Maternal NLRP7 and C6orf221 variants are not a common risk factor for androgenetic moles, triploidy and recurrent miscarriage

Abstract

Maternal effect genes control early events of embryogenesis. Maternal homozygous and compound mutations in two such genes, NLRP7 and c6orf221, have been detected in the majority of women experiencing recurrent biparental hydatidiform moles. It was suggested that other forms of reproductive wastage, including diploid androgenetic moles, partial moles, polyploidy, recurrent spontaneous abortions and stillbirths of uncertain etiology, may be caused by NLRP7 or c6orf221 mutations in the mother. To elucidate which subpopulations of women with adverse reproductive outcomes should be screened for NLRP7/C6orf221 variants, we sequenced coding sequence and exon/intron boundaries of NLRP7 and C6orf221 in a well-defined group of 17 women with recurrent miscarriage and additional triploidy or complete hydatidiform moles. The major findings for this group were non-synonymous variants of NLRP7, rather than clearly pathogenic mutations. To assess the role of these variants, we genotyped them in a larger group including women with primary recurrent miscarriage (n = 39), paternal triploid conceptions (n = 22) and women with proven fertility after age 37 and no prior history of miscarriage or pregnancy complications (n = 52). No associations between non-synonymous NLRP7 variants and primary recurrent miscarriage or partial hydatidiform molar pregnancies were detected. Our findings suggest that neither mutations nor variants in NLRP7 and C6orf221 are major factors contributing to the risk of these types of pregnancy complications. Further studies in larger groups of patients and controls are needed to specify the impact of NLRP7 rare non-synonymous variants on genetic susceptibility to recurrent reproductive wastage.

NLRP7 and the Genetics of Hydatidiform Moles: Recent Advances and New Challenges

“…To date, a total of 17 rare NSVs, 16 missenses, and one nonsense, have been observed in heterozygous state in a total of 24 patients but not in controls (67, 85–89) (Figure 3). Some of these NSVs were later found in the 1000 Genomes database but at very low frequencies.…”

“…However, this is not the case for HM tissues from patients with single heterozygous rare NLRP7 variants. In this category of patients, few HM tissues were genotyped; some were found to be diploid androgenetic monospermic (67, 85, 87, 89) and others were found to be triploid diandric dispermic (102). The reason for this difference is not yet clear and needs to be addressed in future studies.…”

Genetics and Epigenetics of Recurrent Hydatidiform Moles: Basic Science and Genetic Counselling

“…In addition to these mutations, two protein-truncating mutations, a stop codon, L823X [21], and a deletion of 60-kb extending from intron 8 of NLRP7 to intron 11 of NLRP2 [26] and approximately 17 missenses have also been seen as single heterozygous mutations or variants in patients with recurrent and sporadic moles (Fig. 1a) [26–31]. However, the pathological significance of these single mutations or variants is still the subject of debate, and more data are needed to reach a conclusion on their potential involvement in the causation or genetic susceptibility for moles.…”

Aspectos genéticos de la mola hidatidiforme

“…Su asociación con molas androgenéticas, triploidía, abortos y óbitos de etiología desconocida, es controversial 19 . Un segundo gen con efecto materno, el KHDC3L, ha sido asociado con MR 20 .…”