Document Type

Article

Publication Date

9-3-2026

Identifier

DOI: 10.1016/j.ajhg.2026.08.005

Abstract

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.

Journal Title

American journal of human genetics

Volume

113

Issue

9

First Page

1946

Last Page

1971

MeSH Keywords

Male; Humans; Female; Animals; Androgens; Mice; Sex Characteristics; Mutation, Missense; Phenotype; DNA-Binding Proteins; Disease Models, Animal; Testosterone; Orchiectomy

PubMed ID

42692004

Keywords

CHD1; Mendelian disease; neurodevelopmental disorder; sex differences

Comments

Grants and funding

This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed.

Publisher's Link: https://doi.org/10.1016/j.ajhg.2026.08.005

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