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DOI 10.1016/j.ajhg.2026.08.005

Медицинская библиотека · American journal of human genetics · 2026

Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome.

Anderson Kimberley Jade, Thorolfsdottir Eirny Tholl, Nodelman Ilana M, Halldorsdottir Sara Tholl, Benonisdottir Stefania, Alghamdi Malak A, Almontashiri Naif A M, Barry Brenda J, Begemann Matthias, Britton Jacquelyn F, Burke Sarah, Cogne Benjamin, Cohen Ana S A, de Diego Boguñá Carles, Eichler Evan E, Engle Elizabeth C, Fahrner Jill A, Faivre Laurence, Fradin Mélanie, Fuhrmann Nico, Gao Christine W, Garg Gunjan, Grečmalová Dagmar, Grippa Mina, Harris Jacqueline R, Hoekzema Kendra, Hershkovitz Tova, Hubbard Sydney, Janssens Katrien, Jurgens Julie A, Kmoch Stanislav, Knopp Cordula, Koptagel Meral Aktas, Ladha Farah A, Lapunzina Pablo, Lindau Tobias, Meuwissen Marije, Minicucci Andreina, Neuhaus Emily, Nizon Mathilde, Nosková Lenka, Park Kristen, Patel Chirag, Pfundt Rolph, Prasun Pankaj, Rahner Nils, Robin Nathaniel H, Ronspies Carey, Roohi Jasmin, Rosenfeld Jill, Saenz Margarita, Saunders Carol, Stark Zornitza, Thiffault Isabelle, Thull Sarah, Velasco Danita, Velmans Clara, Verseput Jolijn, Vitobello Antonio, Wang Tianyun, Weiss Karin, Wentzensen Ingrid M, Pilarowski Genay, Eysteinsson Thor, Gillentine Madelyn, Stefánsson Kári, Helgason Agnar, Bowman Gregory D, Bjornsson Hans Tomas

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Аннотация

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 (Chd1R616Q/+) displays female-restricted phenotypes, including growth deficiency, anxiety, and hypotonia. Orchiectomy unmasks a growth-deficiency phenotype in male Chd1R616Q/+ 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.

Для цитирования: Anderson Kimberley Jade, Thorolfsdottir Eirny Tholl, Nodelman Ilana M, Halldorsdottir Sara Tholl, Benonisdottir Stefania, Alghamdi Malak A, Almontashiri Naif A M, Barry Brenda J, Begemann Matthias, Britton Jacquelyn F, Burke Sarah, Cogne Benjamin, Cohen Ana S A, de Diego Boguñá Carles, Eichler Evan E, Engle Elizabeth C, Fahrner Jill A, Faivre Laurence, Fradin Mélanie, Fuhrmann Nico, Gao Christine W, Garg Gunjan, Grečmalová Dagmar, Grippa Mina, Harris Jacqueline R, Hoekzema Kendra, Hershkovitz Tova, Hubbard Sydney, Janssens Katrien, Jurgens Julie A, Kmoch Stanislav, Knopp Cordula, Koptagel Meral Aktas, Ladha Farah A, Lapunzina Pablo, Lindau Tobias, Meuwissen Marije, Minicucci Andreina, Neuhaus Emily, Nizon Mathilde, Nosková Lenka, Park Kristen, Patel Chirag, Pfundt Rolph, Prasun Pankaj, Rahner Nils, Robin Nathaniel H, Ronspies Carey, Roohi Jasmin, Rosenfeld Jill, Saenz Margarita, Saunders Carol, Stark Zornitza, Thiffault Isabelle, Thull Sarah, Velasco Danita, Velmans Clara, Verseput Jolijn, Vitobello Antonio, Wang Tianyun, Weiss Karin, Wentzensen Ingrid M, Pilarowski Genay, Eysteinsson Thor, Gillentine Madelyn, Stefánsson Kári, Helgason Agnar, Bowman Gregory D, Bjornsson Hans Tomas. Androgens mediate sexual dimorphism in Pilarowski-Bjornsson syndrome.. American journal of human genetics. 2026. DOI: 10.1016/j.ajhg.2026.08.005.

Предметные рубрики MeSH

MaleHumansFemaleAnimalsAndrogensMiceSex CharacteristicsMutation, MissensePhenotypeDNA-Binding ProteinsDisease Models, AnimalTestosteroneOrchiectomy
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