The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients

Abstract

Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. We compared three parameters of genetic susceptibility in patients with and without mutations and show that patients without mutations are mostly from non-familial cases, have fewer reproductive losses, and more live births. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles. Categorizing these patients according to the genotypic types of their recurrent hydatidiform moles may facilitate the identification of novel genes for this entity.

Molar and nonmolar triploidy: Recurrence or bad luck

“…This was a case of bad luck rather than recurrence; therefore, she did not require completion of serial beta‐hCG monitoring and did not need to avoid pregnancy. In addition, we could reassure her that her risk of a recurrent molar pregnancy was low, 0.6%‐2% after one molar pregnancy, compared to 15% after 2 consecutive molar pregnancies due to mutations such as NLRP7 and KHDC3L . In her subsequent pregnancy, the patient's luck finally changed as she went on to have a normal pregnancy and liveborn.…”

Causative Mutations and Mechanism of Androgenetic Hydatidiform Moles

“…Sections of formalin-fixed, paraffin-embedded (FFPE) tissues were prepared for H&E staining, p57 KIP2 immunohistochemistry, flow cytometry, and microsatellite genotyping as previously described. 13 Microarray analysis search for aneuploidies in products of conception of affected women was performed at Invitae as previously described. 25 Mice Mei1 heterozygous mice (B6.129S1-Mei1m1Jcs/Mmnc) 26…”

“…Bi-allelic mutations in these two genes explain the etiology of RHMs in 60% of affected women. 13 Recurrent molar tissues from women with bi-allelic mutations in the two known genes are all diploid biparental while those from women without mutations are heterogeneous. Among women with no recessive mutations in the known genes, a minority of women have diploid biparental RHMs, half of the remaining women have triploid dispermic PHMs, and the second half have androgenetic monospermic CHMs.…”

“…Among women with no recessive mutations in the known genes, a minority of women have diploid biparental RHMs, half of the remaining women have triploid dispermic PHMs, and the second half have androgenetic monospermic CHMs. 13 Available data on women with diploid androgenetic monospermic RHMs indicate that 17%-37% of them fail to have live births, suggesting that these women may have a strong genetic defect underlying their RHMs. 13,14 To identify mutations responsible for RHMs, we performed whole-exome sequencing (WES) on a total of 65 women with RHMs (including all histopathological and genotypic types), miscarriages, and infertility, who were negative for mutations in NLRP7 and KHDC3L.…”

“…13 Available data on women with diploid androgenetic monospermic RHMs indicate that 17%-37% of them fail to have live births, suggesting that these women may have a strong genetic defect underlying their RHMs. 13,14 To identify mutations responsible for RHMs, we performed whole-exome sequencing (WES) on a total of 65 women with RHMs (including all histopathological and genotypic types), miscarriages, and infertility, who were negative for mutations in NLRP7 and KHDC3L. We identified bi-allelic deleterious mutations in meiotic double-stranded break formation protein 1 (MEI1) (MIM: 608797), type 2 DNA topoisomerase 6 subunit B-like (TOP6BL/C11orf80) (MIM: 616109), and REC114 meiotic recombination (REC114) genes in five unrelated women, of which two had other family members with recurrent miscarriages and infertility.…”