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

European Journal of Human Genetics (2005) 13, 486490

& 2005 Nature Publishing Group All rights reserved 1018-4813/05 $30.00www.nature.com/ejhgARTICLEPatients with familial biparental hydatidiform moles

have normal methylation at imprinted genesOsman El-Maarri1, Muhieddine Seoud2, Jean-Baptiste Rivie`re3, Johannes Oldenburg1,4, JornWalter5, Guy Rouleau3 and Rima Slim*,61Institute of Experimental Haematology and Transfusion Medicine, Bonn, Germany; 2Department of Obstetrics and

Gynecology, American University of Beirut, Beirut, Lebanon;3Department of Medicine, Centre Hospitalier delUniversite de Montreal, Montreal, Canada;4Institute of Transfusion Medicine and Immunohaematology, Frankfurt,Germany;5Saarland University Biosciences Department of Genetics/Epigenetics, Saarbrucken, Germany; 6Department

of Human Genetics and Obstetrics and Gynecology, McGill University Health Center, Montreal, CanadaIn 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 patientsgermline as a result of a false reprogramming

or during the postzygotic development of the conceptuses that led to moles.European Journal of Human Genetics (2005) 13, 486490. doi:10.1038/sj.ejhg.5201353Published online 12 January 2005Keywords: hydatidiform moles; molar pregnancy; methylation analysis; SIRPH; imprintingIntroductionRecurrent complete hydatidiform moles are a rare clinicalentity in which molar tissues are diploids and have abiparental contribution to their genome (BiCHMs). Thesemoles are undistinguishable, at both gross morphologyand histopathology levels, from diploid androgeneticmoles containing two sets of paternal chromosomes.Despite their diploid biparental genotype, the epigenotype

of BiCHMs is abnormal. Others and we demonstratedaberrant methylation and expression of imprinted, bothmaternally or paternally expressed, genes in BiCHMs.13We showed that this aberrant methylation affects only thematernal alleles.3...