Novel STAG3 mutations in a Caucasian family with primary ovarian insufficiency

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.