STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia

Sylvie Jaillard (1, 2, 3) , Kenneth Mcelreavy (4) , Gorjana Robevska (1) , Linda Akloul (3) , Farah Ghieh (5, 6) , Rajini Sreenivasan (1) , Marion Beaumont (3) , Anu Bashamboo (4) , Joelle Bignon-Topalovic (4) , Anne-Sophie Neyroud (3) , Katrina M Bell (1) , Elisabeth Veron-Gastard (3) , Erika Launay (3) , Jocelyn van den Bergen (1) , Bénédicte Nouyou (3) , François Vialard (5, 6, 7) , Marc-Antoine Belaud-Rotureau (2, 3) , Katie L Ayers (1, 8) , Sylvie Odent (3) , Célia Ravel (2, 3) , Elena J Tucker (1, 8) , Andrew H Sinclair (1, 8)

1 MCRI - Murdoch Children's Research Institute
2 Irset - Institut de recherche en santé, environnement et travail
3 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
4 Génétique du Développement humain - Human developmental genetics
5 Université Paris-Saclay
6 BREED - Biologie de la Reproduction, Environnement, Epigénétique & Développement
7 CHI Poissy-Saint-Germain
8 Melbourne Medical School [Melbourne]

Infertility, a global problem affecting up to 15% of couples, can have varied causes ranging from natural aging 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 amenorrhea and elevated follicle stimulating hormone 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.

Keywords: STAG3; non-obstructive azoospermia; premature ovarian insufficiency; whole-exome sequencing

Domains: Life Sciences [q-bio]; Reproductive Biology

Sylvie Jaillard, Kenneth Mcelreavy, Gorjana Robevska, Linda Akloul, Farah Ghieh, et al.. STAG3 homozygous missense variant causes primary ovarian insufficiency and male non-obstructive azoospermia. Molecular Human Reproduction, 2020, 26 (9), pp.665-677. ⟨10.1093/molehr/gaaa050⟩. ⟨hal-02929984⟩