Familial recurrent hydatidiform mole (RHM) is a maternal-effect autosomal recessive disorder
usually associated with mutations of the NLRP7 gene. It is characterized by HM with
excessive trophoblastic proliferation, which mimics the appearance of androgenetic molar
conceptuses despite their diploid biparental constitution. It has been proposed that the phenotypes
of both types of mole are associated with aberrant genomic imprinting. However no
systematic analyses for imprinting defects have been reported. Here, we present the
genome-wide methylation profiles of both spontaneous androgenetic and biparental NLRP7
defective molar tissues. We observe total paternalization of all ubiquitous and placentaspecific
differentially methylated regions (DMRs) in four androgenetic moles; namely gain of
methylation at paternally methylated loci and absence of methylation at maternally methylated
regions. The methylation defects observed in five RHM biopsies from NLRP7 defective
patients are restricted to lack-of-methylation at maternal DMRs. Surprisingly RHMs from
two sisters with the same missense mutations, as well as consecutive RHMs from one
affected female show subtle allelic methylation differences, suggesting inter-RHM variation.
These epigenotypes are consistent with NLRP7 being a maternal-effect gene and involved
in imprint acquisition in the oocyte. In addition, bioinformatic screening of the resulting methylation datasets identified over sixty loci with methylation profiles consistent with
imprinting in the placenta, of which we confirm 22 as novel maternally methylated loci.
These observations strongly suggest that the molar phenotypes are due to defective placenta-specific
imprinting and over-expression of paternally expressed transcripts, highlighting
that maternal-effect mutations of NLRP7 are associated with the most severe form of
multi-locus imprinting defects in humans.