Líffræðifélag Íslands - biologia.is
Líffræðiráðstefnan 2025
Erindi/veggspjald / Talk/poster E95
Höfundar / Authors: Kimberley Jade Anderson(1,2), Eirný Tholl Thorolfdóttir(1), Hans Tómas Björnsson(1,2,3,4)
Starfsvettvangur / Affiliations: 1 Department of Genetics and Molecular Medicine, Landspítali University Hospital; Reykjavík, Iceland. 2 Louma G. Laboratory of Epigenetic Research, Faculty of Medicine, University of Iceland; Reykjavík, Iceland. 3 McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine; Baltimore, MD, USA. 4 Department of Pediatrics, Johns Hopkins University; Baltimore, MD, USA
Kynnir / Presenter: Kimberley Anderson
Pilarowski–Björnsson syndrome (PILBOS, OMIM 617682) is a neurodevelopmental disorder characterised by growth deficiency, hypotonia, and autism spectrum features, caused by variants in CHD1. We now present the largest cohort to date: both sexes carried pathogenic CHD1 variants, though males were overrepresented. Using a patient-derived missense variant in CHD1 (p.R618Q), we determined that recombinant CHD1-R618Q showed impaired nucleosome remodelling, indicating loss of function. To test mechanism and sex bias in vivo, we engineered mice harbouring the patient allele (Chd1R616Q/+). Heterozygous females displayed growth and motor deficits, increased anxiety, elevated hypothalamic oxytocin, and reduced neural progenitor proliferation. Manipulating androgens modulated the phenotype: prepubertal orchiectomy unmasked growth deficiency in mutant males, whereas testosterone rescued female growth and normalized embryonic cortical proliferation; dihydrotestosterone broadly corrected transcriptional dysregulation in mutant NPCs. At the population level (gnomAD, UK Biobank), rare CHD1 missense alleles were enriched in males, and we identified 33 additional highly constrained autosomal genes with male-biased frequencies. Together, our data support a model in which androgens buffer CHD1 insufficiency, linking chromatin remodelling to sex-biased penetrance. This may also open novel avenues to understand the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.