Genetics and stem cells

The genetics of heart defects

“Treatments for heart defects could be improved” by the identification of the gene behind the condition, says The Daily Telegraph. The newspaper also says that the discovery makes screening for the gene a possibility.

The news comes from a genetic study which looked at the frequency of certain gene variants in several thousand children born with complex heart defects, such as holes in the heart or misalignment of the vessels leaving the heart. It found that the risk of defects was linked to certain variants in a gene called ISL1, which plays a role in heart development. However, there are likely to be other genetic variations that contribute to an individual’s risk of heart defects, which means that the current findings alone may not be helpful in screening for individuals at risk of these conditions.

Unlike some newspapers, the research paper authors are cautious in their conclusions: they say their finding adds to understanding of the condition rather than leading directly to new treatments or screening programmes.

Where did the story come from?

The study was mainly carried out by researchers, including cardiologists and geneticists, from the University of Michigan and the Children's Hospital of Philadelphia in the US, along with other international collaborators. It was funded by the Fondacion Leducq international research foundation. The study was published in the peer-reviewed open access journal PLoS ONE.

The Daily Telegraph reported that this new research shows that congenital heart defects “all have a common root in the gene ISL1 which is key to early heart development”. If this were the case, it could potentially lead to new treatments or screening. However, this is a misrepresentation of the results of this study, which have not shown that this is the only gene involved.

What kind of research was this?

The researchers set about testing the genetic code within and around the ISL1 gene, based on existing knowledge that this gene on chromosome 5 is involved in heart development. They explain that they were testing a theory that common variants within this gene could be involved in increasing susceptibility to congenital heart disease.

The ‘common variant-common disease’ theory suggests that many common variations within multiple genes may contribute to an individual’s risk of a common disease, with each genetic variation contributing a small amount of the risk for the disease. This is different to cases where a disease is caused by just a single genetic mutation.

The researchers collected DNA samples from 1,344 children with congenital heart disease and 6,135 healthy children. They analysed the single-letter variants of the genetic code, which are known to exist in and around the ISL1 gene. They also analysed how combinations of these variants related to risk.

What did the research involve?

During the first phase of the study, the researchers recruited US cases and controls from the Children's Hospital of Philadelphia from 2003 to 2008. Out of all the eligible children with heart defects seen during this time, 31.6% (613/1939) agreed to take part in this study.

The second phase of the study was a ‘validation stage’ to check whether the associations from phase one were also present in another population of cases. The cases for this validation stage were all children recruited from Toronto and the Netherlands who had complex congenital heart disease that required surgical repair. Both these sets of children had conditions that included abnormal developments where the coronary artery came from an unusual place, holes in the heart (atrial septal defects, atrioventricular septal defect/AV canal), and various types of misalignments of the arteries from the heart (transposition of the great arteries, double outlet right ventricle, and valve defects).

The researchers used standard techniques to look at 30 single-letter variants of genetic code (single nucleotide polymorphisms, or SNPs) within and around the ISL1 gene, which plays a key role in regulating early cardiac development. They compared the proportions of affected children (cases) and unaffected children (controls) who had each variant or a combination of variants.

The researchers analysed data from the white children and black/African-American children separately. This was because combining results from individuals of different ethnicities can affect results when analysing genetic patterns. The researchers also performed additional analyses to determine the accuracy of their method of defining ethnicity, and to classify those recruits who had unknown ancestry. They did this by analysing ancestral informative markers (AIMs) – genetic variations that can indicate ethnic ancestry – on chromosome 5 for which genotype information was available. They then classified those of unknown ancestry using these gene profiles. Subjects with greater than 65% European ancestry were considered to be white, and subjects with less than 65% European ancestry were considered to be black/African-American.

What were the basic results?

In the first phase of the study, eight of the 30 variants assessed were associated with risk of congenital heart disease.

One site for possible variants within the ISL1 gene is called rs1017. At these variant points the code of each person’s DNA may potentially feature any one of the four nucleotide chemicals found in DNA, respectively referred to by the letters A, C, G or T. Children carrying at least one 'T' variant at this point in the code had a more than two-fold increase in risk of having a genetic heart defect compared with children who had two 'A' variants (odds ratio [OR] 2.28, 95% confidence interval [CI] 1.35 to 3.87).

The researchers then looked at combinations of single nucleotide polymorphisms, known as haplotypes. They found that looking at haplotypes within ISL1 most effectively captured risk of a genetic heart defect. For white individuals, the combinations A-C-T and A-T-T were strongly associated with genetic heart defect risk. Compared to a child with the A-C-A haplotype, the risk of a genetic heart defect was doubled with each copy of the A-C-T haplotype that a child possessed (OR 2.01, 95%CI 1.35 to3.00). The risk was more than three times greater with each copy of the A-T-T haplotype (OR 3.29, 95% CI 1.51 to 7.16).

In the validation stage, the strength of this link was slightly less, although it was still present. There were also clear differences between white and African-American children concerning which combinations of variants conferred an increase in risk. This suggests that the ISL1 gene may be involved in heart defects in both ethnic groups, but that the variants involved may differ.

How did the researchers interpret the results?

The researchers say the results demonstrate that “two different ISL1 haplotypes contribute to risk of CHD in white and black/African-American populations”.

They claim that this is strong evidence that congenital heart disease is consistent with the ‘common variant–common disease hypothesis’ in two ethnically distinct populations. Therefore their study supports the idea that in these types of congenital heart defects, common variations in multiple genes are likely to be contributing to risk, and that variants in ISL1 appear to be one of these contributing genes.


This study has furthered the research understanding of molecular events in the development of heart defects, and it can focus further research efforts on the function of this gene. There are several strong points to this study, including the replication of findings in a separate set of cases and controls, and the separate analysis of different ethnic groups. It is still possible that some of the differences found could be due to the ethnic mix of those with heart defects compared to those without, although the separate analyses performed do reduce this risk. It is also possible that the selection of patients (cases) for the study may have led to bias in the results.

As the ISL1 gene is known to be involved with heart development, the finding of a moderate link with all types of heart defect adds weight to the argument that this gene is an important candidate for further investigation. The strength of the link between three-letter variants (haplotypes) and the defects was found to be different when the researchers looked at the white Americans compared with black/African-Americans. This intriguing finding suggests that more research and larger international genome-wide studies are needed to make sure that this is the only gene involved.

For these reasons, larger studies across broader international populations will be needed to confirm the role of this gene in the development of heart defects. Research in this area is not yet advanced enough to suggest that treatments or screening based on the genetic discovery are close.

NHS Attribution