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.
- 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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