Variants in Maternal Effect Genes and Relaxed Imprinting Control in a Special Placental Mesenchymal Dysplasia Case with Mild Trophoblast Hyperplasia

Abstract

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.

A Challenging Diagnosis: Placental Mesenchymal Dysplasia—Literature Review and Case Report

“…The PMD newborns with normal phenotype should be followed-up for BWS features of the mesenchymal tumor (hepatic mesenchymal hamartoma, congenital adrenal hyperplasia, and vascular hamartoma) [ 51 ]. Some cases of PMD are diagnosed in conjunction with mesenchymal hamartoma of the liver (MHL), while in others, the diagnosis is made after an MHL diagnosis [ 24 , 59 ]. MHL is a benign hepatic tumor characterized by excessive, focal growth of an admixture of epithelial and vascular components, which becomes multicystic as it enlarges, providing a poorer prognosis than for fetuses without structural anomalies (IUFD or neonatal death) [ 54 , 59 ].…”

The structure of the TH/INS locus and the parental allele expressed are not conserved between mammals

“…The location of genes in the imprinted region was visualised for house mouse, human, cattle and tammar wallaby using the DNA Features Viewer library (Zulkower and Rosser 2020 ). ICR locations were from NCBI (Gene ID: 105317033, 105259599) or based on the position of published bisulfite primers (Smits et al 2008 ; Oh et al 2008 ; Robbins et al 2012 ; Wang et al 2015 ; Huang et al 2021 ). The position of KCNQ1OT1 in cattle and the tammar wallaby is from primer positions used to generate a short amplicon of the transcript (Ager et al 2007 ; Robbins et al 2012 ).…”

Placental Mesenchymal Dysplasia and Beckwith–Wiedemann Syndrome

“…Several PMD cases composed entirely of biparental cells have also been reported [ 32 , 74 , 75 , 76 , 77 , 78 ]. Recently, we genotyped 25 macroscopic PMD specimens and found that 9 (36%) showed a normal biparental genotype [ 28 ].…”