The genetics of recurrent hydatidiform moles in China: correlations between NLRP7 mutations, molar genotypes and reproductive outcomes

Abstract

Hydatidiform mole (HM) is a human pregnancy with abnormal embryonic development. NLRP7 is a major autosomal recessive gene responsible for recurrent molar pregnancies and associated reproductive wastage in patients from several populations. Here, we report NLRP7 mutation analysis in 35 unrelated Chinese patients with recurrent reproductive wastage, including at least one HM. We describe three new protein-truncating mutations in NLRP7 and show the presence of three founder mutations in China and Asian populations. We determined the parental contribution to six molar tissues and show the occurrence of three diploid androgenetic moles in patients with one defective allele, while three diploid biparental moles occurred in patients with two defective alleles. We document the failure of pregnancies after assisted reproductive technologies (ARTs) in three patients with two defective alleles each and a successful pregnancy in one of two patients with one defective allele. Our data suggest that patients with a single defective allele have better reproductive outcomes than patients with two defective alleles, and some of them may benefit from ART.

NLRP7 Mutation Analysis in Sporadic Hydatidiform Moles in Tunisian Patients: NLRP7 and Sporadic Mole

“…All these data reflect the notion that the impact of genetic defects due to a single mutated NLRP7 allele may be modulated by environmental and other genetic factors and consequently, they are not always associated with reproductive wastage for all patients and do not impede all of their pregnancies. 33 Our findings add further insight to the hypothesis that NLRP7 heterozygosity may be involved in the development of sporadic molar pregnancies, either complete or partial moles, associated or not with other forms of reproductive failure. We also suggest a comparison of the status of DNA methylation on imprinted genes between cases of sporadic HM with heterozygous NLRP7 mutations and other cases with no mutation.…”

“…Previous reported cases were from patients of various ethnic origins who were either homozygous or compound heterozygous for NLRP7 mutations; however, cases of patients with 1 NLRP7 defective allele have been rarely reported (Table). 26,28,33,34 We found that 3 mutation carriers had CHM and 2 had PHM. Exhaustive histologic criteria were used by 2 experienced pathologists to classify these cases.…”

“…They felt that the data provided in the study of Qian et al 39 (1 stillbirth and 2 miscarriages among 46 pregnancies to carrier women) were not sufficient to support their claim that NLRP7 heterozygosity has adverse reproductive implications, since they reported that there was no reproductive wastage in heterozygous relatives of their patients. In their recent study, Qian et al 33 reported new cases of patients with 1 NLRP7 defective allele who have had recurrent reproductive wastages (Table), and they suggested that some, but not all, heterozygous NLRP7 mutations are associated with reproductive wastage. Messaed et al 34 found that patients with 1 identified defective allele are most likely to have better reproductive outcomes than patients with 2 mutated alleles, who are at higher risk for recurrent molar pregnancies than for sporadic moles.…”

Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7

“…NLRP7 is mutated in 88% and 60% of analyzed familial and singleton cases of RHMs, respectively. [9][10][11][12][13][14] Recently, we demonstrated that ex vivo lipopolysaccharides (LPS)-stimulated peripheral blood mononuclear cells (PBMCs) from patients with mutations and rare variants in NLRP7 have defective interleukin-1 beta (IL-1b) and tumor necrosis factor secretion but normal to higher intracellular levels of pro-and mature-IL-1b. 13,15 The requirement of NLRP7 for normal IL-1b secretion by macrophages was also confirmed in in vitro studies after NLRP7 silencing using small interfering RNA (siRNA).…”

The subcortical maternal complex: multiple functions for one biological structure?

“…Both genes were repeatedly seen to be responsible for recurrent hydatidiform moles (RHMs) [54][55][56][57][58][59][60][61]. Despite being diploid biparental, therefore with a normal biparental contribution to their genomes, RHM tissues lack maternal methylation marks on several maternally imprinted genes.…”