NLRP7 – Complete Hydatidiform Mole

Complete hydatidiform mole (CHM) is characterized by hyperproliferative vesicular trophoblasts without embryonic development, typically androgenetic and sporadic, but recurrent biparental CHM (BiCHM) arises due to maternal-effect mutations ([PMID:18039680]). Patients with recurrent hydatidiform mole (RHM) exhibit a biparental diploid genome and aberrant methylation at imprinted loci.

NLRP7 encodes a pyrin domain-containing NLR family member expressed in oocytes and early embryonic tissues. Autosomal recessive maternal-effect variants in NLRP7 underlie BiCHM; compound-heterozygous alleles were first reported in a family with RHM (c.1720dup (p.Cys574LeufsTer4)) in a mother and her brother, both carriers ([PMID:33252287]).

Genetic studies in diverse cohorts have identified biallelic NLRP7 variants in ≥32 unrelated RHM patients, including truncating indels, missense substitutions, splice-site changes and founder intragenic duplications across Egyptian, Turkish and Japanese populations ([PMID:18039680]; [PMID:20870286]; [PMID:26606510]; [PMID:35842788]).

Segregation analyses confirm consistent maternal transmission of both alleles with full phenotypic penetrance in homozygous or compound-heterozygous females, while heterozygote carriers are generally asymptomatic, supporting autosomal recessive maternal-effect inheritance.

Functional assays show that patient-derived monocytes with NLRP7 mutations secrete significantly less IL-1β and TNF-α upon LPS stimulation and fail to regulate pro-IL-1β trafficking or inflammasome assembly, and yeast two-hybrid and co-immunoprecipitation studies demonstrate disrupted oligomerization ([PMID:22025618]; [PMID:32484253]).

Integration of robust genetic and functional data establishes a definitive gene–disease relationship. Maternal-effect autosomal recessive testing of NLRP7 should be incorporated into diagnostic workups for patients with BiCHM to guide reproductive counseling and management.

Key Take-home: Biallelic NLRP7 pathogenic variants are definitively associated with recurrent biparental complete hydatidiform mole and inform prognosis and genetic counseling.

References

• Molecular human reproduction • 2008 • A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. [PMID:18039680]
• Fetal and pediatric pathology • 2022 • Detection of Parental Contribution to Molar Genome Leads to Diagnosis of Recurrent Hydatidiform Mole in a Family with NLRP7 Variants. [PMID:33252287]
• Placenta • 2010 • Heterogeneity in recurrent complete hydatidiform mole: presentation of two new Turkish families with different genetic characteristics. [PMID:20870286]
• Gynecologic and obstetric investigation • 2016 • Novel Nonsense Mutation in the NLRP7 Gene Associated with Recurrent Hydatidiform Mole. [PMID:26606510]
• Human mutation • 2022 • Biallelic NLRP7 variants in patients with recurrent hydatidiform mole: A review and expert consensus. [PMID:35842788]
• The Journal of biological chemistry • 2011 • NLRP7, a nucleotide oligomerization domain-like receptor protein, is required for normal cytokine secretion and co-localizes with Golgi and the microtubule-organizing center. [PMID:22025618]
• Clinical and experimental immunology • 2020 • Abnormal processing of IL-1β in NLRP7-mutated monocytes in hydatidiform mole patients. [PMID:32484253]

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