NLRP7 or KHDC3L genes and the etiology of molar pregnancies and recurrent miscarriage

Andreasen, Lotte; Christiansen, O.B.; Niemann, Isa; Bolund, Lars; Sunde, Lone

doi:10.1093/molehr/gat056

Cited by 30 publications

(14 citation statements)

References 36 publications

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“…Two studies (Huang et al, 2013, Messaed et al, 2011 polymorphisms. In contrast, two further studies (Andreasen et al, 2013, Manokhina et al, 2013 identified no disease-causing mutations in NLRP7 in women with RPL and similarly Aghajanova et al (Aghajanova et al, 2015) found no mutations in NLRP7, NLR family, pyrin domain-containing 2 (NLRP2) or KHDC3-like protein, subcortical maternal complex member (KHDC3L) (C6orf221).…”

Section: Recurrent Molar Pregnanciesmentioning

confidence: 97%

“…and C6orf221 mutations in women with RPL (Aghajanova et al, 2015, Andreasen et al, 2013, Manokhina et al, 2013.…”

Section: Recurrent Molar Pregnanciesmentioning

confidence: 99%

“…Studies have explored the role of NLRP2, NLR family, pyrin domain-containing 5 (NLRP5), NLRP7 and C6orf221 in other forms of pregnancy loss such as partial moles, RPL, stillbirth, infertility and multi-locus imprinting disturbance (Aghajanova et al, 2015, Andreasen et al, 2013, Huang et al, 2013, Manokhina et al, 2013, Messaed et al, 2011, Docherty et al, 2015. These have shown conflicting results, many showing no evidence of NLRP7, NLRP2…”

Section: Recurrent Molar Pregnanciesmentioning

confidence: 99%

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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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Section: Recurrent Molar Pregnanciesmentioning

confidence: 97%

“…and C6orf221 mutations in women with RPL (Aghajanova et al, 2015, Andreasen et al, 2013, Manokhina et al, 2013.…”

Section: Recurrent Molar Pregnanciesmentioning

confidence: 99%

Section: Recurrent Molar Pregnanciesmentioning

confidence: 99%

See 1 more Smart Citation

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

Colley

Hamilton

Smith

et al. 2019

Human Reproduction Update

111

View full text Add to dashboard Cite

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“…In addition, a study published in 2017 suggested that the father's occupational profession may be a risk factor in the development of HM. 14,19,[23][24][25][26][27][28] The diagnosis of hydatidiform mole is made by evaluation of beta human chorionic gonadotropin (beta HCG), ultrasonography imaging (USG) and histopathological examination of the abortion or termination material. There is no predictive laboratory test for the early diagnosis of HM.…”

Section: Discussionmentioning

confidence: 99%

Predictivity of inflammatory cell counts in early diagnosis of hydatidiform mole

Eroğlu

Adalı

2019

Int J Res Med Sci

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Background: Hydatidiform mole (HM) is the most frequently encountered disease among gestational trophoblastic diseases. HM can invade myometrium and result in hysterectomy and because of the absence of any predictive method, the disease can be lately diagnosed in the periphery. Author aimed to evaluate predictive value of the inflammatory cell counts in molar pregnancies in this study.Methods: Nineteen (19) cases with histopathologic HM diagnosis and 19 cases of control group with pregnancy termination or abortion material reached to a university hospital's pathology department on the same day were included in the study. The data on the same day or the day before the operation was used as the hemogram data.Results: The mean age of the cases were 33.84±8.477. The mean of neutrophil, lymphocyte, monocyte, basophil and eosinophil numbers of the HM group and control group were compared in the 95% confidence interval with the independent t test. No statistical significance was observed in any of the inflammatory cell means (p>0.05). The ratio of lymphocyte means was statistically significant (p=0.006).Conclusions: In this study, author assessed whether the inflammatory cell counts were a predictive in detecting HM. The statistically significant results that author founded in the means of lymphocyte, suggests that this finding may be predictive of early diagnosis. They concluded that this result can be routinely used after the confirmation of the results in larger series of cases.

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“…Recent studies of patients with familial recurrent hydatidiform moles identified 2 candidate genes called NLRP7 and KHDC3L that are located on chromosome 19 and 6, respectively. [ 19 , 20 ] To date, approximately 50 NLRP7 mutations and 4 KHDC3L mutations have been uncovered in familial molar pregnancy patients in either homozygous or compound heterozygous fashion. [ 21 ] The cytoplasmic NLRP7 protein is a member of the CATERPILLER protein family with implications in inflammation, apoptosis and innate immunity.…”

Section: Discussionmentioning

confidence: 99%

Hepatic toxicity following actinomycin D chemotherapy in treatment of familial gestational trophoblastic neoplasia

Yin²,

Wang³

et al. 2018

Medicine

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Rationale:Familial hydatidiform mole is extremely rare while familial gestational trophoblastic neoplasia (GTN) has never been reported. Inspired by 2 biological sisters with postmolar GTN and liver toxicity, we reviewed susceptible maternal-effect genes and explored the role of possible drug transporter genes in the development of GTN.Patient concerns:We reported one Chinese family where the two sisters developed postmolar GTN while experiencing fast remission and significant hepatic toxicity from actinomycin D chemotherapy.Diagnoses:The index pregnancy was diagnosed with curettage. The following GTN was confirmed when there was a rise in beta-hCG for three consecutive weekly measurements over at least a period of 2 weeks. Computed tomography was used to identify lung metastasis. The elder sister was diagnosed with gestational trophoblastic neoplasia (III: 2) while the younger sister was diagnosed as III: 3 according to WHO scoring system.Interventions:Patients were treated with actinomycin D of 10 μg/kg intravenously for 5 days every 2 weeks. When hepatic toxicity was indicated, polyene phosphatidyl choline and magnesium isoglycyrrhizinate were prescribed.Outcomes:Both patients responded extremely well to the 5-day actinomycin D regimen. Beta-hCG remained less than 2 mIU/ml after 5 cycles while computed tomography scan showed downsized pulmonary nodules. Both experienced significant rise in ALT and AST levels that could be ameliorated with corresponding medication. Monthly followed-up showed negative beta-hCG levels and normal liver enzyme levels.Lessons:We speculated that the known or unknown NLRP7 and KHDC3L mutations might be correlated with drug disposition in liver while liver drug transporters such as P-glycoprotein family that are also expressed in trophoblasts might be correlated to GTN susceptibility. Future genomic profiles of large samples alike using next generation sequencing are needed to confirm our hypothesis and discover yet unknown genes.

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NLRP7 or KHDC3L genes and the etiology of molar pregnancies and recurrent miscarriage

Cited by 30 publications

References 36 publications

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

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

Predictivity of inflammatory cell counts in early diagnosis of hydatidiform mole

Hepatic toxicity following actinomycin D chemotherapy in treatment of familial gestational trophoblastic neoplasia

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