| Title: | Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency |
| Journal: | Nature Medicine |
| Published: | 22 Jun 2023 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/37349538/ |
| DOI: | https://doi.org/10.1038/s41591-023-02405-5 |
| Citations: | 13 (13 in last 2 years) as of 8 Aug 2024 |
Publication 11585
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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.</p>
7 Keywords
- Adult
- Basic Helix-Loop-Helix Transcription Factors
- Female
- Humans
- Menopause, Premature
- Penetrance
- Primary Ovarian Insufficiency
19 Authors
- Saleh Shekari
- Stasa Stankovic
- Eugene J. Gardner
- Gareth Hawkes
- Katherine A. Kentistou
- Robin N. Beaumont
- Alexander Mörseburg
- Andrew R. Wood
- Julia K. Prague
- Gita D. Mishra
- Felix R. Day
- Julia Baptista
- Caroline F. Wright
- Michael N. Weedon
- Eva R. Hoffmann
- Katherine S. Ruth
- Ken K. Ong
- John R. B. Perry
- Anna Murray
3 Applications
| Application ID | Title |
|---|---|
| 871 | Genetic factors associated with being at different extremes of the reproductive lifespan |
| 9072 | The Genetics of anthropometric traits ? Height, weight, BMI and waist circumference |
| 9905 | Using genetics to elucidate the relationship between socioeconomic/behavioural traits and disease |
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