A genetic basis for congenital heart defects?

In a previous blog, I discussed some of the potential environmental causes of congenital heart defects (see here). Is there also a genetic basis to congenital heart defects? Surely there is some genetic component given that ~13% of patients with a congenital heart defect have a chromosomal abnormality (Hartman et al., 2011 Pediatric Cardiology) and congenital heart defects appear to be inherited within families (Oyen et al., 2009 Circulation 120,295-301). Yet, there is still very little known about the genetic or environmental causes of congenital heart defects.

Here is a brief review of what we know now about the genetic causes of congenital heart defects:

1) Chromosomal abnormalities are associated with congenital heart defects. Perhaps the most well known and most understood of the potential ’causes’ of congenital heart defects are chromosomal abnormalities. In humans, all of our cells have 23 pairs of chromosomes (so a total of 46). The different pairs of chromosomes can be ordered from largest to smallest and are numbered (1-22) plus the XX or XY chromosomes (the sex chromosomes or chromosome 23). When sperm or egg cells are being produced by the process of meiosis, each sperm or egg cell (‘germ cells’) should get 23 chromosomes (so the pairs split in half). However, sometimes the pair of chromosomes won’t split and the sperm/egg cell gets an extra chromosome or one of the sperm/egg cells is missing that specific chromosome. These extra (trisomy) or missing (monosomy) chromosomes are called ‘aneuploidies’ and they are the most well known type of chromosomal abnormality that is associated with congenital heart defects are aneuploidies. For example, Trisomy 21 (Down’s Syndrome) is caused by having 3 chromosomes at the 21st position. There are also other types of chromosomal abnormalities that do not involve the addition or subtraction of whole chromosomes. For example some chromosomal abnormalities, such as 22q11.2 deletion, only involve the subtraction of specific parts of a chromosome, in this case a small part of the 22 chromosome.

The exact proportion of individuals with a congenital heart defect that also exhibit a chromosomal abnormality is not entirely known with exact clarity but recent studies estimate that it is around 12% (e.g., Hartman et al., 2011 Pediatric Cardiology 32, 1147-1157). There are, of course, many different types of chromosomal abnormalities and different types of congenital heart defects may be associated with different types of chromosomal abnormalities. For example, in a study of 547 patients with congenital heart defects born near Atlanta, Georgia from 1994-2005 that also exhibited a chromosomal abnormality, ~53% had trisomy 21, ~13% had trisomy 18, ~12% had 22q11.2 deletion (also called DiGeorge Syndrome), and ~6% had trisomy 13 (Hartman et al., 2011). Moreover, there were associations between the congenital heart defect and whether the patient also exhibited a congenital heart defect. For example, for patients with an interrupted aortic arch or atrioventricular septal defect, 67-69% of them also had a chromosomal abnormality (Hartman et al., 2011).

Chromosomal abnormalities are associated with congenital heart defects, yet only around 12% of congenital heart defects appear to be ’caused’ by them. However, it is also possible that some of these chromosomal abnormalities underlying a congenital heart defect were missed. We have known approximately how many chromosomes humans have for ~100 years now and have been able to visualize and count (a karyotype) the number of pairs of chromosomes for around the same period of time. This can be done in an elementary science laboratory and observing extra or missing chromosomes is quite obvious (the classic cytogenetic techniques). But what about these other types of chromosomal abnormalities such as chromosomal deletions (22q11.2 deletion) or so called microdeletions (7q11.23. or Williams syndrome) that may underlie other congenital heart defects yet they are undetected? New molecular methods that are applied in a clinical setting may improve our ability to detect how often patients with congenital heart defects also exhibit chromosomal abnormalities other than aneuplodies (discussed in Pierpont et al., 2007 Circulation 1015, 3015-3038). Regardless, it would be interesting to know how often patients or the parents of patients with a congenital heart defect are offered more than just a genetic consultation to assess the possibility that a chromosomal abnormality us behind a congenital heart defect.

2) Some congenital heart defects appear to be inherited as they can reoccur within families. In addition to the relatively uniform distribution of wealth, Scandinavian countries have a lot of great things going for them. For example, every child born with a congenital heart defect is registered into a nationwide database, which allows researchers to follow these individuals throughout their lifetime and potentially identify the environmental or genetic risk factors associated with congenital heart defects. One area of research that has benefited from this large database of patients born with congenital heart defects is understanding the recurrence of congenital heart defects within families. If you have a child with a congenital heart defect, is your next child more likely to have a congenital heart defect? Well, it seems to depend on the type of congenital heart defect the first child exhibits. In a large survey of Danish people born from 1977-2005 (nearly 2 million patients!), 18,708 were born with some type of congenital heart defect (Oyen et al., Circulation 2009, 120, 295-301). What was interesting about these data was that within the families of individuals with specific types of congenital heart defects (e.g., heterotaxia, conotruncal defects, atrioventricular septal defects) there was an increased risk of recurrence of that type of congenital heart defect if another family member had also exhibited that congenital heart defect. This study estimated the ‘recurrence risk ratio’, which is a statistical measure of the recurrence of a specific type of disease (in this case congenital heart defect) within a family. You can use the presence/absence of a congenital heart defect within a family (siblings, cousins, etc.) to estimate the recurrence risk ratio. A high recurrence risk ratio means that the disease or congenital heart defect clusters within a family (so it occurs within a family more often than chance). In this study, they found that the recurrence risk ratio for congenital heart defects such as heterotaxia, atrioventricular septal defects, and right ventricular outflow tract obstruction (which includes pulmonary atresia and hypoplastic right heart syndrome) were quite high meaning that families that had one individual with such a congenital heart defect had a higher risk of producing another individual with the same congenital heart defect. However, overall, having a family history within first-degree relatives (that is your parents or older siblings had a congenital effect) was actually quite a low predictor of whether or not the child produced by the parents or the next child (with the older sibling having a congenital heart defect) would also exhibit a congenital heart defect. Only around 2% of patients with a congenital heart defect were attributed to a family history (parents or older sibling having a congenital heart defect). In other words, most families with one individual having a congenital heart defect did NOT produce another child having the same or different congenital heart defect (though sadly some did).

This study by Oyen et al. (2009) suggests two things. 1) There is some clustering within families of congenital heart defects, which could suggest either a shared genetic OR shared environmental cause. It doesn’t necessarily reflect that is inherited genetically as these types of statistical analyses cannot separate the effects of shared genes from a shared environment (e.g., Guo 2002, Am J Hum Genet. 79, 818–819), though as a side note this is likely possible using quantitative genetic analyses if a genetic pedigree was available. 2) The fact that a low proportion of the congenital heart defects (~2%) were attributed to a parent or older sibling also having a congenital heart defect again suggests the role of the early environment in causing congenital heart defects, which the authors discuss.

3) Does a single gene cause a congenital heart defect? There is a lot of hope that we can identify single genes that cause specific diseases (such as congenital heart defects) and somehow identify the presence of these specific genes in patients and mitigate the consequences. Although there has been much progress in this area, there are some major problems and actually few congenital heart defects have been associated with specific genes. Finding a single gene that causes a congenital heart defect relies on the expectation that a single gene has a large effect on some characteristic or trait. This isn’t necessarily true and more and more some have argued that this single gene approach has lost its luster. Most characteristics or traits of individuals are affected by many many different genes all with small effects on that specific characteristic. That makes it difficult to target a specific gene because a mutation in some gene might have a small effect on that characteristic and therefore can be difficult to detect by researchers. However, there are some gene mutations that appear to be highly associated with specific congenital heart defects. For example, a mutation of the gene PROSIT240 that causes changes in the expression of that specific gene in specific areas of the body (heart) may be associated with an increased risk of developing transposition of the great arteries (Muncke et al., 2003 Circulation 108, 2843-2850). Even in this example, however, the evidence implicating this gene being involved in the development of this congenital heart defect is quite weak. Of 97 patients with transposition of the great arteries, only 3 patients had a specific type of mutation in this gene PROSIT240, though admittedly this specific type of mutation wasn’t found in 400 patients without transposition of the great arteries. Clearly there is more work to do in this area but its impact on understanding the development of congenital heart defects remains to be seen.

4) Changes in the expression of genes that ‘build’ the heart early in life? A growing area of research in all scientific disciplines that may help address some of the genetic causes of congenital heart defects is developmental genetics. Developmental genetics focuses on understanding how genes or the interactions of genes and their products affect the growth and differentiation of cells and how these cells become tissues and organs. Basically, how do the cells that eventually become the heart tissue develop? A second area of growing research is how the early environment affects the expression of genes early in life. That is, we know that the production of proteins from specific genes during development that ‘builds’ tissues/organs like the heart, but we also know that the environment experienced early in life can alter the rate of production of those specific proteins during development. These could be broadly called gene (nature) by environment (nurture) interactions. However, there really is no longer a debate about whether a trait is caused by nature or nurture but it is more the interaction of the two (both genes and the environment). Amazingly, the four chambers of the human heart are formed around 32 days into pregnancy and much of the heart anatomy is formed <60 days into pregnancy (for a great animation of this see here). This means that there is ample opportunity for the early environment (that is the environment before most people know that they are actually pregnant) to affect heart development.

An interesting feature of a recent paper about this subject by Bruneau (2008, Nature 451) is describing recent developments in developmental genetics regarding heart formation. That is, our understanding of how the heart develops early in life, including the genes responsible for this development, has recently grown exponentially. The development of the heart involves the complex signaling of many genes early in life. One particularly fruitful area of research in the developmental genetics of congenital heart defects comes from understanding how the transcription rates of genes are involved in heart development. Transcription of a gene is the first step in the expression of a protein from a gene. The details are beyond this blog but if the transcription rate of the specific gene is increased, the amount of protein it produces generally also increases. The opposite is true when transcription of a gene is decreased. There are also genes that produce transcription factors, which can decrease or increase the expression of another gene. Currently, most of our understanding about the developmental genetics of congenital heart defects comes from identifying genes that produce transcription factors that cause structural changes in heart development. For example, the gene TBX5 is a transcription factor that appears to regulate the expression of specific genes involved in early heart development (Bruneau, 2008). Patients with Holt-Oram syndrome that also exhibit congenital heart defects (such as atrial or ventricular septal defects) have a mutation in the TBX5 gene that may alter the expression of genes in the heart during early development that actually causes the congenital heart defect. The important thing here is that these studies and others (reviewed in Bruneau 2008) identify that mutations in transcription factor genes that regulate the expression of other genes involved in early heart development may be important in identifying the causes of congenital heart defects. So it isn’t necessarily a mutation in a specific gene involved in the production of the tissue that forms the heart (discussed above in #3) but it could be a mutation in another gene that regulates the expression of many different genes involved in early heart development. What is even more interesting is that these mutations to transcription factor genes can be inherited but they can also be caused by the environment. I hope to expand on this area in a future blog post.

Conclusion: My conclusion from what I have discussed above is that chromosomal abnormalities are of course associated with congenital heart defects yet the use of more modern detection methods that detect more than just missing/absent chromosomes needs to be increased to fully recognize the importance of chromosomal abnormalities in causing congenital heart defects. Second, the recurrence of some specific types of congenital heart defects within families can be quite high but being a parent with a congenital heart defect or producing a child with a congenital heart defect doesn’t necessarily mean that the child or next child will have a congenital heart defect or the same defect. Third, identifying single genes that ’cause’ a congenital heart defect will be a challenge but identifying how the expression of specific genes that produce the heart early in life is an important future area of research. This is predominately because alterations in the expression of these specific genes can be caused by genetic factors that are inherited but also by environmental factors that disrupt gene expression early in life.

Links to these papers:






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