Genetics of Early Miscarriages


Early miscarriage or early pregnancy loss (EPL) is defined by an embryonic foetal loss occurring before 13 weeks of gestation. In this article, we focus on the genetics of this complex human disease from studies of human patients, sometimes including foetal losses occurring before 20 weeks. Most of the mouse studies on EPL are based on gene invalidation experiments having much wider and pleiotropic effects than a mere defect of implantation or placental development, and therefore they will not be analyzed here. In addition, many good reviews are already available on gene polymorphisms relevant to early miscarriage and are only briefly summarised here. We develop more in‐depth aspects connected to microRNA and copy number variations with EPL, issues that have been much less reviewed in the past.

Key Concepts

  • Early pregnancy loss is a complex multifactorial disease, leading to embryo loss in an estimated >70% of the fertilisation events in humans.
  • Besides chromosome anomalies, detected by cytogenetics or CGH arrays (array‐based comparative genomic hybridisation), gene variants are associated with an increased risk of pregnancy loss. These genes may be regulators of immune response including cytokines, modulators of the coagulation cascade, equilibrators of the oxidative stress or, rarely, genes involved in chromosome segregation at meiosis or mitosis. Other genes may be found by genome‐wide association studies.
  • Recent novel studies are developing on the impact of epigenetic regulators (essentially microRNAs) on miscarriages. These can be relevant markers to categorise gene expression deregulation in pregnancy losses.

Keywords: fertility; implantation; miscarriage; microRNA; genomics

Figure 1. (a) Wenn diagrams presenting the miRNA found deregulated in three independent studies. As shown in the diagram, the overlap between the different studies is limited. (b) A list of miRNA that are found deregulated in common in at least two studies. The consistency in the sense of deregulation is not systematically conserved.
Figure 2. A summary of the genes known today to be involved in recurrent spontaneous abortion (RSA), classified in physiological cascades. As explained in the text, the review focuses on genes for which genetic variants have been found associated with this syndrome. In humans, there is a large proportion of aneuploïdies (estimated at ∼75–80%) and specific variants in genes important for chromosome segregation have been involved in RSA. Logically, proteins involved in immunity are a first group of actors in the materno‐foetal dialogue and specific variants have been found associated with RSA in various human populations. Similarly, in all the implantation and early development processes, there is a prominent role of coagulation and complement cascades; oxidative stress mechanisms are also very important in implantation and early development. Above these regulations, specific miRNAs have been found as important regulators of gene expression in the placenta‐uterine context, as described in the text.


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Further Reading

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Vaiman, Daniel(Sep 2016) Genetics of Early Miscarriages. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0025043]