Androgens protect against the effects of a rare genetic disorder

Androgens – the male sex hormones – seem to reduce the effects of pathogenic variants that cause a rare neurodevelopmental disorder, potentially explaining why the condition manifests differently between the sexes. These are the findings of a new international study led by scientists in Iceland, which also sheds new light on sex-specific effects of genetic disorders.

This study focused on Pilarowski-Björnsson syndrome, a rare neurodevelopmental disorder with significant impact on speech and language development. The condition is caused by pathogenic variants in the gene CHD1, which plays an important role in regulating which genes are active in the body’s cells.

The findings were recently published in The American Journal of Human Genetics (AJHG). The condition was first described eight years ago by Hans Tómas Björnsson, professor of pediatrics at UI and senior consultant at the Landspítali Children’s Hospital, and Genay Pilarowski, his PhD student at Johns Hopkins University, together with their colleagues. The syndrome is named after both scientists.

This new study is the work of Hans Tómas and Kimberley Anderson, a former employee at Landspítali University Hospital and UI and currently a lecturer at the University of Akureyri, and Eirný Þöll Þórolfsdóttir, clinical genetic counsellor at Landspítali, together with a multinational team of researchers.

“Dominant genetic disorders are generally not believed to have strong sex-specific effects, but here we have described one such condition, Pilarowski-Björnsson syndrome, in which pathogenic variants in the CHD1 gene seem to have a greater impact on women than men. Our research on mice indicates that androgens could reduce the effects of these variants, and it could well be that other disorders behave in a similar way,” says Hans Tómas.

Almost 60 people from all over the world

When Pilarowski-Björnsson syndrome was first described, only a handful of people with the condition had been identified. This new study describes the symptoms of almost 60 people from all over the world.

The first indication of a significant difference between the sexes emerged in this group. Eirný Þöll Þórólfsdóttir, genetic counsellor at Landspítali University Hospital, collected data on a large group of people with the condition. It came to light that significantly more boys than girls carry severe variants in the CHD1 gene.

“This suggests that female embryos carrying such variants do not survive pregnancy. We see the same pattern in healthy individuals who have been sequenced in large genomic databases. There are more rare genetic variants in men than women, which suggests that males tolerate pathogenic variants better than females,” explains Hans Tómas.

This is an unexpected finding. According to this interpretation, the fact that more boys have the condition does not necessarily mean that they are more vulnerable to the variants. On the contrary, the explanation could be that they are better able to tolerate severe variants in the gene.

The sex difference surprised the researchers

At the same time, Kimberley Anderson studied the impact of a Chd1 variant in mice, which revealed that symptoms were more pronounced in females than males.

“She began phenotyping mice with the Chd1 variant and noticed that the phenotypes were more frequently observed in females than males. Together, these findings led to the hypothesis that androgens may have a protective effect,” says Hans Tómas.

The sex difference surprised the researchers and highlights the importance of including both sexes in animal research. “A lot of studies on mice only look at one sex, often males, so a lot of researchers might have missed this difference. But we felt that the sex difference was probably genuine, since we observed it in the cohort collected by Eirný Þöll, in Kimberly’s mice and in healthy individuals in databases such as UK Biobank and gnomAD,” says Hans Tómas.

UK Biobank and gnomAD are large international databases containing genetic and health data from hundreds of thousands of people, which are used, for example, to study how common different genetic variants are.

Androgens appear to provide protection

Interestingly, the research suggests that androgens could partially counteract the effects of CHD1 variants, helping the cells to function normally.
“We believe that CHD1 and the androgen receptor may, to some extent, activate the same genomic regions. When a pathogenic variant is present in the CHD1 gene, it is probably more difficult to open and activate these genomic regions. Androgens could help the cell tolerate variants in this gene,” says Hans Tómas.

The androgen receptor is a protein in cells that receives signals from androgens, such as testosterone, and can thereby influence the activity of genes. To put it simply, it appears that when a CHD1 variant disrupts CHD1 function and makes it more difficult to activate a gene, androgens can help the cell overcome the difficulty and activate those genes.

Could tell us more about genetic disorders in general

The findings could have relevance far beyond Pilarowski-Björnsson syndrome. Many other dominant genetic disorders also show sex-specific differences, and it is possible that similar explanations may apply.

“I think there are a few lessons to be learned. Firstly, dominant disorders that are not linked to sex chromosomes can still have significant sex-specific effects. Secondly, there are many other dominant disorders that have equally or even more pronounced sex differences than Pilarowski-Björnsson syndrome. Thirdly, here we have an explanation for this sex difference, which probably also applies to some other dominant disorders,” says Hans Tómas.

One of the study’s most interesting conclusions is that researchers need to reconsider how sex differences in the frequency of genetic disorders are interpreted.

“I think that many geneticists have often thought that if a disorder is more common in one sex, it’s because that sex is more vulnerable to it, but here we demonstrate that the opposite may be true. More boys with this disorder means that they tolerate the variant better. This could be one of the reasons that neurodevelopmental disorders such as autism are much more common in boys than girls,” says Hans Tómas.

Potential treatment

The study also raises the question of whether it might be possible to harness the protective effects of androgens for therapeutic purposes. Further research is required, however, before it will be possible to answer that.

Eirný Þöll is currently working on a study monitoring individuals with the condition, which includes collecting data on testosterone levels. Particular focus will be on what happens when the individuals go through puberty.

“This study opens up new treatment possibilities for this group, since testosterone in low doses has relatively few side effects, at least in boys. But before we research those possibilities, we want to see what occurs naturally at puberty, whether symptoms improve with higher levels of testosterone. It would also be interesting to try to define which other disorders could potentially be treated in the same way,” says Hans Tómas.

For Hans Tómas, this study is a continuation of the work that began when Pilarowski-Björnsson syndrome was first described eight years ago.
“It is particularly satisfying to go from helping people on their diagnostic journey by describing a new condition to starting to understand the fundamental causes of the disorder and trying to identify potential treatments,” he says.