Biallelic
 NLRP7
 variants in patients with recurrent hydatidiform mole: A review and expert consensus

Slim, Rima; Fisher, Rosemary A.; Milhavet, Florian; Hemida, Reda; Rojas, Samantha K.; Rittore, Cécile; Bagga, Rashmi; Aguinaga, Mónica; Touitou, Isabelle

doi:10.1002/humu.24439

Cited by 11 publications

(11 citation statements)

References 70 publications

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“…According to the literature, most of the cases have different genetic variations and frequent mutations that can be called a hotspot have not been identified [ 15 ]. To date, 275 variants have been identified in the NLRP7 gene, the majority of which consist of benign, likely benign, silent or unclassified deep intronic variants [ 16 ]. Two of the three cases in our series have the same variant and there was no consanguinity between them.…”

Section: Discussionmentioning

confidence: 99%

High Risk of Gestational Trophoblastic Neoplasia Development in Recurrent Hydatidiform Moles with NLRP7 Pathogenic Variations

Kocabey

Gülhan

Koç

et al. 2022

Balkan Journal of Medical Genetics

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Objective Pathogenic variations of the NLRP7 and KHDC3L genes are responsible for familial recurrent hydatidiform moles, a rare autosomal recessive phenomenon that can lead to severe comorbidities. Little is known about the diversity of genetic defects or the natural course of disease progression among recurrent hydatidiform mole cases from distinct ethnicities. In this study, we aimed to investigate the mutation profile and pregnancy outcomes in patients with multiple molar pregnancies. Material and Methods Three unrelated cases with recurrent molar pregnancies are included in this study. None of the patients had a known family history of molar pregnancy. Clinical findings and follow-up results are documented. Sanger sequencing is used to reveal genetic defects in exons and exon-intron boundaries of NLRP7 and KHDC3L genes. Results NLRP7 pathogenic variants were found in all three cases. In two cases, homozygous, c.2471+1G>A canonical splice cite variant was identified and in one case a homozygous, c.2571dupC (p.Ile858HisfsTer11) frameshift variant was identified. No variant in the KHDC3L gene was found in any case. In all cases, the development of gestational trophoblastic neoplasia complicated the clinical course and the treatment plans. Conclusions We found that defects of the NLRP7 gene are principally responsible for etiology in our region, and the mutation profile suggests a founder effect in the Turkish population. We suggest early genetic diagnosis and counseling in molar pregnancies and recommend close follow-up in terms of conversion to gestational trophoblastic neoplasia.

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Section: Discussionmentioning

confidence: 99%

High Risk of Gestational Trophoblastic Neoplasia Development in Recurrent Hydatidiform Moles with NLRP7 Pathogenic Variations

Kocabey

Gülhan

Koç

et al. 2022

Balkan Journal of Medical Genetics

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“…Diploid and biparental HMs suggest a diagnosis of familial recurrent HM (FRHM), an autosomal recessive condition predisposing women to recurrent molar pregnancies. Sequencing of the gene NLRP7 , using DNA extracted from the patient’s blood, showed the patient to be homozygous for p.Pro716Ala, a pathogenic variant frequently found in patients with FRHM [18].…”

Section: Section 3: When a Patient Has Recurrent Molar Pregnanciesmentioning

confidence: 99%

When to Consult a Geneticist Specialising in Gestational Trophoblastic Disease

McMahon¹,

Maher²,

Joyce³

et al. 2023

Gynecol Obstet Invest

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Background: Gestational trophoblastic disease comprises hydatidiform moles and a rare group of malignancies that derive from trophoblasts. Although there are typical morphological features that may distinguish hydatidiform moles from non-molar products of conception, such features are not always present, especially at early stages of pregnancy. Furthermore, mosaic/chimeric pregnancies and twin pregnancies make pathological diagnosis challenging while trophoblastic tumours can also pose diagnostic problems in terms of their gestational or non-gestational origin. Objectives: The aim of this study was to show that ancillary genetic testing can be used to aid diagnosis and clinical management of GTD. Methods: Each author identified cases where genetic testing, including short tandem repeat (STR) genotyping, ploidy analysis, next-generation sequencing, and immunostaining for p57, the product of the imprinted gene CDKN1C, facilitated accurate diagnosis and improved patient management. Representative cases were chosen to illustrate the value of ancillary genetic testing in different scenarios. Outcome: Genetic analysis of placental tissue can aid in determining the risk of developing gestational trophoblastic neoplasia, facilitating discrimination between low risk triploid (partial) and high risk androgenetic (complete) moles, discriminating between a hydatidiform mole twinned with a normal conceptus and a triploid conception and identification of androgenetic/biparental diploid mosaicism/chimerism. STR genotyping of placental tissue and targeted gene sequencing of patients can identify women with an inherited predisposition to recurrent molar pregnancies. Genotyping can distinguish gestational from non-gestational trophoblastic tumours using tissue or circulating tumour DNA and can also identify the causative pregnancy which is the key prognostic factor for placental site and epithelioid trophoblastic tumours. Conclusions and Outlook: STR genotyping and p57 immunostaining have been invaluable to the management of gestational trophoblastic disease in many situations. The use of next-generation sequencing and of liquid biopsies is opening up new pathways for GTD diagnostics. Development of these techniques has the potential to identify novel biomarkers of GTD and further refine diagnosis.

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“…In the second case, a fertilization error occurs: one enucleate oocyte is fertilized by two genetically normal sperms or by a diploid sperm (resulting from an error of male meiosis-diandry) (Figure 1). Another possible mechanism concerns an error of fertilization-dispermia-with the formation of a triploid embryo, followed by the loss of maternal genetic material [20]. In 15-25% of complete hydatidiform moles, the mechanism is dispermia [14].…”

Section: Genetic Particularities Of the Complete Hydatidiform Molementioning

confidence: 99%

“…Other genetic changes implied in complete hydatidiform moles are the presence of a maternal mutation that affects imprinting in the offspring. In this situation, the genetic material has a biparental origin, with a normal 46,XX or 46,XY karyotype [20].…”

Section: Genetic Particularities Of the Complete Hydatidiform Molementioning

confidence: 99%

Hydatidiform Mole—Between Chromosomal Abnormality, Uniparental Disomy and Monogenic Variants: A Narrative Review

Florea,

Caba,

Grigore

et al. 2023

Life

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A hydatidiform mole (HM) or molar pregnancy is the most common benign form of gestational trophoblastic disease characterized by a proliferation of the trophoblastic epithelium and villous edema. Hydatidiform moles are classified into two forms: complete and partial hydatidiform moles. These two types of HM present morphologic, histopathologic and cytogenetic differences. Usually, hydatidiform moles are a unique event, but some women present a recurrent form of complete hydatidiform moles that can be sporadic or familial. The appearance of hydatidiform moles is correlated with some genetic events (like uniparental disomy, triploidy or diandry) specific to meiosis and is the first step of embryo development. The familial forms are determined by variants in some genes, with NLRP7 and KHDC3L being the most important ones. The identification of different types of hydatidiform moles and their subsequent mechanisms is important to calculate the recurrence risk and estimate the method of progression to a malign form. This review synthesizes the heterogeneous mechanisms and their implications in genetic counseling.

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Biallelic NLRP7 variants in patients with recurrent hydatidiform mole: A review and expert consensus

Cited by 11 publications

References 70 publications

High Risk of Gestational Trophoblastic Neoplasia Development in Recurrent Hydatidiform Moles with NLRP7 Pathogenic Variations

High Risk of Gestational Trophoblastic Neoplasia Development in Recurrent Hydatidiform Moles with NLRP7 Pathogenic Variations

When to Consult a Geneticist Specialising in Gestational Trophoblastic Disease

Hydatidiform Mole—Between Chromosomal Abnormality, Uniparental Disomy and Monogenic Variants: A Narrative Review

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