Live births in women with recurrent hydatidiform mole and two NLRP7 mutations

Akoury, Elie; Gupta, Neerja; Bagga, Rashmi; Brown, Stephen; Dery, Christine; Kabra, Madhulika; Srinivasan, Radhika; Slim, Rima

doi:10.1016/j.rbmo.2015.03.011

Cited by 41 publications

(49 citation statements)

References 32 publications

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“…24 This difference is statistically significant (two-sided Fisher's exact test, P- value=0.0097). In addition, 5 out of a total of 131 patients (3.8%) with NLRP7 recessive mutations had six live births out of a total of 612 pregnancies, 26 whereas to date, no live births have been reported among the 65 conceptions of patients with two defective KHDC3L alleles. These data suggest that mutations in KHDC3L may be more severe than those in NLRP7 and may not be associated with other forms of reproductive loss or with live births.…”

Section: Discussionmentioning

confidence: 96%

Two novel mutations in the KHDC3L gene in Asian patients with recurrent hydatidiform mole

et al. 2016

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Recurrent hydatidiform mole (RHM) is defined by the occurrence of repeated molar pregnancies in affected women. Two genes, NLRP7 and KHDC3L, play a causal role in RHM and are responsible for 48–80% and 5% of cases, respectively. Here, we report the results of screening these two genes for mutations in one Iranian and one Indian patient with RHM. No mutations in NLRP7 were identified in the two patients. KHDC3L sequencing identified two novel protein-truncating mutations in a homozygous state, a 4-bp deletion, c.17_20delGGTT (p.Arg6Leufs*7), in the Iranian patient and a splice mutation, c.349+1G>A, that affects the invariant donor site at the junction of exon 2 and intron 2 in the Indian patient. To date, only four mutations in KHDC3L have been reported. The identification of two additional mutations provides further evidence for the important role of KHDC3L in the pathophysiology of RHM and increases the diversity of mutations described in Asian populations.

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Section: Discussionmentioning

confidence: 96%

Two novel mutations in the KHDC3L gene in Asian patients with recurrent hydatidiform mole

et al. 2016

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“…25 In recent studies, donor eggs containing intact ooplasm led to successful pregnancies in women with maternal effect variants in NLRP7. 17 Although aberrant NLRP7 protein may be present in the maternal oocyte and ooplasm, PGD is focused on variants in the embryonic genome. Thus, egg donation and PGD are potential facilitators of successful pregnancy.…”

Section: Discussionmentioning

confidence: 99%

“…Available studies have identified homozygous or compoundheterozygous variants in NLRP7 in a total of more than 130 women. Nearly all these women experienced reproductive failure, but single live-births from donated ova and even from spontaneous conceptions have also been reported (for review, Akoury et al 17 ). Besides HM, some of these aberrant pregnancies comprised mosaic aneuploidies.…”

Section: Introductionmentioning

confidence: 99%

Maternal heterozygous NLRP7 variant results in recurrent reproductive failure and imprinting disturbances in the offspring

et al. 2017

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It has been shown previously that homozygous and compound-heterozygous variants affecting protein function in the human NLRP genes impact reproduction and/or fetal imprinting patterns. These variants represent so-called 'maternal effect mutations', that is, although female variant carriers are healthy, they are at risk of reproductive failure, and their offspring may develop aberrant methylation and imprinting disorders. In contrast, the relevance to reproductive failure of maternal heterozygous NLRP7 variants remains unclear. The present report describes the identification of a heterozygous NLRP7 variant in a healthy 28-year-old woman with a history of recurrent reproductive failure, and the molecular findings in two of the deceased offspring. Next-generation sequencing (NGS) for NLRP variants was performed. In the tissues of two offspring (one fetus; one deceased premature neonate) methylation of imprinted loci was tested using methylation-specific assays. Both pregnancies had been characterized by the presence of elevated human chorionic gonadotropin (hCG) levels and ovarian cysts. In the mother, a heterozygous nonsense 2-bp deletion in exon 5 of the NLRP7 gene was identified (NM_001127255.1:c.2010_2011del, p.(Phe671Glnfs*18)). In the two investigated offspring, heterogeneous aberrant methylation patterns were detected at imprinted loci. The present data support the hypothesis that heterozygous NLRP7 variants contribute to reproductive wastage, and that these variants represent autosomal dominant maternal effect variants which lead to aberrant imprinting marks in the offspring. Specific screening and close prenatal monitoring of NLRP7 variant carriers is proposed. Egg donation might facilitate successful pregnancy in heterozygous NLRP7 variant carriers.

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“…This finding was confirmed when assisted reproductive cycles using donated oocytes in 3 patients with recessive NLRP7 mutations resulted in 4 normal offspring. 8 Unfortunately, at present, ovum donation, which is not acceptable in some communities, is probably the most likely way of achieving a normal pregnancy, although a small number of normal pregnancies have been reported in women with FRHM. 8 In addition, Fallahian et al 11 reported a case of 2 sisters with diploid biparental complete moles.…”

Section: Discussionmentioning

confidence: 99%

“…8 Unfortunately, at present, ovum donation, which is not acceptable in some communities, is probably the most likely way of achieving a normal pregnancy, although a small number of normal pregnancies have been reported in women with FRHM. 8 In addition, Fallahian et al 11 reported a case of 2 sisters with diploid biparental complete moles. They have a total of 6 molar pregnancies with no living child.…”

Section: Discussionmentioning

confidence: 99%

A Novel Genetic Mutation in a Patient With Recurrent Biparental Complete Hydatidiform Mole: A Brief Report

Hemida

Doorn

Fisher

2016

Int J Gynecol Cancer

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Recurrent hydatidiform moles are defined by the occurrence of two or more molar pregnancies in the same patient. Familial recurrent hydatidiform moles (FRHM) is a rare autosomal recessive condition where women have an inherited predisposition to have molar pregnancies. Genotyping demonstrated that they are diploid and biparental. We report a case of FRHM from Egypt with a history of 6 recurrent complete moles. Sequencing of the NLPR7 gene revealed a deleterious homozygous base change in exon 2, c.197G>A, which would result in a truncated protein p.W66*. To the best of our knowledge, this mutation has not been described before.

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Live births in women with recurrent hydatidiform mole and two NLRP7 mutations

Cited by 41 publications

References 32 publications

Two novel mutations in the KHDC3L gene in Asian patients with recurrent hydatidiform mole

Two novel mutations in the KHDC3L gene in Asian patients with recurrent hydatidiform mole

Maternal heterozygous NLRP7 variant results in recurrent reproductive failure and imprinting disturbances in the offspring

A Novel Genetic Mutation in a Patient With Recurrent Biparental Complete Hydatidiform Mole: A Brief Report

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