1. STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia
- Author
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Anne-Sophie Neyroud, Kenneth McElreavy, Sylvie Jaillard, Joelle Bignon-Topalovic, Marion Beaumont, Andrew H. Sinclair, François Vialard, Célia Ravel, Farah Ghieh, Katrina M. Bell, Anu Bashamboo, Bénédicte Nouyou, Jocelyn van den Bergen, Sylvie Odent, Katie L. Ayers, Marc-Antoine Belaud-Rotureau, Elena J. Tucker, Gorjana Robevska, Linda Akloul, Erika Launay, Elisabeth Veron-Gastard, Rajini Sreenivasan, Jonchère, Laurent, Laboratoires d'excellence - Stem Cells in Regenerative Biology and Medicine - - REVIVE2010 - ANR-10-LABX-0073 - LABX - VALID, Etude des mécanismes du développement des gonades chez l'homme - - MGonDev2017 - ANR-17-CE14-0038 - AAPG2017 - VALID, Murdoch Children's Research Institute (MCRI), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Génétique du Développement humain - Human developmental genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris-Saclay, Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), CHI Poissy-Saint-Germain, Melbourne Medical School [Melbourne], Faculty of Medicine, Dentistry and Health Sciences [Melbourne], University of Melbourne-University of Melbourne, CHU Rennes- Rennes 1 University- Faculty of Medicine in France- Peter Doherty Early Career Fellowship (1054432, to E.J.T.)- National Health and Medical Research Council programme grant (1074258, to A.H.S.)- fellowship (1062854, to A.H.S.) from the Australian National Health and Medical Research Council, the Victorian Government’s Operational Infrastructure Support Program- European Society of Pediatric Endocrinology (to A.B.)- ANR-10-LABX-73 REVIVE - ANR-17-CE14-0038-01 (to K.M.), ANR-10-LABX-0073,REVIVE,Stem Cells in Regenerative Biology and Medicine(2010), ANR-17-CE14-0038,MGonDev,Etude des mécanismes du développement des gonades chez l'homme(2017), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), and Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)
- Subjects
0301 basic medicine ,Proband ,Infertility ,Adult ,Male ,Embryology ,premature ovarian insufficiency ,Cohesin complex ,STAG3 ,[SDV]Life Sciences [q-bio] ,Mutation, Missense ,Physiology ,Cell Cycle Proteins ,030105 genetics & heredity ,Biology ,Primary Ovarian Insufficiency ,Premature ovarian insufficiency ,Male infertility ,03 medical and health sciences ,Consanguinity ,Genetics ,medicine ,Missense mutation ,Humans ,non-obstructive azoospermia ,whole-exome sequencing ,Molecular Biology ,Infertility, Male ,[SDV.BDLR] Life Sciences [q-bio]/Reproductive Biology ,Azoospermia ,Siblings ,Female infertility ,Homozygote ,Obstetrics and Gynecology ,[SDV.BDLR]Life Sciences [q-bio]/Reproductive Biology ,Cell Biology ,medicine.disease ,Pedigree ,[SDV] Life Sciences [q-bio] ,030104 developmental biology ,Reproductive Medicine ,Female ,Infertility, Female ,Developmental Biology - Abstract
Infertility, a global problem affecting up to 15% of couples, can have varied causes ranging from natural ageing to the pathological development or function of the reproductive organs. One form of female infertility is premature ovarian insufficiency (POI), affecting up to 1 in 100 women and characterised by amenorrhoea and elevated FSH before the age of 40. POI can have a genetic basis, with over 50 causative genes identified. Non-obstructive azoospermia (NOA), a form of male infertility characterised by the absence of sperm in semen, has an incidence of 1% and is similarly heterogeneous. The genetic basis of male and female infertility is poorly understood with the majority of cases having no known cause. Here, we study a case of familial infertility including a proband with POI and her brother with NOA. We performed whole-exome sequencing (WES) and identified a homozygous STAG3 missense variant that segregated with infertility. STAG3 encodes a component of the meiosis cohesin complex required for sister chromatid separation. We report the first pathogenic homozygous missense variant in STAG3 and the first STAG3 variant associated with both male and female infertility. We also demonstrate limitations of WES for the analysis of homologous DNA sequences, with this variant being ambiguous or missed by independent WES protocols and its homozygosity only being established via long-range nested PCR.
- Published
- 2020
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