Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome.

Fiche publication

Date publication

septembre 2026

Journal

American journal of human genetics

Auteurs

Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence

Tous les auteurs :
Anderson KJ, Thorolfsdottir ET, Nodelman IM, Halldorsdottir ST, Benonisdottir S, Alghamdi MA, Almontashiri NAM, Barry BJ, Begemann M, Britton JF, Burke S, Cogne B, Cohen ASA, de Diego Boguñá C, Eichler EE, Engle EC, Fahrner JA, Faivre L, Fradin M, Fuhrmann N, Gao CW, Garg G, Grečmalová D, Grippa M, Harris JR, Hoekzema K, Hershkovitz T, Hubbard S, Janssens K, Jurgens JA, Kmoch S, Knopp C, Koptagel MA, Ladha FA, Lapunzina P, Lindau T, Meuwissen M, Minicucci A, Neuhaus E, Nizon M, Nosková L, Park K, Patel C, Pfundt R, Prasun P, Rahner N, Robin NH, Ronspies C, Roohi J, Rosenfeld J, Saenz M, Saunders C, Stark Z, Thiffault I, Thull S, Velasco D, Velmans C, Verseput J, Vitobello A, Wang T, Weiss K, Wentzensen IM, Pilarowski G, Eysteinsson T, Gillentine M, Stefánsson K, Helgason A, Bowman GD, Bjornsson HT

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/42692004

Résumé

Sex-specific penetrance in autosomal-dominant Mendelian conditions is largely understudied. The neurodevelopmental disorder Pilarowski-Bjornsson syndrome (PILBOS) was initially described in females. Here, we describe the clinical and genetic characteristics of the largest PILBOS cohort to date, showing that both sexes can exhibit PILBOS features, although males are overrepresented. A mouse model carrying a human-derived Chd1 missense variant (Chd1) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1 mice, while testosterone rescues the phenotype in females, implicating androgens in phenotype modulation. In the gnomAD and UK Biobank databases, rare missense variants in CHD1 are overrepresented in males, supporting a male-protective effect. We identify 33 additional highly constrained autosomal genes with missense variant overrepresentation in males. Our results support androgen-regulated sexual dimorphism in PILBOS and open avenues toward understanding the mechanistic basis of sexual dimorphism in other autosomal Mendelian disorders.