Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency.

Autor: Shekari S; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.; School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia., Stankovic S; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Gardner EJ; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Hawkes G; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK., Kentistou KA; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Beaumont RN; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK., Mörseburg A; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.; Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Wood AR; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK., Prague JK; Exeter Centre of Excellence for Diabetes Research, University of Exeter, Exeter, UK.; Macleod Diabetes and Endocrinology Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK., Mishra GD; School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia., Day FR; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK., Baptista J; Peninsula Medical School, University of Plymouth, Plymouth, UK., Wright CF; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK., Weedon MN; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK., Hoffmann ER; Department of Cellular and Molecular Medicine, DNRF Center for Chromosome Stability, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Ruth KS; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK., Ong KK; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK., Perry JRB; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. john.perry@mrc-epid.cam.ac.uk.; Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK. john.perry@mrc-epid.cam.ac.uk., Murray A; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK. A.Murray@exeter.ac.uk.
Jazyk: angličtina
Zdroj: Nature medicine [Nat Med] 2023 Jul; Vol. 29 (7), pp. 1692-1699. Date of Electronic Publication: 2023 Jun 22.
DOI: 10.1038/s41591-023-02405-5
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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