Recent studies have shown genes encoding chromatin modifiers, cilia related proteins, and cilia-transduced cell signaling pathways play important roles in CHD A condition where the major blood vessels supplying the heart are narrowed.Coronary Artery Disease
Full Answer
How does genetics affect the development of congenital heart defects?
From congenital heart defects due to chromosomal aneuploidy to single gene defects causing isolated CHD, genetics has a much greater influence on the development of various types of CHD than previously appreciated.
What is the clinical approach to genetic testing for congenital heart disease?
Genetic testing in congenital heart disease: A clinical approach 1 Choosing a genetic test. An individualized approach to genetic testing begins with... 2 Interpretation of a genetic test. When a genetic variation is diagnosed,... 3 Appropriate management. Non-cardiac organ involvement: An accurate diagnosis could alert...
Can single-gene defects lead to isolated congenital heart disease?
These new developments demonstrate that single-gene defects can lead to isolated congenital heart disease, and reveal more about molecular pathways important in cardiac morphogenesis. Table 3. Non-Syndromic CHD Resulting from Single Gene Defects Cardiac Anomalies Gene ASD, atrioventricular conduction delay, TOF, tricuspid valve abnormalities NKX2.5
What is the role of Genetics in the diagnosis of CHD?
Genetic investigation in CHD may carry the potential to improve prognosis by yielding valuable information with regards to personalized medical care, confidence in the clinical diagnosis, and/or targeted patient follow-up.
How does genetics affect heart disease?
Genetics can influence the risk for heart disease in many ways. Genes control every aspect of the cardiovascular system, from the strength of the blood vessels to the way cells in the heart communicate. A genetic variation (mutation) in a single gene can affect the likelihood of developing heart disease.
How can genetics cause CHD?
CHD is genetically heterogeneous. That mutations in different genes cause an identical malformation underscores the highly interdependent roles of molecules involved in heart development.
Is there a genetic test for congenital heart disease?
Genetic tests are not available for all forms of congenital heart disease. Your cardiologist can help you determine if you are a good candidate.
What is the most common genetic cause of congenital heart disease?
Genetic conditions Down's syndrome is the most widely-known genetic condition that can cause congenital heart disease. Children with Down's syndrome are born with a range of disabilities as the result of a genetic abnormality. About half of all children with Down's syndrome have congenital heart disease.
What is the treatment of congenital heart disease?
Many children with congenital heart defects don't need treatment, but others do. Treatment can include medicines, catheter procedures, surgery, and heart transplants. The treatment depends on the type of the defect, how severe it is, and a child's age, size, and general health.
How is congenital heart disease diagnosed?
Congenital heart disease may initially be suspected during a routine ultrasound scan of the baby in the womb. Specialist ultrasound, called foetal echocardiography, will then be carried out at around 18 to 22 weeks of the pregnancy to try to confirm the exact diagnosis.
Is congenital heart disease genetic or environmental?
Congenital heart disease (CHD) is a prevalent birth defect that can occur from genetic variations, environmental exposures, and other factors. Genetic risk factors for CHD include Mendelian mutations, copy number variants (CNVs), translocations, and single nucleotide polymorphisms (SNPs) (1–3).
What role do you see genetic testing playing in the overall management of congenital heart disease in the pediatric and adolescent population?
Determining the genetic cause of congenital heart disease can provide a more accurate prognosis by providing insight into potential unanticipated extracardiac involvement, other associated cardiac complications, and long-term outcomes (Chaix et al., 2016).
What is a genetic basis?
“genetic. basis of common. disease” means the extent to which variation in the individual risk of acquiring any specific com- mon disease is conditioned by the hereditary material acquired at conception.
What genes cause heart defects?
Some of the genetic syndromes that have a higher rate of heart defects include:Marfan syndrome.Smith-Lemli-Opitz syndrome.Ellis-van Creveld syndrome.Holt-Oram syndrome.Noonan syndrome.Mucopolysaccharidoses.Alagille syndrome.
What classification is congenital heart disease?
CHD can be subdivided in non-cyanotic CHD and cyanotic CHD which is also called critical congenital heart disease (CCHD). CCHD can be further classified into 3 different types of lesions: right heart obstructive lesions, left heart obstructive lesions, and mixing lesions.
What causes congenital heart disease in babies?
Researchers aren't sure exactly what causes most of these defects, but they think genetics, certain medical conditions, some medications, and environmental or lifestyle factors, such as smoking, may play a role. There are many different types of congenital heart defects.
What is the genetics of congenital heart disease?
Genetics of Congenital Heart Disease. Congenital heart disease (CHD) is one of the most common birth defects. Studies in animal models and humans have indicated a genetic etiology for CHD. About 400 genes have been implicated in CHD, encompassing transcription factors, cell signaling molecules, and structural proteins that are important ….
How many genes are involved in CHD?
Studies in animal models and humans have indicated a genetic etiology for CHD. About 400 genes have been implicated in CHD, encompassing transcription factors, cell signaling molecules, and structural proteins that are important for heart development.
What is the most common birth defect?
Congenital heart disease (CHD) is one of the most common birth defects. Studies in animal models and humans have indicated a genetic etiology for CHD. About 400 genes have been implicated in CHD, encompassing transcription factors, cell signaling molecules, and structural proteins that are important ….
What is congenital heart disease?
Congenital heart disease (CHD) is a structural abnormality of the heart and great vessels that is present at birth. 1 It is the most common birth defect, affecting ≈1% of all liveborn infants. 2 CHD results from perturbation of the normal program of cardiac development ( Figure 1A ). Historically, CHD has been categorized based on a combination of final anatomic and physiological phenotypes ( Figure 1B ), such as conotruncal defects that affect the ventricular septum and outflow tract, defects that lead to obstruction to left ventricular outflow (LVO), defects resulting from abnormal left–right relationships within the heart (heterotaxy), defects affecting the inflow such as the mitral and tricuspid valve abnormalities seen in atrioventricular canal defect, and a broad range of other defects including isolated atrial or ventricular septal defects. 3 Approximately one third of patients with CHD have disease that is categorized as severe (comprising univentricular hearts, heterotaxy, conotruncal defects, atrioventricular canal defects, total anomalous pulmonary venous return, LVO obstruction, and right ventricular outflow obstruction except isolated valvar pulmonary stenosis) and require intervention in the first year of life. 4 Despite progress in medical and surgical treatments, CHD remains the leading cause of mortality from birth defects in the developed world. Furthermore, among the world’s poorest populations, CHD has a greater contribution to cardiovascular disease–associated disability-adjusted life-years than ischemic heart disease or stroke. 5
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
What is the role of transcriptional regulation in CHD?
The prominent role of transcriptional regulation in CHD predicts that mutations affecting regulatory elements will contribute to CHD. For example, homozygous variation in a TBX5 enhancer was found in a patient with isolated septal defects. 129 An important obstacle of detecting noncoding mutations in CHD is to delineate cardiac-specific regulatory elements and promoters at appropriate developmental time points. Projects, such as ENCODE and the Cardiovascular Genomic Consortium, continue to build these data sets, and thus may be helpful in identifying rare de novo events in these noncoding elements. Other sources of WGS discovery could focus on cis -acting regulatory sequences, allelic selective gene expression in regulatory elements, and identification of epistatic and modifying mutations in diseases with known coding mutations, but with poor penetrance. An example of the latter has been shown in another developmental disorder, craniosynostosis, where rare SMAD6 loss of function mutations modified by a common variant in BMP2 resulted in complete penetrance of this disease. 130 Exploration of the noncoding DNA will require WGS, which provides the most comprehensive view of the genome. Beyond complete determination of mutations outside the coding region, WGS provides more complete coverage of the exome and leads to improved detection of exonic CNVs and translocations. The potential challenges of WGS include greater expense, larger amounts of acquired and stored data, and the greater challenge of interpreting sequence variation in noncoding DNA. At present, evidence that WGS comes close to WES in efficiency of discovery of rare mutations with large effect remains limited. 131 Moreover, the 10-fold lower conservation of enhancer sequences indicates a much lower power to find disease-related mutations and adds to the challenge. One study of patients with severe intellectual disability, however, identified a conclusive cause in 42% of patients by WGS, compared with 27% by WES; it is notable that many of the mutations identified by WGS in this study actually affected the exome. 132 This limitation of WES is progressively being overcome by improved capture technologies that generate progressively more complete coverage of all exonic sequences. 133 The genomic technologies applied to CHD gene discovery and patient with CHD diagnosis are rapidly evolving. Currently, WGS is likely contribute to understanding the genetic cause of CHD, but it is most effective when applied in patients without WES evidence of damaging de novo mutations or likely pathogenic dominant and recessive mutations.
What is genetic mosaicism?
Genetic mosaicism is defined as the presence of having multiple populations of genetically distinct cells within an individual . Mosaic de novo variants have been shown to contribute up to 20% of sporadic cases in several developmental disorders, including Sturge–Weber syndrome, 117 facioscapulohumeral muscular dystrophy, 118 and segmental neurofibromatosis. 119 There have also been clinical reports suggesting pathogenic mosaic CNVs in patients with CHD. 120 Small studies using array comparative genomic hybridization have not identified any CNVs with differential presence between cardiac tissue and peripheral whole blood. 121 A recent study identified an excess of extreme allele-specific expression events in cardiac tissue from patients with CHD compared with controls, and as only 15% of the allele-specific expression events were explained by genomic variants, it is possible that some of these were secondary to mosaicism. 122 However, such studies are limited because of sample size, lack of developmentally relevant cardiac tissues, and imperfect statistical tools to detect mosaic variation. Larger cohorts of sequencing data, continued developmental of analysis tools, and ascertainment of cardiac tissues could help in identification of mosaic mutations, such as (1) de novo mutations with mosaic tissue distributions with involvement of cardiac tissues or precursors that would directly influence heart development and (2) parental mosaicism where the unaffected parents of an affected offspring with CHD harbors mutation in the germline and any somatic tissue not involved in cardiac developmental, such that the mutation is constitutively transmitted to the affected offspring.
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 is the overwhelming majority of phenotypes caused by large effect mutations?
Unbiased genetic discovery by positional cloning in humans, mice, and fruit flies has demonstrated that the overwhelming majority of phenotypes caused by large-effect mutations are caused by coding sequence mutations . This has identified mutations in ≈3500 genes underlying known Mendelian phenotypes.
Is CHD heterogenic?
Genetics of CHD has made giant leaps forward in parallel with the evolution of genome analysis technologies. The suspicion that CHD is extremely heterogenic has been validated , and the anticipated complexity of CHD genetics further increased by relatively limited observed genotype–phenotype correlations. Even syndromes that were thought to be well-defined clinically, such as CHARGE and Kabuki, are showing tremendous variation in phenotype when they are defined on the basis of the molecular finding. It is distinctly possible that some of the outcome in CHD is substantially influenced by the underlying genetic cause, in addition to the morphology and hemodynamics that underpin the impressively successful medical and surgical management of CHD to date. 3 This observation drives the hope that early identification of genetic causes of CHD will allow more tailored management of CHD and will hopefully improve the outcome, especially, with respect to the many comorbidities of CHD that have a profound impact in quality of life for patients living with CHD. For example, identification of neurodevelopmental risk genes can identify patients who can benefit from early intervention programs long before any clinical signs of NDD, such as learning disabilities become apparent. In addition to the clinical implications of a more complete understanding of CHD genetics, the genes uncovered in human patients have already provided tremendous insights into the basic mechanisms underlying cardiac development.
Is congenital heart disease more common than birth defect?
Congenital heart disease is the most common birth defect, and because of major advances in medical and surgical management, there are now more adults living with congenital heart disease (CHD) than children. Until recently, the cause of the majority of CHD was unknown.
Is congenital heart disease genetic?
Genetics and Genomics of Congenital Heart Disease. Congenital heart disease is the most common birth defect, and because of major advances in medical and surgical management, there are now more adults living with congenital heart disease (CHD) than children. Until recently, the cause of the majority of CHD was unknown.
Abstract
This review provides an updated summary of the state of our knowledge of the genetic contributions to the pathogenesis of congenital heart disease.
CONGENITAL HD EPIDEMIOLOGY AND IMPORTANCE OF IDENTIFYING A GENETIC BASIS FOR 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%).
MOLECULAR TECHNIQUES AND DIAGNOSIS
In addition to aneuploidies and large chromosomal rearrangements, the past 10 years of genetics research has advanced a contemporary understanding of normal and pathogenic human genetic variation based on the concept of detecting individual differences relative to a reference sequence defined as normal.
CHROMOSOMAL ANEUPLOIDIES AND CNVs ASSOCIATED WITH CONGENITAL HD
Aneuploidy is an abnormal number of chromosomes, and aneuploidies that most commonly survive to term include trisomy 21, 18, and 13 and sex chromosome aneuploidies such as Turner syndrome ( Appendix ). There is an increased risk of many aneuploidies with increasing maternal age.
COPY NUMBER VARIANTS
On average as a group, children with pathogenic CNVs 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.
DESCRIPTIONS OF SPECIFIC CNVs ASSOCIATED WITH CONGENITAL HD
In this section, several CNVs are highlighted. The Appendix provides information on other less frequent CNVs.
WELL-CHARACTERIZED SYNDROMES CAUSED BY SINGLE-GENE VARIATION
During the past 10 to 15 years, a period of active gene discovery, the molecular basis of many syndromes has been identified Numerous syndromes caused by single-gene variants (traditionally referred to as mutations) have additionally been found to be genetically heterogeneous, which means that an individual variant in >1 gene is capable of causing a similar condition ( Table 5 ).
What is congenital heart disease?
Congenital Heart Disease: Causes, Diagnosis, Symptoms, and Treatments. The congenital heart disease includes abnormalities in heart structure that occur before birth. Such defects occur in the fetus while it is developing in the uterus during pregnancy.
How many people have congenital heart disease?
Such defects occur in the fetus while it is developing in the uterus during pregnancy. About 500,000 adults have congenital heart disease in USA (WebMD, Congenital heart defects medications, www.WebMD.com ….
How is DNA extracted for genetics?
For genetic study, first DNA is extracted from blood followed by DNA sequence analysis and any defect in nucleotide sequence of DNA is determined. For congenital heart disease, genes in chromosome 1 show some defects in nucleotide sequence.
Can alcohol cause heart disease in children?
The excessive alcohol consumption during pregnancy and use of medications, maternal viral infection, such as Rubella virus, measles (German), in the first trimester of pregnancy, all these are risk factors for congenital heart disease in children, and the risk increases if parent or sibling has a congenital heart defect.
Can congenital heart disease cause shortness of breath?
There are no particular symptoms of congenital heart disease, but shortness of breath and limited ability to do exercise, fatigue, abnormal sound of heart as heart murmur, which is diagnosed by a physician while listening to the heart beats.