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:






Environmental causes of congenital heart defects?

Congenital heart defects are the most common type of birth defect (at least in the United States). Around 1% of all babies that born in each year have some type of a heart defect, though that percentage halves (0.6%) if you only consider moderate to severe heart defects like tricuspid atresia or hypoplastic left heart syndrome (Hoffman and Kaplan 2002 J American College of Cardiology 39, 1890-1900; Reller et al., 2008 J of Pediatrics 153, 807-813).

As you can see, many parents or friends/relatives of patients with heart defects are left wondering why this happened to them if it is so rare. Sadly, some more recent studies have noticed an upward trend in the incidence of heart defects. For example, from 1968-1997 the incidence of moderate-severe congenital heart defects was 6.2/1000 births (0.62%) but from 1995-1997, the incidence was 9/1000 births (0.9%: Botto et al., Pediatrics 107). Some of this increase is obviously because our ability to detect minor or major congenital heart defects has increased over this period of time. But other features about our environment have changed and they are an easy target to blame the incidence or rise in the incidence of congenital heart defects.

In a new paper by Liu et al. (2013, Environmental Health 12) titled “Association between maternal exposure to housing renovation and offspring with congenital heart disease: a multi-hospital case-control study”, the authors report the correlation/association between being exposed to housing renovation during pregnancy and the incidence of congenital heart defects in the resulting children. We tend to worry more about the level of pollution outside our home than inside our home, yet we spend most of our days inside. Also, during a home renovation or after moving into a new house, occupants can be exposed to a variety of synthetic substances that are released from the materials used in the housing renovation or construction of the new home (e.g., volatile organic compounds, formaldehyde, heavy metals). This form of “indoor pollution” can arise from new paint on the walls, new caulk, new carpet or plastic flooring  (volatile organic compounds) or from cabinets or other furniture made from pressed wood (formaldehyde). Basically, bad stuff that people should avoid but especially pregnant women.

A few recent studies have looked at how such exposure to these renovation materials may increase in the incidence of congenital heart defects in children. A recent study concluded that exposure to new paint (volatile organic compounds) may be associated with the formation of congenital heart defects (Hjortebjerg et al., 2012, Environmental Health 11, 54). In the present study by Liu et al., the authors identified patients in four hospitals in China and screened their babies for fetal defects with ultrasound. They identified a group carrying babies with congenital heart defects and a control group from the same hospital during the same study period. They then gave both groups a questionnaire about their perceived non-occupational exposure to organic solvents or other such compounds. They excluded individuals who stated that they thought they had high occupational exposure to these toxins or if they had chromosomal abnormalities. Finally, they had a face-to-face interview with these pregnant women and asked about their exposure to housing renovations during three time periods: 7-12 months before pregnancy, 4-6 months before pregnancy, 0-3 months before pregnancy, or during the first trimester. Their criteria for housing renovation was that it involved installing at least one or more of the following list: marble surfaces, laminated board, plywood, carpets, ceramic tiles, paints, or wallpapers.

What did this study show about environmental causes of congenital heart defects?

1) Women with a fetus with a congenital heart defect were more likely to have been exposed to a housing renovation. Around 30% of the women that were pregnant with a fetus with a congenital heart defect had been exposed to a housing renovation project compared to 19% of the women without a fetus with a congenital heart defect. Not huge effect sizes but a statistical difference.

2) Mothers that smoke were more likely to be carrying a baby with a congenital heart defect (CHD). Around 46% of women carrying a fetus with a CHD smoked or were exposed to smoke compared to 30% of women carrying a fetus without a CHD.

3) Mothers living near a factory or landfill were more likely to be carrying a baby with a congenital heart defect. Around 30% of women carrying a fetus with a CHD lived near a factor/landfill whereas about 18% of women carrying a fetus without a CHD did so.

4) The overall risk of fetus developing a congenital heart defect was increased with exposure to indoor housing renovations. The odds of a fetus developing a CHD were on average 1.89 times higher if they were exposed to indoor housing renovations prior to or soon into pregnancy compared to mothers not exposed to such indoor pollution. These results are similar to a previous study in Denmark where being exposed to paint fumes during the first trimester was associated with an increased (though very slight) risk of producing a fetus with a congenital heart defect (Hjortebjerg et al., 2012 Environmental Health 11, 54-61).

5) The timing of exposure to housing renovations was important in affecting the risk of a fetus developing a congenital heart defect. Mothers exposed to a housing renovation that occurred within i) 3 months before pregnancy or ii) during the first trimester had an increased risk of producing a fetus with a CHD but only if they had moved into a house that had had a renovation within 1 month previous. Given that much of the heart development happens during the first trimester (e.g., both of the ventricles and atria are formed by 32 days after conception: Bruneau, 2008 Nature 451, 943-948), it is not necessarily surprising that being exposed to such indoor pollution in the first trimester was associated with an increased incidence of CHD. However, it is surprising that women that were exposed to indoor pollution (renovation) 3 months before pregnancy had a higher incidence of producing a fetus with a CHD. The second interesting point was that mothers (either 3 months prior to conception or 1st trimester) that moved in to a house that had been renovated within the previous month had a higher incidence of producing a fetus with a CHD. The authors discuss how this is also not surprising given that the amount of volatile organic compounds and other substances declines as the amount of time since renovation increases.

Conclusion: First, this is of course a correlational study and can only suggest associations between environmental variables and the incidence of congenital heart defects. However, recent studies suggest that ~12% of patients with a congenital heart defect have a chromosomal abnormality (e.g., Hartman et al., 2011 Pediatric Cardiology 32, 1147-1157), so there may also be a genetic basis to the development of some CHDs. However, it is important to emphasize that 1) such genetic studies are also associations and 2) this doesn’t necessarily mean that ~88% of patients with a CHD have an environmental (rather than genetic) basis. Most genes have small effects on the characteristics of an individual such that there could be many genes of small effect that interact to increase the incidence of CHD. However, this study by Liu et al. and others (Hjortebjerg et al., 2012 Environmental Health 11, 54-61) clearly provide quantitative support for common sense. That is, don’t paint your house while you are pregnant and consider the consequences of indoor pollution. This study supports the idea that effective campaigns for preventing CHD’s should involve promoting awareness of the negative consequences of indoor pollution produced by housing renovations.

Link to this paper: