胎盘间质发育不良(PMD)和部分葡萄胎(PHM)胎盘具有相似的特征,如胎盘过度生长和葡萄样胎盘组织。区分PMD和PHM至关重要,因为前者可以导致正常出生,而后者的诊断会导致人工流产。非整倍体和印迹基因表达剂量的改变与PHM和一些PMD病例的发病机理有关。二重三倍体是导致PHM的主要原因,而胎盘组织中的镶嵌二倍体雄激素细胞与PMD的形成有关。这里,我们报告了一个非常特殊的PMD病例,也表现为滋养细胞增生表型,这是PHM的标志。该PMD胎盘具有正常的双亲二倍体核型,并且在功能上足以支持正常的胎儿生长。我们利用这个独特的病例进一步剖析了这两种疾病之间潜在的共同病因。我们显示NESP55的差异甲基化区域(DMR),位于GNAS基因座中的次级DMR,在PMD胎盘中明显高甲基化。此外,我们在母亲基因组中发现了NLRP2的杂合突变和NLRP7的纯合变异。NLRP2和NLRP7是已知的母体效应基因,并且它们在怀孕女性中的突变会影响胎儿发育。两个基因中的变体/突变都与痣形成中的印迹缺陷有关,并可能导致在这种情况下观察到的轻度异常印迹。最后,我们发现了X连锁ATRX基因的杂合突变,患者中已知的母体合子印迹调节剂。总的来说,我们的研究表明,PMD和PHM可能与印迹基因的缺陷/放松剂量控制具有重叠的病因,代表光谱的两个极端。
Placental mesenchymal dysplasia (PMD) and partial hydatidiform mole (PHM) placentas share similar characteristics, such as placental overgrowth and grape-like placental tissues. Distinguishing PMD from PHM is critical because the former can result in normal birth, while the latter diagnosis will lead to artificial abortion. Aneuploidy and altered dosage of imprinted gene expression are implicated in the pathogenesis of PHM and also some of the PMD cases. Diandric triploidy is the main cause of PHM, whereas mosaic diploid androgenetic cells in the placental tissue have been associated with the formation of PMD. Here, we report a very special PMD
case also presenting with trophoblast hyperplasia phenotype, which is a hallmark of PHM. This PMD placenta has a normal biparental diploid karyotype and is functionally sufficient to support normal fetal growth. We took advantage of this unique
case to further dissected the potential common etiology between these two diseases. We show that the differentially methylated region (DMR) at NESP55, a secondary DMR residing in the GNAS locus, is significantly hypermethylated in the PMD placenta. Furthermore, we found heterozygous mutations in NLRP2 and homozygous variants in NLRP7 in the mother\'s genome. NLRP2 and NLRP7 are known maternal effect genes, and their mutation in pregnant females affects fetal development. The variants/mutations in both genes have been associated with imprinting defects in mole formation and potentially contributed to the mild abnormal imprinting observed in this
case. Finally, we identified heterozygous mutations in the X-linked ATRX gene, a known maternal-zygotic imprinting regulator in the patient. Overall, our study demonstrates that PMD and PHM may share overlapping etiologies with the defective/relaxed dosage control of imprinted genes, representing two extreme ends of a spectrum.