Do hormones affect genetic disorders?

Kimberley Jade Anderson, Assistant Professor at the Faculty of Resource Sciences at the University of Akureyri, is the first author of a new study published today in the prestigious journal The American Journal of Human Genetics. The research provides important new insights into Pilarowski-Björnsson syndrome (PILBOS), a rare neurodevelopmental disorder caused by pathogenic variants in the CHD1 gene.

The study is the result of a large international collaboration involving clinical and genetic data from more than 50 individuals with the syndrome from around the world. Its findings suggest that sex hormones may play an important role in shaping how genetic disorders develop and how severely they affect individuals.

Boys are diagnosed more often, while girls show more severe symptoms

Pilarowski-Björnsson syndrome affects neurological development and may lead to speech and language delays, intellectual disability, and autism-related features. When the condition was first described, all known cases were female.

The new study demonstrates that both males and females can develop the syndrome. However, researchers found that males were diagnosed more frequently, while affected females tended to exhibit more severe symptoms. This unexpected pattern raised the possibility that biological sex may influence how the disorder manifests.

Mouse model points to a protective role for testosterone

To investigate the underlying mechanisms, the research team developed a mouse model carrying the same disease-causing genetic variant found an affected individual.

Female mice displayed clear symptoms, including reduced growth, low muscle tone, and anxiety-like behaviours. In contrast, male mice showed far fewer effects.

When the influence of male sex hormones was removed, growth deficiencies became apparent in male mice. Conversely, testosterone treatment improved growth outcomes in female mice. Additionally, testosterone protected against growth deficits in developing brain cells. These findings suggest that androgens, including testosterone, may help protect against some of the effects of harmful CHD1 variants.

Similar patterns found in major genetic databases

The team also analysed data from two of the world's largest genetic databases, UK Biobank and gnomAD. Rare CHD1 variants were found more frequently in males than females, providing further evidence of a possible protective effect in males.

Importantly, researchers identified similar sex-related patterns in a number of other genetic disorders. This suggests that the mechanisms uncovered in the study may extend beyond Pilarowski-Björnsson syndrome and may be relevant to a broader range of neurodevelopmental conditions.

Opening new avenues for research

According to Kimberley Jade Anderson, the findings raise important questions about the role of sex hormones in genetic disease and neurodevelopment.

“This study provides a new perspective on how biological sex can influence inherited disorders. It opens exciting opportunities to explore whether protective effects of sex hormones may also help explain sex differences observed in other neurodevelopmental conditions,” says Anderson.

The publication has already attracted considerable attention within the scientific community. Alongside the article, The American Journal of Human Genetics has also published an interview with Anderson discussing the study and its broader implications.

Click here to access the arcticle.