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.

术语多位点印记障碍 (MLID) 描述了基因组中多个印记基因座的异常甲基化，并且 MLID 发生在患有携带甲基化缺陷的印记障碍的患者中。第一个数据表明，胎儿和母体基因组表达的因子的功能变异会导致 MLID。母体基因组中此类基因的分子变化称为母体效应变异体，它们影响卵母细胞中皮层下母体复合体 (SCMC) 的成员，该复合体在早期胚胎发育过程中起重要作用。尽管 SCMC 基因NLRP2、NLRP5、NLRP7和KHDC3L的变异对生殖失败和异常印记的病因学的贡献已被广泛接受，但PADI6的参与MLID 形成的变体正在讨论中。我们现在报告在患有不同流产并生下两个患有 MLID 的孩子的妇女中鉴定出双等位基因变异。从而证实了 PADI6 在早期发育过程中维持适当印记状态的作用。因此，PADI6变异不仅会导致（早期）流产，而且该基因中的母体效应变异会导致与其他 SCMC 编码基因中的变异相同的妊娠结果谱，包括染色体畸变和印记紊乱。母体效应变异的鉴定需要遗传和生殖咨询，因为这些变异的携带者具有生殖失败的高风险。