Abstract
Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10-6) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10-4). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.
DOI
10.1038/s41591-023-02405-5
Publication Date
2023-06-22
Publication Title
Nature Medicine
Volume
29
Publisher
Nature Research
ISSN
1546-170X
Embargo Period
2024-11-19
First Page
1692
Last Page
1699
Recommended Citation
Pereira Baptista, J. (2023) 'Evaluating the penetrance of pathogenic genetic variants associated with Premature Ovarian Insufficiency', Nature Medicine, 29, pp. 1692-1699. Nature Research: Available at: https://doi.org/10.1038/s41591-023-02405-5
