Genetic diagnosis in first or second trimester pregnancy loss using exome sequencing: a systematic review of human essential genes

J Assist Reprod Genet. 2019 Aug;36(8):1539-1548. doi: 10.1007/s10815-019-01499-6. Epub 2019 Jul 4.


Purpose: Non-aneuploid recurrent pregnancy loss (RPL) affects approximately 100,000 pregnancies worldwide annually. Exome sequencing (ES) may help uncover the genetic etiology of RPL and, more generally, pregnancy loss as a whole. Previous studies have attempted to predict the genes that, when disrupted, may cause human embryonic lethality. However, predictions by these early studies rarely point to the same genes. Case reports of pathogenic variants identified in RPL cases offer another clue. We evaluated known genetic etiologies of RPL identified by ES.

Methods: We gathered primary research articles from PubMed and Embase involving case reports of RPL reporting variants identified by ES. Two authors independently reviewed all articles for eligibility and extracted data based on predetermined criteria. Preliminary and amended analysis isolated 380 articles; 15 met all inclusion criteria.

Results: These 15 articles described 74 families with 279 reported RPLs with 34 candidate pathogenic variants in 19 genes (NOP14, FOXP3, APAF1, CASP9, CHRNA1, NLRP5, MMP10, FGA, FLT1, EPAS1, IDO2, STIL, DYNC2H1, IFT122, PADI6, CAPS, MUSK, NLRP2, NLRP7) and 26 variants of unknown significance in 25 genes. These genes cluster in four essential pathways: (1) gene expression, (2) embryonic development, (3) mitosis and cell cycle progression, and (4) inflammation and immunity.

Conclusions: For future studies of RPL, we recommend trio-based ES in cases with normal parental karyotypes. In vitro fertilization with preimplantation genetic diagnosis can be pursued if causative variants are found. Utilization of other sequencing technologies in concert with ES should improve understanding of the causes of early embryonic lethality in humans.

Keywords: Embryonic lethal; Exome sequencing; Pregnancy loss; Recurrent pregnancy loss.

Publication types

  • Systematic Review

MeSH terms

  • Abortion, Habitual / diagnosis*
  • Abortion, Habitual / genetics*
  • Exome Sequencing / methods*
  • Female
  • Genes, Essential*
  • Humans
  • Pregnancy
  • Pregnancy Trimester, First / genetics*
  • Pregnancy Trimester, Second / genetics*