Recurrent hydatidiform mole: detection of two novel mutations in the NLRP7 gene in two Egyptian families

Abdalla, Ebtesam; Hayward, Bruce E.; Shamseddin, Ahmed; Nawar, Mona M.

doi:10.1016/j.ejogrb.2012.06.017

Cited by 9 publications

(4 citation statements)

References 26 publications

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“…The mutations segregated in the studied families and each patient had two defective alleles, each inherited from one parent as expected for an autosomal recessive disease. Later, others and we confirmed the causality of NLRP7 mutations in patients from different populations (54, 60, 63, 66, 67, 69, 71, 72), demonstrating that NLRP7 is a major gene for RHMs. To date, approximately 42 different mutations have been reported in patients with two defective alleles (Figure 3) (73) Of these mutations, 65% are protein-truncating (stop codon, splice mutations, small insertions and deletions, and large rearrangements) and 35% are missense mutations, which are, respectively, higher and lower than the frequencies of these two categories of mutations observed in all human diseases, 56 and 44% ().…”

Section: Lessons From Studying Extreme Phenotypessupporting

confidence: 66%

“…Consequently, we and others believed that the familial form of moles was extremely rare. However, this was not true and approximately 30 new familial cases have been reported since 1999 (47, 53–69) indicating that familial RHMs are not extremely rare as originally believed, but were probably under-reported. In addition, about 88 singleton cases of RHMs have been described since 1999.…”

Section: The Importance Of Crossing Our Disciplinementioning

confidence: 93%

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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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Section: Lessons From Studying Extreme Phenotypessupporting

confidence: 66%

Section: The Importance Of Crossing Our Disciplinementioning

confidence: 93%

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

Slim

Wallace

2013

Front. Immunol.

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“…One study (Parry et al, 2011) identified biallelic mutations in chromosome 6 open reading frame 221 (C6orf221) in three consanguineous families with familial biparental HM. Three studies (Abdalla et al, 2012, Brown et al, 2013, Ulker et al, 2013 reported case studies of an individual consanguineous family, two non-consanguineous families and two consanguineous families with RHM.…”

Section: Recurrent Molar Pregnanciesmentioning

confidence: 99%

Potential genetic causes of miscarriage in euploid pregnancies: a systematic review

Colley

Hamilton

Smith

et al. 2019

Human Reproduction Update

111

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BACKGROUND Approximately 50% of pregnancy losses are caused by chromosomal abnormalities, such as aneuploidy. The remainder has an apparent euploid karyotype, but it is plausible that there are cases of pregnancy loss with other genetic aberrations that are not currently routinely detected. Studies investigating the use of exome sequencing and chromosomal microarrays in structurally abnormal pregnancies and developmental disorders have demonstrated their clinical application and/or potential utility in these groups of patients. Similarly, there have been several studies that have sought to identify genes that are potentially causative of, or associated with, spontaneous pregnancy loss, but the evidence has not yet been synthesized. OBJECTIVE AND RATIONALE The objective was to identify studies that have recorded monogenic genetic contributions to pregnancy loss in euploid pregnancies, establish evidence for genetic causes of pregnancy loss, identify the limitations of current evidence, and make recommendations for future studies. This evidence is important in considering additional research into Mendelian causes of pregnancy loss and appropriate genetic investigations for couples experiencing recurrent pregnancy loss. SEARCH METHODS A systematic review was conducted in MEDLINE (1946 to May 2018) and Embase (1974 to May 2018). The search terms ‘spontaneous abortion’, ‘miscarriage’, ‘pregnancy loss’, or ‘lethal’ were used to identify pregnancy loss terms. These were combined with search terms to identify the genetic contribution including ‘exome’, ‘human genome’, ‘sequencing analysis’, ‘sequencing’, ‘copy number variation’, ‘single-nucleotide polymorphism’, ‘microarray analysis’, and ‘comparative genomic hybridization’. Studies were limited to pregnancy loss up to 20 weeks in humans and excluded if the genetic content included genes that are not lethal in utero, PGD studies, infertility studies, expression studies, aneuploidy with no recurrence risk, methodologies where there is no clinical relevance, and complex genetic studies. The quality of the studies was assessed using a modified version of the Newcastle–Ottawa scale. OUTCOMES A total of 50 studies were identified and categorized into three themes: whole-exome sequencing studies; copy number variation studies; and other studies related to pregnancy loss including recurrent molar pregnancies, epigenetics, and mitochondrial DNA aberrations. Putatively causative variants were found in a range of genes, including CHRNA1 (cholinergic receptor, nicotinic, alpha polypeptide 1), DYNC2H1 (dynein, cytoplasmic 2, heavy chain 1), and RYR1 (ryanodine receptor 1), which were identified in multiple studies. Copy number variants were also identified to have a causal or associated link with recurrent miscarriage. WIDER IMPLICATIONS Identification of genes that are causative of or predisposing to pregnancy loss will be of significant individual patient impact with respect to counselling and treatment. In addition, knowledge of specific genes that contribute to pregnancy loss could also be of importance in designing a diagnostic sequencing panel for patients with recurrent pregnancy loss and also in understanding the biological pathways that can cause pregnancy loss.

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“…NLRP7 and KHDC3L have been identified from familial recurrent HMs (RHM) as two main pathogenic genes. NLRP7 (NACHT, leucine-rich repeating and PYD containing 7) has been identified in 48-80% of RHM patients among different populations [2][3][4] and KHDC3L (also known as c6orf221) is mutated in 10-14% of RHM patients with no NLRP7 mutation [5,6].…”

Section: Introductionmentioning

confidence: 99%

Abnormal processing of IL-1β in NLRP7-mutated monocytes in hydatidiform mole patients

Zhang

Zhu

et al. 2020

Clinical and Experimental Immunology

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Summary NOD‐like receptor pyrin 7 (NLRP7) has been identified as the major gene responsible for the recurrent hydatidiform mole (RHM). The immunological role of NLRP7 mutation in HM patients has not been conclusively demonstrated. Hence, we aim to demonstrate this role in our study. We followed 12 new patients with NLRP7 non‐synonymous variations (NSVs) from date to date. Peripheral blood mononuclear cells (PBMCs) were collected separately from patients with and without NLRP7 mutation. Supernatant interleukin (IL)‐1β secretion, intracellular pro‐IL‐1β and mature IL‐1β expressions were measured after 24 h lipopolysaccharide (LPS) stimulation. Plasmids with corresponding NSVs were generated to evaluate the ability of processing pro‐IL‐1β into mature IL‐1β in vitro. Homozygous or compound heterozygous NLRP7 mutations secreted less IL‐1β in roots of abnormal intracellular pro‐IL‐1β or mature IL‐1β, according to different domains. Plasmids with NSVs could also affect processing or/and trafficking together with caspase‐1 and apoptosis‐associated speck‐like protein (ASC). Inflammasome‐related NLRP7 mutation is a potential mechanism of RHM.

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Recurrent hydatidiform mole: detection of two novel mutations in the NLRP7 gene in two Egyptian families

Cited by 9 publications

References 26 publications

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

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

Potential genetic causes of miscarriage in euploid pregnancies: a systematic review

Abnormal processing of IL-1β in NLRP7-mutated monocytes in hydatidiform mole patients

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