review incorporates 84 references and integrates insights from six different guidelines to create a comprehensive clinical management section.
Results:
BAV presents complexities in its aetiology, with specific polymorphisms and gene disorders observed in groups with elevated BAV prevalence, contributing to increased susceptibility to other cardiovascular conditions. The altered hemodynamics inherent to BAV instigate adverse remodelling of the aorta and heart, thus fostering the development of epigenetically linked aortic and heart diseases. Employing TTE screening for first-degree relatives of BAV patients might be beneficial for disease tracking and enhancing clinical outcomes. While SAVR is the primary recommendation for indicated AVR in BAV, TAVR might be an option for certain patients endorsed by adept aortic teams. In addition, proficient teams can perform aortic valve repair for AR cases. Aortic surgery necessitates personalized evaluation, accounting for genetic makeup and risk factors. While the standard aortic replacement threshold stands at 55 mm, it may be tailored to 50 mm or even 45 mm based on patient-specific considerations.
Conclusion:
This review reiterates the significance of considering the multifactorial nature of BAV as well as the need for further research to be carried out in the field.
