Genetics and Epigenetics of Hydatidiform Moles


A hydatidiform mole (HM) is an abnormal human pregnancy characterised by absence of, or abnormal, embryonic development, excessive trophoblastic proliferation and hydropic degeneration of placental villi. The common types of moles are sporadic, not recurrent, and affect 1 in 1000 pregnancies in western countries. HM may recur in the same patient, which is referred to as recurrent HM (RHM), and indicates that the patient is genetically susceptible to HM. Through the examination of rare familial cases of RHM, two maternal‐effect genes, NLRP7 and KHDC3L, responsible for this condition have been identified. Pathogenic variants in these genes appear to impair imprinting establishment during oogenesis. Herein, we review current knowledge on the genetics and epigenetics of RHM, and highlight the benefits of testing patients for pathogenic variants in the known genes.

Key Concepts

  • RHM from patients with recessive pathogenic variants in NLRP7 or KHDC3L are diploid biparental and originate from a different mechanism than sporadic androgenetic or triploid HM.
  • At the epigenetic level, RHM from patients with recessive pathogenic variants in NLRP7 or KHDC3L lack maternal methylation marks on differentially methylated regions (DMR) and mimic diploid androgenetic CHM, which lack a maternal genome.
  • RHM from patients with recessive pathogenic variants in NLRP7 have defective oocytes and benefit from ovum donation.
  • Diploid biparental HM from patients with pathogenic variants in NLRP7 have an imbalance between embryonic tissue differentiation and trophoblastic proliferation. The same imbalance is also observed in sporadic androgenetic and triploid HM.
  • NLRP7 is part of the innate immune system and its pathogenic variants downregulate inflammation.

Keywords: hydatidiform mole; recurrent hydatidiform mole; NLRP7; KHDC3L; reproductive loss; imprinting; epigenetics; oocyte; trophoblastic proliferation; androgenetic monospermic HM; triploid dispermic HM; ovum donation

Figure 1. Gross morphology of a hydatidiform mole. The photo was taken directly after the evacuation of the HM by curettage and suction. Arrows indicate some vesicles.
Figure 2. Histopathology of complete and partial hydatidiform moles. (a) A microphotograph of a CHM. CV stands for chorionic villi and arrows indicate circumferential trophoblastic proliferation around one chorionic villous. (b) Two chorionic villi displaying important karyorrhexis. The inset shows a higher magnification of karyorrhectic debris (arrows). (c) A microphotograph of a partial hydatidiform mole showing the presence of two populations of chorionic villi, the large hydropic chorionic villi (asterisk) and the small ones. Focal trophoblastic proliferation around one chorionic villous is indicated by arrows. A microphotograph of a different PHM showing foetal membranes in (d) and some skeletal bones of embryonic origin (arrows) in (e). (f) A microphotograph of a PHM showing nucleated red blood cells (arrows) inside a chorionic villous.
Figure 3. NLRP7 protein structure and reported pathogenic variants observed in a recessive state by various groups ( NLRP7 protein has mainly three domains. Protein truncating variants (stop codon, deletions, insertions and invariant splice mutations) are in red and missense variants are in blue. The large deletions that begin before the start codon are indicated by an arrow towards the 5′ untranslated region.
Figure 4. KHDC3L protein structure and reported pathogenic variants in recessive state by various groups. The two pathogenic variants affecting the start codon are indicated by question marks because their consequences on the protein are not known (


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Slim, Rima, Khawajkie, Yassemine, Rahimi, Kurosh, and Sauthier, Philippe(Jan 2017) Genetics and Epigenetics of Hydatidiform Moles. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0026452]