Genetic clue to penis birth defect

The BBC reports that “scientists have identified a gene which may play a role in a common defect affecting the genitalia of baby boys”. The condition in question is called hypospadias, where the open end of the urethral tube is not in its normal position at the tip of the penis, but is instead positioned somewhere along the underside of the penis or scrotum.

This research identified variations in a gene called DGKK, which are associated with an increased risk of one form of hypospadias. It also demonstrated that a gene that was suspected of being involved was active in the tissue of the penis, and that the gene was less active in males carrying one of the variants. One of the strengths of this study is that it confirmed its findings in more than one sample.

As the authors of this research say, there are probably many different risk factors for hypospadias, and these may include both genetic and environmental factors. Further research will be needed to confirm and investigate the role of the DGKK gene in this condition, and to identify other risk factors.

Where did the story come from?

The study was carried out by researchers from Radboud University Nijmegen Medical Centre and other research institutions in the Netherlands, Sweden, USA and the UK. It was funded by the Radboud University Nijmegen Medical Centre and the Urology Foundation 1973 in the Netherlands. The study was published in the peer-reviewed scientific journal Nature Genetics.

BBC News covers this study well.

What kind of research was this?

Hypospadias is a birth defect that affects the penis. In hypospadias the open end of the urethral tube is not at the tip of the penis as it would normally be, and instead is somewhere along the underside of the penis or scrotum. It is reported to affect about one in 750 births in Europe, and the condition is usually treated by surgery in early childhood.

The causes of hypospadias are not clear, but boys with a male relative with the condition are at increased risk, so genetic factors are thought to play a role. This “familial clustering” is found in hypospadias where the urethral opening is positioned somewhere between the middle and front end of the penis (called anterior or middle hypospadias), but not in those where the opening is further up towards the base of the penis or scrotum. Because of this genetic connection, the researchers decided to look at anterior or middle hypospadias only.

The current study was a genome-wide association study looking for common genetic variants that might be associated with an increased risk of anterior or middle hypospadias. This is an appropriate study design for addressing this question.

What did the research involve?

The researchers compared the DNA of 436 males with anterior or middle hypospadias (cases) and 494 unaffected males (controls). All of the males were of European descent to avoid ethnic differences affecting the results. The researchers looked at just over 900,000 single letter variations across the DNA, to identify variants that were more or less common in the cases than controls.

The 10 variants that had the strongest association with hypospadias and that were near genes were then assessed separately to verify the association. This second assessment was in 133 Dutch males with hypospadias and their parents, and 266 Swedish males with hypospadias and 402 controls.

The researchers then examined the genetic variants that showed the strongest link with the risk of hypospadias in all three samples, and assessed how much of the risk in the population could be attributed to these variants. They also identified the genes that contained these variants or lay near to these variants and tested whether the genes were active in samples from the foreskins of 14 males with hypospadias and 10 males without the condition. The activity of the genes was compared between males with and without the condition, and also between males with and without the risk variants, to see whether these variants were associated with different levels of activity of the genes.

What were the basic results?

The researchers identified two variants in a gene called DGKK that were associated with an increased risk of hypospadias in all of the samples tested. The DGKK gene lies on the X chromosome, and plays a role in signalling within the cells. In the first sample of European males and in the Swedish sample, cases were about twice as likely to carry the variants as controls. In the Dutch sample, cases were almost four times as likely to carry the variants as controls. The researchers calculated that the identified variants could account for about 30% of the risk of hypospadias in the Dutch and Swedish populations.

The researchers found that the DGKK gene was similarly active in the foreskin tissue in cases and controls. The DGKK gene was less active in the foreskin tissue in males carrying one of the variants associated with hypospadias risk, called rs1934179.

How did the researchers interpret the results?

The researchers conclude that they have identified a new area of DNA associated with the risk of anterior or middle hypospadias. They suggest that the DGKK gene might be responsible for this increase in risk, and that it could also be important in other similar conditions.

Conclusion

This study has identified genetic variants associated with an increased risk of the penile birth defect hypospadias. It also demonstrated that a gene that was suspected of being involved was active in the tissue of the penis, and that the gene’s activity was lower in males with one of the variants. One of the strengths of this study is that it confirmed its findings in more than one sample. Ideally, these findings will also be confirmed by other research in more hypospadias samples.

It is important to note that the variants identified in this study are common variants. They only increase the risk of hypospadias, rather than guaranteeing that it will occur.

As the authors of the research report, there are probably many different risk factors for hypospadias, and these may include both genetic and environmental factors. Further research will be needed to confirm and investigate the role of the DGKK gene in this condition, and to identify other risk factors.