Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family
Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family
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DOI：
10.1038/s41431-020-00762-0
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发表时间：
2020-11-21
影响因子：
5.2
通讯作者：
Elbracht, Miriam
中科院分区：
文献类型：
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作者：
Eggermann, Thomas;Kadgien, Gundula;Elbracht, Miriam
术语多位点印迹障碍（MLID）描述了基因组中多个印迹位点的异常甲基化，并且MLID发生在患有携带甲基化缺陷的印迹障碍的患者中。第一个数据表明，从胎儿以及母体基因组表达的因子中的功能变体引起MLID。母体基因组中这些基因的分子变化被称为母体效应变体，它们影响卵母细胞中在早期胚胎发育中起重要作用的皮质下母体复合体（SCMC）的成员。尽管SCMC基因NLRP2、NLRP5、NLRP7和KHDC3L中的变体对生殖失败和异常印记的病因学的贡献被广泛接受，但PADI6变体参与MLID的形成仍在讨论中。我们现在报告的鉴定双等位基因变异的妇女患有不同的流产，生下两个孩子MLID。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变体不仅导致（早期）妊娠丢失，而且该基因中的母体效应变体导致与其他SCMC编码基因中的变体相同的妊娠结局谱，包括染色体畸变和干扰的印记。母体效应变异的识别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。
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.