Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family


The term multilocus imprinting disturbance (MLID) describes the aberrant methylation of multiple imprinted loci in the genome, and MLID occurs in patients suffering from imprinting disorder carrying methylation defects. First data indicate that functional variants in factors expressed from both the fetal as well as the maternal genome cause MLID. Molecular changes in such genes of the maternal genome are called maternal effect variants, they affect members of the subcortical maternal complex (SCMC) in the oocyte which plays an important role during early embryonic development. Whereas the contribution of variants in the SCMC genes NLRP2, NLRP5, NLRP7, and KHDC3L to the etiology of reproductive failure and aberrant imprinting is widely accepted, the involvement of PADI6 variants in the formation of MLID is in discussion. We now report on the identification of biallelic variants in a woman suffering from different miscarriages and giving birth to two children with MLID. Thereby the role of PADI6 in maintaining the proper imprinting status during early development is confirmed. Thus, PADI6 variants do not only cause (early) pregnancy losses, but maternal effect variants in this gene cause the same spectrum of pregnancy outcomes as variants in other SCMC encoding genes, including chromosomal aberrations and disturbed imprinting. The identification of maternal effect variants requires genetic and reproductive counseling as carriers of these variants are at high risks for reproductive failure.

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Fig. 1: Localization of the PADI6 variants already described in the literature and the new variants from our family (in bold face, upper panel).
Fig. 2: Pedigree of the family showing the compound heterozygosity for PADI6 variants in the mother and the reproductive outcome.
Fig. 3: MS MLPA results achieved from blood samples of the two BWS patients and their mother.


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This work was funded by the Deutsche Forschungsgemeinschaft (DFG, EG110/15–1; 948/32–1 FUGG). This work was supported by the Genomics Facility, a core facility of the Interdisciplinary Center for Clinical Research (IZKF) Aachen within the Faculty of Medicine at RWTH Aachen University.

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Eggermann, T., Kadgien, G., Begemann, M. et al. Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family. Eur J Hum Genet (2020).

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