Patients with familial biparental hydatidiform moles have normal methylation at imprinted genes

Abstract

In molar tissues from patients with recurrent biparental hydatidiform moles, we could previously demonstrate that differentially methylated regions (DMRs) of four imprinted genes are abnormally methylated on the maternal alleles. It remained unclear if this abnormal methylation originated de novo in the molar tissues or if it is even recognizable in the patient somatic tissues. To address this question, we investigated the DNA methylation of four imprinted genes in total blood from the two sister-patients. Here, we show that both patients retain normal methylation levels at the DMRs of the four genes in blood tissues. For two maternally expressed genes, we could use informative SNPs to follow the inheritance of the abnormally methylated maternal alleles in the molar tissues. We find that the transmitted abnormally methylated maternal alleles to the moles originated from the maternal grandmother and that the same alleles are not methylated in the patients. Our data suggest that the abnormal methylation in familial biparental molar tissues was acquired de novo in the patients'germline as a result of a false reprogramming or during the postzygotic development of the conceptuses that led to moles.

The genetics of hydatidiform moles: new lights on an ancient disease

“…To investigate whether this gain of methylation is the result of an abnormal erasure of the grandparental marks in the primordial germ cells of the patients, we traced the inheritance of the abnormally methylated alleles to the molar tissues and found that the gain of methylation occurred in two cases on unmethylated alleles in the patients. This indicated that the abnormal methylation, at least on these two genes, was acquired de novo either in the maternal germline or post‐zygotically before or after implantation (65). So far, only one study addressed by immunohistochemistry the expression of an imprinted gene, p57 KIP2 , in RHMs caused by defect in 19q13.4 and showed its underexpression (29), which is in agreement with the above‐mentioned methylation data.…”

Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring

“…This is also expected, because imprinted expression of this gene depends on the maternal methylation of the KCNQ1OT1 DMR. Finally, the DNA methylation status of investigated DMRs at imprinted genes is normal in the mothers of the affected pregnancies (El-Maarri et al, 2005), further supporting the observation that the imprinting defects arise de novo during female gametogenesis. What might cause the different results at the H19 DMR between these studies?…”

The Diagnosis of Choriocarcinoma in Molar Pregnancies: A Revised Approach in Clinical Testing

“…A complete mole with p57 positivity was observed in this study ( Table 3 ), suggesting either retention of the maternal chromosome 11 [ 15 ], or a biparental complete mole. Biparental complete moles are generally the result of abnormal methylation of maternal alleles [ 16 ] and usually show complete lack of p57 staining [ 12 ], although maternal homozygous or compound heterozygous mutations in the NLRP7 and C6orf221 (KHDC3L) genes have also been implicated when fetuses are shown to be diploid and biparental in origin [ 17-19 ]. Both the 6q13 C6orf221 (OMIM #614293) and 19q13.42 NLRP7 (OMIM #609661) genes are expressed in oocytes, and are thought to be involved in setting and/or maintaining the maternal imprint [ 19 ], with mutations in the latter thought to be linked to early cleavage errors and subsequent reduced maternal immune response that allows abnormal cells to persist [ 18 ].…”