Molecular Genetics and Genomics

, Volume 294, Issue 6, pp 1527–1534 | Cite as

Novel STAG3 mutations in a Caucasian family with primary ovarian insufficiency

  • Abdelkader Heddar
  • Philippe Dessen
  • Delphine Flatters
  • Micheline MisrahiEmail author
Original Article


Primary ovarian insufficiency (POI) affects ~ 1–3, 7% of women under forty and is a public health problem. Most causes are unknown, but an increasing number of genetic causes have been identified recently. The identification of such causes is essential for genetic and therapeutic counseling in patients and their families. We performed whole exome sequencing in two Caucasian sisters displaying non syndromic POI and their unaffected mother. We identified two novel pathogenic variants in STAG3 encoding a meiosis-specific subunit of the cohesin ring, which ensures correct sister chromatid cohesion: a c.3052delC truncating mutation in exon 28 yielding p.Arg1018Aspfs*14, and a c.659T > G substitution in exon seven yielding p.Leu220Arg. Leu220, highly conserved throughout species, belongs to the STAG domain conserved with other mitotic subunits of the cohesion complex STAG1 and 2. In silico analysis reveals that this substitution markedly impacts the structure of this domain. The truncation removes the last 206 C-terminal residues, not conserved in STAG1 and 2, supporting an important specific role in STAG3, especially meiosis. This is the first occurrence of STAG3 mutations in a Caucasian family. Very little is known about the function of STAG proteins domains. The “knock out-like” phenotype described here supports the crucial role of a single residue in the STAG domain and of the C-terminal region in STAG3 function. In conclusion, this observation shows the necessity to perform the genetic study of POI worldwide including STAG3. This could lead to appropriate genetic counseling and long term follow-up since these patients may develop ovarian tumors.


Primary ovarian insufficiency STAG3 Meiosis STAG domain Whole exome sequencing Mutation Genetics 



We thank Prof. Reiner Veitia and Dr Sandrine Caburet (Jacques Monod Institute, Paris) for their support and helpful discussions.


This work was supported by the Universities Paris South-Paris Saclay and Paris Diderot and by The French National Biomedical Agency (ABM).

Compliance with ethical standard

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

438_2019_1594_MOESM1_ESM.doc (45 kb)
Supplementary material 1 (DOC 45 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Faculté de MédecineUniversités Paris Sud-Paris SaclayParisFrance
  2. 2.Unité de Génétique Moléculaire des Maladies Métaboliques et de la ReproductionHôpitaux Universitaires Paris-Sud, Hôpital Bicêtre AP-HPParisFrance
  3. 3.INSERM U1170, Gustave Roussy InstituteUniversités Paris Sud, Paris SaclayParisFrance
  4. 4.INSERM UMR973, Molécules Thérapeutiques in silicoUniversité Paris Diderot-Paris VII, Sorbonne Paris CitéParisFrance

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