Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome

The effect of sex on the penetrance of autosomal dominant Mendelian conditions is an understudied area of research. Variants in CHD1 have previously been identified in females with Pilarowski-Bjornsson syndrome (PILBOS), a recently described cause of developmental delay. We now demonstrate that both sexes can show signs of PILBOS, although males are more likely to display PILBOS phenotypes when carrying more severe variants. A novel mouse model carrying a human-derived missense variant in the Chd1 gene (Chd1R616Q/+) shows female-restricted disease phenotypes including growth retardation, anxiety and hypotonia. Orchiectomy of male mice unmasks a growth retardation phenotype in Chd1R616Q/+ mutants compared to orchiectomized wild type (WT) littermates. Conversely, testosterone supplementation in female Chd1R616Q/+ mice and WT littermates rescues the growth phenotype, suggesting that androgens dictate PILBOS disease penetrance. On the human population level, we demonstrate a significant overrepresentation of healthy males carrying rare missense variants in CHD1 in the gnomAD database, further supporting a male protective effect against CHD1 variants. We further identify 212 other genes that show similar missense variant overrepresentation in males. Together our data suggests androgen-regulated sexual dimorphism in Pilarowski-Bjornsson syndrome and opens up novel avenues to understand the mechanistic basis of sexual dimorphism of autosomal Mendelian disorders. Overall design: In order to examine the functional impact of the CHD1 R616Q variant, we performed bulk RNA-sequencing (RNAseq) using E18.5 NPCs derived from mouse embryos of both mutant and wild-type genotypes. Futhermore, we treated the cells with DMSO vehicle control or dihydrotestosterone (DHT) in order to assess the impact of androgens on the gene expression of these cells.