Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome

CHD1

Androgen-driven modulation of the penetrance of CHD1 missense variants, with a male-protective effect

The authors describe the largest Pilarowski-Bjornsson syndrome cohort to date and show that both sexes can display features of the condition, with males over-represented, although the entity was initially described in females. A mouse model carrying a human-derived missense variant, heterozygous Chd1 R616Q, shows female-restricted phenotypes including growth deficiency, anxiety and hypotonia. Orchiectomy unmasks the growth-deficiency phenotype in mutant males, while testosterone rescues it in females, directly implicating androgens. In gnomAD and UK Biobank, rare CHD1 missense variants are over-represented in males, supporting a male-protective effect. The authors identify 33 further highly constrained autosomal genes with the same male over-representation of missense variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

Sex-dependent penetrance demonstrated experimentally by castration and testosterone supplementation goes beyond mere association, and that is rare. The practical consequence in genetic counselling is immediate: a CHD1 missense variant inherited from an unaffected father can no longer be dismissed on that argument alone. The list of 33 constrained genes with male over-representation is worth keeping at hand, as it suggests this bias is far more general than pedigrees reveal.

Analysis by Dr Thibaut Benquey