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Abstract：
Placental mesenchymal dysplasia (PMD) is a morphological abnormality resembling partial hydatidiform moles. It is often associated with androgenetic/biparental mosaicism (ABM) and complicated by Beckwith-Wiedemann syndrome (BWS), an imprinting disorder. These phenomena suggest an association between PMD and aberrant genomic imprinting, particularly of CDKN1C and IGF2. The existence of another type of PMD containing the biparental genome has been reported. However, the frequency and etiology of biparental PMD are not yet fully understood.
We examined 44 placental specimens from 26 patients with PMD: 19 of these were macroscopically normal and 25 exhibited macroscopic PMD. Genotyping by DNA microarray or short tandem repeat analysis revealed that approximately 35% of the macroscopic PMD specimens could be classified as biparental, while the remainder were ABM. We performed a DNA methylation analysis using bisulfite pyrosequencing of 15 placenta-specific imprinted differentially methylated regions (DMRs) and 36 ubiquitous imprinted DMRs. As expected, most DMRs in the macroscopic PMD specimens with ABM exhibited the paternal epigenotype. Importantly, the biparental macroscopic PMD specimens exhibited frequent aberrant hypomethylation at seven of the placenta-specific DMRs. Allelic expression analysis using single-nucleotide polymorphisms revealed that five imprinted genes associated with these aberrantly hypomethylated DMRs were biallelically expressed. Frequent aberrant hypomethylation was observed at five ubiquitous DMRs, including GRB10 but not ICR2 or ICR1, which regulate the expression of CDKN1C and IGF2, respectively. Whole-exome sequencing performed on four biparental macroscopic PMD specimens did not reveal any pathological genetic abnormalities. Clinical and molecular analyses of babies born from pregnancies with PMD revealed four cases with BWS, each exhibiting different molecular characteristics, and those between BWS and PMD specimens were not always the same.
These data clarify the prevalence of biparental PMD and ABM-PMD and strongly implicate hypomethylation of DMRs in the pathogenesis of biparental PMD, particularly placenta-specific DMRs and the ubiquitous GRB10, but not ICR2 or ICR1. Aberrant hypomethylation of DMRs was partial, indicating that it occurs after fertilization. PMD is an imprinting disorder, and it may be a missing link between imprinting disorders and placental disorders incompatible with life, such as complete hydatidiform moles and partial hydatidiform moles.
We examined 44 placental specimens from 26 patients with PMD: 19 of these were macroscopically normal and 25 exhibited macroscopic PMD. Genotyping by DNA microarray or short tandem repeat analysis revealed that approximately 35% of the macroscopic PMD specimens could be classified as biparental, while the remainder were ABM. We performed a DNA methylation analysis using bisulfite pyrosequencing of 15 placenta-specific imprinted differentially methylated regions (DMRs) and 36 ubiquitous imprinted DMRs. As expected, most DMRs in the macroscopic PMD specimens with ABM exhibited the paternal epigenotype. Importantly, the biparental macroscopic PMD specimens exhibited frequent aberrant hypomethylation at seven of the placenta-specific DMRs. Allelic expression analysis using single-nucleotide polymorphisms revealed that five imprinted genes associated with these aberrantly hypomethylated DMRs were biallelically expressed. Frequent aberrant hypomethylation was observed at five ubiquitous DMRs, including GRB10 but not ICR2 or ICR1, which regulate the expression of CDKN1C and IGF2, respectively. Whole-exome sequencing performed on four biparental macroscopic PMD specimens did not reveal any pathological genetic abnormalities. Clinical and molecular analyses of babies born from pregnancies with PMD revealed four cases with BWS, each exhibiting different molecular characteristics, and those between BWS and PMD specimens were not always the same.
These data clarify the prevalence of biparental PMD and ABM-PMD and strongly implicate hypomethylation of DMRs in the pathogenesis of biparental PMD, particularly placenta-specific DMRs and the ubiquitous GRB10, but not ICR2 or ICR1. Aberrant hypomethylation of DMRs was partial, indicating that it occurs after fertilization. PMD is an imprinting disorder, and it may be a missing link between imprinting disorders and placental disorders incompatible with life, such as complete hydatidiform moles and partial hydatidiform moles.
摘要：
胎盘间质发育不良（PMD）是一种形态异常，类似于部分葡萄胎。它通常与雄激素/双亲镶嵌（ABM）有关，并伴有Beckwith-Wiedemann综合征（BWS），印记障碍。这些现象表明PMD和异常基因组印记之间的关联，特别是CDKN1C和IGF2。已经报道了含有双亲基因组的另一种类型的PMD的存在。然而,双亲PMD的发生频率和病因尚未完全了解.
我们检查了26例PMD患者的44例胎盘标本：其中19例宏观正常，25例表现出宏观PMD。通过DNA微阵列或短串联重复分析进行基因分型显示，大约35％的宏观PMD标本可以归类为双亲，其余为ABM。我们使用亚硫酸氢盐焦磷酸测序对15个胎盘特异性印迹差异甲基化区域（DMRs）和36个普遍存在的印迹DMRs进行了DNA甲基化分析。不出所料,带有ABM的宏观PMD标本中的大多数DMR均表现出父系表观基因型。重要的是,双亲宏观PMD标本在7个胎盘特异性DMRs中表现出频繁的异常低甲基化。使用单核苷酸多态性的等位基因表达分析显示，与这些异常低甲基化DMRs相关的五个印迹基因被双等位基因表达。在五个普遍存在的DMRs中观察到频繁的异常低甲基化，包括GRB10，但不包括ICR2或ICR1，它们分别调节CDKN1C和IGF2的表达。对四个双亲宏观PMD标本进行的全外显子组测序未发现任何病理遗传异常。从妊娠PMD出生的婴儿的临床和分子分析显示4例BWS，每个都表现出不同的分子特征，BWS和PMD样本之间的样本并不总是相同。
这些数据阐明了双亲PMD和ABM-PMD的患病率，并强烈暗示DMRs的低甲基化在双亲PMD的发病机理中，特别是胎盘特异性DMRs和普遍存在的GRB10，但不是ICR2或ICR1。DMRs的异常低甲基化是部分的，表明它发生在受精后。PMD是一种印记障碍，这可能是印记障碍和与生活不相容的胎盘障碍之间缺失的联系，如完全葡萄胎和部分葡萄胎。
我们检查了26例PMD患者的44例胎盘标本：其中19例宏观正常，25例表现出宏观PMD。通过DNA微阵列或短串联重复分析进行基因分型显示，大约35％的宏观PMD标本可以归类为双亲，其余为ABM。我们使用亚硫酸氢盐焦磷酸测序对15个胎盘特异性印迹差异甲基化区域（DMRs）和36个普遍存在的印迹DMRs进行了DNA甲基化分析。不出所料,带有ABM的宏观PMD标本中的大多数DMR均表现出父系表观基因型。重要的是,双亲宏观PMD标本在7个胎盘特异性DMRs中表现出频繁的异常低甲基化。使用单核苷酸多态性的等位基因表达分析显示，与这些异常低甲基化DMRs相关的五个印迹基因被双等位基因表达。在五个普遍存在的DMRs中观察到频繁的异常低甲基化，包括GRB10，但不包括ICR2或ICR1，它们分别调节CDKN1C和IGF2的表达。对四个双亲宏观PMD标本进行的全外显子组测序未发现任何病理遗传异常。从妊娠PMD出生的婴儿的临床和分子分析显示4例BWS，每个都表现出不同的分子特征，BWS和PMD样本之间的样本并不总是相同。
这些数据阐明了双亲PMD和ABM-PMD的患病率，并强烈暗示DMRs的低甲基化在双亲PMD的发病机理中，特别是胎盘特异性DMRs和普遍存在的GRB10，但不是ICR2或ICR1。DMRs的异常低甲基化是部分的，表明它发生在受精后。PMD是一种印记障碍，这可能是印记障碍和与生活不相容的胎盘障碍之间缺失的联系，如完全葡萄胎和部分葡萄胎。
