The significant contribution of maternal effect genes for recurrent pregnancy loss: Preliminary results from the pedigree analysis
Prenatal Genetics
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Primary Categories:
- Genetic Counseling
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Secondary Categories:
- Genetic Counseling
Introduction:
Maternal Effect Genes (MEGs) are genes whose mRNAs or protein products are present in the oocyte and play a vital role in early embryonic development. MEGs influence the phenotype of the embryo independent of the embryo’s genotype. Murine knock-out studies suggest that deficiency in MEGs cause early embryonic lethality, which may manifest in human as recurrent pregnancy loss (RPL) defined as two or more failed clinical pregnancies. The contribution of maternal effect genes in human RPL has been recognized in a small number of families as case reports. We hypothesize that human MEGs may contribute more significantly to unexplained RPL.
Methods:
We reviewed pedigrees from 87 women with a history of first trimester RPL that were euploids who participated in the NIH study of Genomic Predictors of Recurrent Pregnancy Loss (GPRPL). A detailed three-generation family history was collected. We identified women with RPL and no live births and carefully ruled out known maternal causes of RPL. The enrolled participants satisfied our study inclusion criteria: two or more pregnancy losses <20 weeks gestation but no documented conditions that are known causes of RPL. We performed the pedigree analysis for 87 families and assess the likelihood of contribution of maternal effect genes.
Results:
Among the 87 women (Aged: 23 to 45) who are enrolled in the GPRPL project at Yale, 19 (21.8%) experienced two or more pregnancy loss (most of these losses occurred in the first trimester) but no live births and no identifiable conditions in mothers that could contribute to the recurrent pregnancy loss. The majority of the study population is of European ancestry. Of these 19 women, 7 had three losses, 3 had four losses, and 9 had more than four losses, with no live births in each case. Additionally, 2 of the 19 women experienced additional pregnancy losses using a surrogate. From this analysis of pedigree, we hypothesized that the cause in 21.8% of women with earlier consecutive RPL without live birth are likely due to genetic defects in maternal effect genes. Additional families experiencing a skewed pattern of pregnancy loss to live births may also have MEGs contributing to their pregnancy outcomes.
Conclusion:
The significance of the MEGs on pregnancy loss has not been established previously. The finding from the pedigree analysis provides support for maternal factor as the cause of RPL. We propose to analyse maternal genome, both nuclear and mitochondrial, in identifying genetic causes of recurrent pregnancy loss. The findings from maternal genome analysis may broaden the understanding of maternal contribution to the embryonic development and suggest new mechanisms that are beyond the mechanisms of MEGs to the zygotic development learned from another organism.
Maternal Effect Genes (MEGs) are genes whose mRNAs or protein products are present in the oocyte and play a vital role in early embryonic development. MEGs influence the phenotype of the embryo independent of the embryo’s genotype. Murine knock-out studies suggest that deficiency in MEGs cause early embryonic lethality, which may manifest in human as recurrent pregnancy loss (RPL) defined as two or more failed clinical pregnancies. The contribution of maternal effect genes in human RPL has been recognized in a small number of families as case reports. We hypothesize that human MEGs may contribute more significantly to unexplained RPL.
Methods:
We reviewed pedigrees from 87 women with a history of first trimester RPL that were euploids who participated in the NIH study of Genomic Predictors of Recurrent Pregnancy Loss (GPRPL). A detailed three-generation family history was collected. We identified women with RPL and no live births and carefully ruled out known maternal causes of RPL. The enrolled participants satisfied our study inclusion criteria: two or more pregnancy losses <20 weeks gestation but no documented conditions that are known causes of RPL. We performed the pedigree analysis for 87 families and assess the likelihood of contribution of maternal effect genes.
Results:
Among the 87 women (Aged: 23 to 45) who are enrolled in the GPRPL project at Yale, 19 (21.8%) experienced two or more pregnancy loss (most of these losses occurred in the first trimester) but no live births and no identifiable conditions in mothers that could contribute to the recurrent pregnancy loss. The majority of the study population is of European ancestry. Of these 19 women, 7 had three losses, 3 had four losses, and 9 had more than four losses, with no live births in each case. Additionally, 2 of the 19 women experienced additional pregnancy losses using a surrogate. From this analysis of pedigree, we hypothesized that the cause in 21.8% of women with earlier consecutive RPL without live birth are likely due to genetic defects in maternal effect genes. Additional families experiencing a skewed pattern of pregnancy loss to live births may also have MEGs contributing to their pregnancy outcomes.
Conclusion:
The significance of the MEGs on pregnancy loss has not been established previously. The finding from the pedigree analysis provides support for maternal factor as the cause of RPL. We propose to analyse maternal genome, both nuclear and mitochondrial, in identifying genetic causes of recurrent pregnancy loss. The findings from maternal genome analysis may broaden the understanding of maternal contribution to the embryonic development and suggest new mechanisms that are beyond the mechanisms of MEGs to the zygotic development learned from another organism.
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