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Penetrance of pathogenic genetic variants associated with premature ovarian insufficiency.
Shekari, Saleh; Stankovic, Stasa; Gardner, Eugene J; Hawkes, Gareth; Kentistou, Katherine A; Beaumont, Robin N; Mörseburg, Alexander; Wood, Andrew R; Prague, Julia K; Mishra, Gita D; Day, Felix R; Baptista, Julia; Wright, Caroline F; Weedon, Michael N; Hoffmann, Eva R; Ruth, Katherine S; Ong, Ken K; Perry, John R B; Murray, Anna.
Afiliación
  • Shekari S; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
  • Stankovic S; School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
  • Gardner EJ; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Hawkes G; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Kentistou KA; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
  • Beaumont RN; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Mörseburg A; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
  • Wood AR; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Prague JK; Metabolic Research Laboratory, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Mishra GD; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
  • Day FR; Exeter Centre of Excellence for Diabetes Research, University of Exeter, Exeter, UK.
  • Baptista J; Macleod Diabetes and Endocrinology Centre, Royal Devon and Exeter National Health Service Foundation Trust, Exeter, UK.
  • Wright CF; School of Public Health, Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia.
  • Weedon MN; MRC Epidemiology Unit, Wellcome-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Hoffmann ER; Peninsula Medical School, University of Plymouth, Plymouth, UK.
  • Ruth KS; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
  • Ong KK; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
  • Perry JRB; Department of Cellular and Molecular Medicine, DNRF Center for Chromosome Stability, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • Murray A; Department of Clinical and Biomedical Sciences, University of Exeter, Exeter, UK.
Nat Med ; 29(7): 1692-1699, 2023 07.
Article en En | MEDLINE | ID: mdl-37349538
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Menopausia Prematura / Insuficiencia Ovárica Primaria Tipo de estudio: Risk_factors_studies Límite: Adult / Female / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Menopausia Prematura / Insuficiencia Ovárica Primaria Tipo de estudio: Risk_factors_studies Límite: Adult / Female / Humans Idioma: En Revista: Nat Med Asunto de la revista: BIOLOGIA MOLECULAR / MEDICINA Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos