Next generation sequencing in recurrent pregnancy loss-approaches and outcomes

Eur J Med Genet. 2020 Feb;63(2):103644. doi: 10.1016/j.ejmg.2019.04.001. Epub 2019 Apr 13.


Next generation sequencing (NGS) has revolutionized the diagnosis of postnatal genetic diseases, but so far has been used less frequently to study reproductive disorders. Here we provide an overview of approaches and outcomes of genome sequencing for identifying causes of recurrent pregnancy loss (RPL). This includes exome sequencing to look for pathogenic sequence changes in the whole exome or in a preselected list of genes considered important for early embryonic development and pregnancy maintenance, as well as low coverage whole genome sequencing useful for identifying cryptic balanced chromosome rearrangements and copy number variants (CNVs) in couples with RPL and miscarriages. For the purpose of this review only studies with at least 2 pregnancy losses were included with NGS performed on complete families, or only on miscarriages, couples or females with RPL. Overall, mutations in candidate genes responsible for recurrent embryonic/fetal loss were found in up to 60% of cases, opening the door for possible identification of affected future pregnancies at the preimplantation stage. Recurrence of specific mutations or affected genes in different studies was rare (e.g.DYNC2H1, KIF14, RYR1 and GLE1) however genes involved in cell division, cilia function or fetal movement were frequently identified as candidates, the later possibly reflecting the fact that a large number of studied cases had features of fetal akinesia deformation sequence (FADS). Genome sequencing of the couple and miscarriages is most informative, as it allows analysis of the individual mutations as well as their collective burden on the genome and biological processes. However genome sequencing of the couple with RPL with follow up of candidate parental mutations in miscarriages appears to be a promising avenue when miscarriage DNA amounts or quality are suboptimal for whole genome studies. In the future, increasing the number of studied families, establishment of a database cataloguing CNVs and mutations found in early pregnancy loss as well as their functional assessment in miscarriage cells and parental reproductive tissues is needed for improved understanding of their role in adverse pregnancy outcome.

Keywords: Exome; Recurrent pregnancy loss; Whole genome sequencing.

Publication types

  • Review

MeSH terms

  • Abortion, Habitual / genetics*
  • DNA Copy Number Variations
  • Exome Sequencing*
  • Family Characteristics
  • Female
  • High-Throughput Nucleotide Sequencing*
  • Humans
  • Male
  • Mutation
  • Pregnancy
  • Whole Genome Sequencing*