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. 2021 Nov;38(11):2893-2908.
doi: 10.1007/s10815-021-02312-z. Epub 2021 Sep 23.

NLRP7 variants in spontaneous abortions with multilocus imprinting disturbances from women with recurrent pregnancy loss

Elena A Sazhenova  1 , Tatyana V Nikitina  2 , Stanislav A Vasilyev  2 , Ekaterina N Tolmacheva  2 , Oksana Yu Vasilyeva  2 , Anton V Markov  2 , Sergey Yu Yuryev  3 , Nikolay A Skryabin  2 , Alexey A Zarubin  2 , Nikita A Kolesnikov  2 , Vadim A Stepanov  2 , Igor N Lebedev  2
Affiliations

NLRP7 variants in spontaneous abortions with multilocus imprinting disturbances from women with recurrent pregnancy loss

Elena A Sazhenova et al. J Assist Reprod Genet. 2021 Nov.

Abstract

Purpose: Comparative analysis of multilocus imprinting disturbances (MLIDs) in miscarriages from women with sporadic (SPL) and recurrent pregnancy loss (RPL) and identification of variants in the imprinting control gene NLRP7 that may lead to MLIDs.

Methods: Chorionic cytotrophoblast and extraembryonic mesoderm samples from first-trimester miscarriages were evaluated in 120 women with RPL and 134 women with SPL; 100 induced abortions were analyzed as a control group. All miscarriages had a normal karyotype. Epimutations in 7 imprinted genes were detected using methyl-specific PCR and confirmed with DNA pyrosequencing. Sequencing of all 13 exons and adjusted intron regions of the NLRP7 gene was performed.

Results: Epimutations in imprinted genes were more frequently detected (p < 0.01) in the placental tissues of miscarriages from women with RPL (7.1%) than in those of women with SPL (2.7%). The predominant epimutation was postzygotic hypomethylation of maternal alleles of imprinted genes (RPL, 5.0%; SPL, 2.1%; p < 0.01). The frequency of MLID was higher among miscarriages from women with RPL than among miscarriages from women with SPL (1.7% and 0.4%, respectively, p < 0.01). Variants in NLRP7 were detected only in miscarriages from women with RPL. An analysis of the parental origin of NLRP7 variants revealed heterozygous carriers in families with RPL who exhibited spontaneous abortions with MLIDs and compound heterozygosity for NLRP7 variants.

Conclusion: RPL is associated with NLRP7 variants that lead to germinal and postzygotic MLIDs that are incompatible with normal embryo development.

Trial registration: Not applicable.

Keywords: DNA methylation; Multilocus imprinting disturbances (MLID); NLRP7; Placenta; Recurrent pregnancy loss; Trophoblast.

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Conflict of interest statement

The authors declare that they have no conflicts of interest that could be perceived as prejudicing the impartiality of this manuscript.

Figures

Fig. 1
Fig. 1
Frequency of epimutations in imprinted genes in miscarriages from women with recurrent and sporadic pregnancy loss
Fig. 2
Fig. 2
The positions of detected genetic variants in NLRP7
Fig. 3
Fig. 3
Methylation indices of imprinted genes in spontaneous abortion No. 1. Hypermethylation of PEG1 (a); simultaneous hypomethylation of imprinted genes PEG10 (b), DLK1 (c), PLAGL1 (d); and methylation of all studied imprinted loci (e)
Fig. 4
Fig. 4
Methylation indices of imprinted genes in spontaneous abortion No. 3. Hypermethylation of the imprinted genes PEG1 (a) and PEG10 (b), hypomethylation of KCNQ1OT1 (c) and PEG3 (d), and methylation of all studied imprinted loci (e)
Fig. 5
Fig. 5
Methylation indices of imprinted genes in spontaneous abortion No. 5. Hypermethylation of the imprinted gene PEG1 (a); hypomethylation of DLK1 (b), GRB10 (c), KCNQ1OT1 (d), and PEG10 (e); and methylation of all studied imprinted loci (f)
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