Logo Università degli Studi di Milano


Whole Exome Sequencing e studi funzionali in Drosophila per svelare le basi genetiche dell’insufficienza ovarica primaria

Whole Exome Sequencing e studi funzionali in Drosophila per svelare le basi genetiche dell’insufficienza ovarica primaria


Primary ovarian Insufficiency (POI), a condition occurring in 1% of women under 40 years of age, affects women’s fertility leading to a premature loss of ovarian reserve. The genetic causes of POI are highly heterogeneous and several determinants contributing to its prominent oligogenic inheritance pattern still need to be elucidated.


The DNAs of 41 Italian women with non-syndromic primary and early secondary amenorrhoea occurring before age 25 were processed by targeted WES including 542 RefSeq genes expressed or functioning during distinct reproductive or ovarian processes (e.g. DNA repair, meiosis, oocyte maturation, folliculogenesis and menopause). Extremely rare variants were filtered and selected by means of a Fisher Exact test using several publicly available datasets: 64 validated single-nucleotide variants in 59 genes in 30 out of 41 screened women were identified. A case-control Burden test was applied to highlight the most significant genes using two ad-hoc control female cohorts, and 13 ovarian genes resulted the most enriched and significant.
To support the obtained data, the identified 59 genes were screened on a novel cohort of 60 Caucasian POI patients including 35 French and 25 American women and the same case-control analysis was carried out. Burden analysis on the second cohort yielded 11 significantly enriched genes. Among them, AFP, DMRT3, MOV10, FYN and MYC were significant in both patient cohorts and hence were considered strong candidates for POI.
Comparative analysis of the human identified genes was performed on mouse and Drosophila melanogaster by analysing the orthologous genes in their ovarian phenotype and revealed a conserved role through the evolution of several candidates.
Functional studies using a Drosophila model, when applicable, supported the conserved role of the MOV10 armitage and DMRT3 dmrt93B orthologues in female fertility.


The genomic, statistical, comparative and functional approaches integrated in our study convincingly support the extremely heterogeneous oligogenic nature of POI, and confirm the maintenance across the evolution of some key genes safeguarding fertility and successful reproduction. Two principal classes of genes were identified: (i) genes primarily involved in meiosis, namely in synaptonemal complex formation, asymmetric division and oocyte maturation and (ii) genes safeguarding cell maintenance (piRNA and DNA repair pathways).

Paper citation

Bestetti I, Barbieri C, Sironi A, Specchia V, Yatsenko SA, De Donno MD, Caslini C, Gentilini D, Crippa M, Larizza L, Marozzi A, Rajkovic A, Toniolo D, Bozzetti MP, Finelli P. Targeted whole exome sequencing and Drosophila modelling to unveil the molecular basis of primary ovarian insufficiency. Hum Reprod. 2021 Sep 4:deab192. doi: 10.1093/humrep/deab192. Epub ahead of print. PMID: 34480478.



Prof.ssa Palma Finelli and Dr. Ilaria Bestetti, Department of Medical Biotechnology and Translational Medicine, University of Milan; IRCCS Istituto Auxologico Italiano, Lab. Sperimentale di Ricerche di Citogenetica Medica e Genetica Molecolare
Email: palma.finelli@unimi.it / ilaria.bestetti@unimi.it / i.bestetti@auxologico.it


27 settembre 2021
Torna ad inizio pagina