Mutations in<i>NLRP7</i>are associated with diploid biparental hydatidiform moles, but not androgenetic complete moles

Dixon, Peter H.; Trongwongsa, Pirada; Abu-Hayyah, Shadi; Ng, Sze Hwei; Akbar, Syed Ali; Khawaja, Nuzhat Parveen; Seckl, Michael J.; Savage, Philip; Fisher, Rosemary A.

doi:10.1136/jmedgenet-2011-100602

Cited by 39 publications

(29 citation statements)

References 32 publications

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“…Homozygous and compound heterozygous mutations in this gene have been identified as a major cause of recurrent biparental hydatidiform mole pregnancies, but also stillbirths and spontaneous abortions were frequently reported, while live births are extremely rare ([14-19] and others). Heterozygous mutation carriers were also described, but reports on reproductive outcomes vary [18,20-22].…”

Section: Introductionmentioning

confidence: 99%

Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects

et al. 2013

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NLRP7 is a maternal effect gene as maternal mutations in this gene cause recurrent hydatidiform moles, spontaneous abortions and stillbirths, whereas live births are very rare. We have studied a patient with multiple anomalies born to a mother with a heterozygous NLRP7 mutation. By array-based CpG methylation analysis of blood DNA from the patient, his parents and 18 normal controls on Illumina Infinium HumanMethylation27 BeadChips we found that the patient had methylation changes (delta ß ≥ 0.3) at many imprinted loci as well as at 87 CpGs associated with 85 genes of unknown imprinting status. Using a pseudoproband (permutation) approach, we found methylation changes at only 7-24 CpGs (mean 15; standard deviation 4.84) in the controls. Thus, the number of abberantly methylated CpGs in the patient is more than 14 standard deviations higher. In order to identify novel imprinted genes among the 85 conspicuous genes in the patient, we selected 19 (mainly hypomethylated) genes for deep bisulfite amplicon sequencing on the ROCHE/454 Genome Sequencer in the patient and at least two additional controls. These controls had not been included in the array analysis and were heterozygous for a single nucleotide polymorphism at the test locus, so that allele-specific DNA methylation patterns could be determined. Apart from FAM50B, which we proved to be imprinted in blood, we did not observe allele-specific DNA methylation at the other 18 loci. We conclude that the patient does not only have methylation defects at imprinted loci but (at least in blood) also an excess of methylation changes at apparently non-imprinted loci.

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Section: Introductionmentioning

confidence: 99%

Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects

et al. 2013

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“…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.…”

Section: Significance Of Rare Nlrp7 Nsvs Found In Heterozygous State mentioning

confidence: 99%

“…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.…”

Section: Genotype Of Hm Tissues In Patients With Nlrp7 Mutationsmentioning

confidence: 99%

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

Slim

Wallace

2013

Front. Immunol.

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NOD-like receptor proteins (NLRPs) are emerging key players in several inflammatory pathways in Mammals. The first identified gene coding for a protein from this family is Nlrp5 and was originally called Mater for “Maternal Antigen That Mouse Embryos Require” for normal development beyond the two-cell stage. This important discovery was followed by the identification of other NLRPs playing roles in inflammatory disorders and of the first maternal-effect gene in humans, NLRP7, which is responsible for an aberrant form of human pregnancy called hydatidiform mole (HM). In this review, we recapitulate the various aspects of the pathology of HM, highlight recent advances regarding NLRP7 and its role in HM and related forms of reproductive losses, and expand our discussion to other NLRPs with a special emphasis on those with known roles in mammalian reproduction. Our aim is to facilitate the genetic complexity of recurrent fetal loss in humans and encourage interdisciplinary collaborations in the fields of NLRPs and reproductive loss.

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“…Detailed homozygosity mapping and gene mutation screening in these settings has identified two causative loci, 19q13.4 and 6q13—chromosomal regions which contain NLRP7 and KHDC3L, respectively [4]. Of note, approximately 70% of women affected by familial recurrent HM have autosomal recessive mutations of NLRP7 [5]. Compelling evidence that an abnormal oocyte is responsible for the pathophysiology of recurrent HM is provided from observations that in vitro fertilization (IVF) cycles using donated oocytes for women with NLRP7 mutations result in normal offspring [6].…”

Section: Introductionmentioning

confidence: 99%

Pathogenic variant in NLRP7 (19q13.42) associated with recurrent gestational trophoblastic disease: Data from early embryo development observed during in vitro fertilization

Sills

Obregón-Tito²,

Gao³

et al. 2017

Clin Exp Reprod Med

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ObjectiveTo describe in vitro development of human embryos derived from an individual with a homozygous pathogenic variant in NLRP7 (19q13.42) and recurrent hydatidiform mole (HM), an autosomal recessive condition thought to occur secondary to an oocyte defect.MethodsA patient with five consecutive HM pregnancies was genomically evaluated via next generation sequencing followed by controlled ovarian hyperstimulation, in vitro fertilization (IVF) with intracytoplasmic sperm injection, embryo culture, and preimplantation genetic screening. Findings in NLRP7 were recorded and embryo culture and biopsy data were tabulated as a function of parental origin for any identified ploidy error.ResultsThe patient was found to have a pathogenic variant in NLRP7 (c.2810+2T>G) in a homozygous state. Fifteen oocytes were retrieved and 10 embryos were available after fertilization via intracytoplasmic sperm injection. Developmental arrest was noted for all 10 embryos after 144 hours in culture, thus no transfer was possible. These non-viable embryos were evaluated by karyomapping and all were diploid biparental; two were euploid and eight had various aneuploidies all of maternal origin.ConclusionThis is the first report of early human embryo development from a patient with any NLRP7 mutation. The pathogenic variant identified here resulted in global developmental arrest at or before blastocyst stage. Standard IVF should therefore be discouraged for such patients, who instead need to consider oocyte (or embryo) donation with IVF as preferred clinical methods to treat infertility.

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Mutations inNLRP7are associated with diploid biparental hydatidiform moles, but not androgenetic complete moles

Abstract: NLRP7 mutations do not represent a major cause of AnCHM.

Cited by 39 publications

References 32 publications

Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects

Deep Bisulfite Sequencing of Aberrantly Methylated Loci in a Patient with Multiple Methylation Defects

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

Pathogenic variant in NLRP7 (19q13.42) associated with recurrent gestational trophoblastic disease: Data from early embryo development observed during in vitro fertilization

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