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Developmental defects
Communication
A protein-truncating mutation in CCNB3 in a patient with recurrent miscarriages and failure of meiosis I
  1. Maryam Rezaei1,
  2. William Buckett2,
  3. Eric Bareke3,
  4. Urvashi Surti4,
  5. Jacek Majewski3,
  6. Rima Slim1
  1. 1 Human Genetics, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada
  2. 2 Obstetrics and Gynecology, McGill University Health Centre, Montréal, Québec, Canada
  3. 3 McGill University and Génome Québec Innovation Centre, Montréal, Québec, Canada
  4. 4 Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
  1. Correspondence to Dr Rima Slim, Human Genetics, Research Institute of the McGill University Health Centre, Montreal, Quebec H3A 0G4, Canada; rima.slim{at}muhc.mcgill.ca

https://doi.org/10.1136/jmedgenet-2021-107875

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    Recurrent miscarriage (RM) is defined by the occurrence of at least two pregnancy losses prior to 22 weeks of gestation and affects up to 5% of couples trying to conceive.1–3 RM has a significant emotional impact on couples and the repetitive nature intensifies the grief experienced. A recessive missense in cyclin B3 (CCNB3) has recently been shown in two sisters with RM and triploidy of maternal origin.4 Here, we report a novel recessive CCNB3 mutation, c.4091+1G>A, p.Val1321Glyfs*4, in a patient with 16 RM and show that one of her miscarriages is triploid digynic resulted from the failure of meiosis I.

    RM is clinically and genetically highly heterogeneous. After comprehensive clinical and laboratory testing, in 50% of couples, no abnormalities are identified, and such cases are categorised as RM of unexplained clinical aetiology. To date, little is known about their genetic causes, and known genes explain only a minority of cases. One of the many factors that have hampered our understanding of the genetics of recurrent miscarriages is their complexity, genetic heterogeneity and the difficulties in homogenising these entities to simplify their studies. In many cases of recurrent miscarriages of unknown clinical aetiology, it is impossible to know whether the defect originates from the male or the female, and whether it is in a dominant or a recessive state. Also, it is impossible to know if the defect is transmitted from the parents to the miscarried conception or if it occurred de novo in the miscarriage. While the germline origin of male causes of miscarriages could be sometimes diagnosed based on semen analysis, diagnosing the origin of female causes of miscarriages is more challenging; in many cases, it is impossible to distinguish germline from uterine or systemic defects. Consequently, despite the use of next-generation sequencing, which has greatly facilitated …

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    Footnotes

    • Contributors MR did the experiments and contributed to the writing of some sections of the manuscript. RS completed the writing and supervised the work. WB referred the patient and contributed to the writing of the clinical description section. US performed the FISH analysis. EB and JM filtered raw data of exome sequencing.

    • Funding This work was supported by the “Fondation Grand Defi Pierre Lavoie” to RS.

    • Competing interests None declared.

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