Kimberley Jade Anderson, Sara Þöll Halldórsdóttir and Hans Tómas Björnsson
Introduction: Pilarowski-Bjornsson Syndrome (PILBOS, OMIM: 617682) is a neurodevelopmental disorder first described by our group, characterised by growth retardation, hypotonia, autism and intellectual disability, caused by variants in the gene CHD1. Initially identified exclusively in females, PILBOS stands in stark contrast to the male overrepresentation seen in autism.
Methods: We used CRISPR-Cas9 to generate a mouse model harbouring a patient-specific PILBOS variant (Chd1R616Q/+). We assessed weight, behaviour and cellular proliferation in the brain, along with transcriptomic profiling. Using the gnomAD database, we analysed rare missense variants for sex differences in allele frequencies.
Results: Heterozygous mice displayed female-limited weight and motor deficits, and increased anxiety-like behaviour. Consistent with a protective role of androgens, orchiectomy of male mice at postnatal day 15 unveiled a weight deficit in mutants. Testosterone treatment of pregnant dams rescued proliferation defects in the embryonic brain. Treatment with dihydrotestosterone rescued transcriptional changes caused by Chd1R616Q/+, suggesting androgens may counteract CHD1 dysfunction by promoting an opposing transcriptional program. Using the gnomAD database, we identified significant enrichment of rare missense alleles in CHD1 within the male population compared to females, suggesting that males may be protected even at the population level. Finally, we extended our analysis to all highly constrained (pLI > 0.9) autosomal genes and identified a further 212 genes with male sex-bias, suggesting a broader phenomenon of genes with sexually dimorphic effects on human development.
Conclusions: These findings unveil a novel mechanism underlying sex-specificity in PILBOS and pave the way for future investigations into sex-specific contributions to disease.
