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Biallelic variant in cyclin B3 is associated with failure of maternal meiosis II and recurrent digynic triploidy
  1. Nayeralsadat Fatemi1,2,
  2. Najmeh Salehi2,
  3. Laura Pignata3,4,
  4. Pietro Palumbo5,
  5. Maria Vittoria Cubellis6,
  6. Fariba Ramazanali7,
  7. Pierre Ray8,9,
  8. Maryam Varkiani2,
  9. Fakhreddin Reyhani-Sabet2,
  10. Alireza Biglari1,
  11. Angela Sparago3,
  12. Basilia Acurzio3,4,
  13. Orazio Palumbo5,
  14. Massimo Carella5,
  15. Andrea Riccio3,4,
  16. Mehdi Totonchi2,10
  1. 1Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
  2. 2Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
  3. 3Department of Environmental, Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania "Luigi Vanvitelli", Caserta, Italy
  4. 4Institute of Genetics and Biophysics (IGB) "Adriano Buzzati-Traverso", Consiglio Nazionale delle Ricerche (CNR), Napoli, Italy
  5. 5IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy
  6. 6Department of Biology, Università degli Studi di Napoli "Federico II", Napoli, Italy
  7. 7Department of Endocrinology and Female Infertility, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
  8. 8Genetic Epigenetic and Therapies of Infertility, Institute for Advanced Biosciences, INSERM 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble F38000, France
  9. 9Unité Médicale de génétique de l'infertilité et de diagnostic pré-implantatoire (GI-DPI), Centre Hospitalier Universitaire Grenoble Alpes, Grenoble 38000, France
  10. 10Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
  1. Correspondence to Dr Andrea Riccio, Università degli Studi della Campania Luigi Vanvitelli, Caserta 81100, Italy; andrea.riccio{at}; Dr Mehdi Totonchi, Department ofGenetics, Reproductive Biomedicine Research Center, Royan Institute forReproductive Biomedicine, ACECR, Tehran, Iran; m.totonchi{at}


Background Triploidy is one of the most common chromosome abnormalities affecting human gestation and accounts for an important fraction of first-trimester miscarriages. Triploidy has been demonstrated in a few cases of recurrent pregnancy loss (RPL) but its molecular mechanisms are unknown. This study aims to identify the genetic cause of RPL associated with fetus triploidy.

Methods We investigated genomic imprinting, genotyped sequence-tagged site (STS) markers and performed exome sequencing in a family including two sisters with RPL. Moreover, we evaluated oocyte maturation in vivo and in vitro and effect of the candidate protein variant in silico.

Results While features of hydatidiform mole were excluded, the presence of triploidy of maternal origin was demonstrated in the fetuses. Oocyte maturation was deficient and all the maternally inherited pericentromeric STS alleles were homozygous in the fetuses. A deleterious missense variant (p.V1251D) of the cyclin B3 gene (CCNB3) affecting a residue conserved in placental mammals and located in a region that can interact with the cyclin-dependent kinase 1 or cyclin-dependent kinase 2 cosegregated in homozygosity with RPL.

Conclusion Here, we report a family in which a damaging variant in cyclin B3 is associated with the failure of oocyte meiosis II and recurrent fetus triploidy, implicating a rationale for CCNB3 testing in RPL.

  • copy-number
  • reproductive medicine

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  • Contributors MT designed and conceptualised the study, NF, NS, LP, PP, MVC, FR, PR, MV, FR-S, AB, AS, BA, OP and MC performed analysis and interpreted the data. AR and MT drafted the manuscript. All authors critically revised the manuscript, contributed significantly to this work and declare to meet the ICMJE criteria for authorship.

  • Funding This work was supported in part by a grant from Royan Institute, Iran; Université Grenoble Alpes, France and Italian MIUR-PRIN 2015 JHLY35 (AR and MVC); Telethon-Italia GGP15131 (AR), Associazione Italiana Ricerca sul Cancro IG 2016 N.18671 (AR); 'Progetti per la ricerca oncologica della Regione Campania' Grant: I-Cure (AR) and 'Progetti competitivi intra-Ateneo' Programma VALERE (VAnviteLli pEr la RicErca) 2019 Grant: MIRIAM, Università degli studi della Campania 'Luigi Vanvitelli' (AR and AS). AS was supported by Programma VALERE (VAnviteLli pEr la RicErca) from Università degli studi della Campania 'Luigi Vanvitelli'.

  • Disclaimer The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The study was approved by the Royan Institute ethics committee and conducted in accordance with the declaration of Helsinki.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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