| Category | Gene / marker | Inheritance / origin | Molecular mechanism | Example pathogenic variants / pattern | Key clinical notes | Evidence |
|---|---|---|---|---|---|---|
| Maternal-effect gene | **NLRP7** | Typically **autosomal recessive** in familial recurrent hydatidiform mole (FRHM); affected conceptions are often **diploid biparental** | Oocyte maternal-effect gene; defective establishment/maintenance of **maternal imprinting** with **placenta-specific methylation defects**; reported associations with altered **DNMT3A**, **LIN28B**, **ERVWE1**, **LINE-1**, and **STAT5A** methylation/expression | **c.2471+1G>A** (canonical splice-site; homozygous), **c.2571dupC, p.Ile858HisfsTer11** (frameshift; homozygous), **c.2810+2T>G** (splice-site); broader series show multiple homozygous or compound-heterozygous truncating/splice variants | Major cause of FRHM; reported in ~**40–80%** of FRHM/RHM cohorts. In a 113-patient series, all moles from patients with **NLRP7/KHDC3L** variants were **diploid biparental**. In a 3-case 2023 series, **all** NLRP7-positive recurrent cases progressed to **GTN** after evacuation and required single-agent methotrexate; one review notes only ~**7%** chance of normal live birth with biallelic NLRP7 variants, supporting counseling about **oocyte donation** | (pqac-00000019, pqac-00000020, pqac-00000022, pqac-00000023, pqac-00000024) |
| Maternal-effect gene | **KHDC3L** | Typically **autosomal recessive**; affected conceptions classically **diploid biparental** | Maternal-effect / imprinting gene involved in oocyte competence; variants associated with **abnormal genomic imprinting** and recurrent biparental mole formation | No variant examples with c./p. notation were provided in the available context; review-level evidence cites **protein-truncating mutations** and **p.M1V founder mutation** | Accounts for roughly **5–14%** of familial recurrent mole cases depending on cohort/review; testing is generally recommended **after NLRP7** if NLRP7 is negative in recurrent HM workup | (pqac-00000018, pqac-00000020, pqac-00000022, pqac-00000023, pqac-00000024) |
| Maternal-effect gene | **PADI6** | Recessive maternal-effect etiology reported in recurrent HM / reproductive failure | SCMC-related maternal-effect dysfunction; linked to abnormal early embryogenesis and HM, with review evidence that **missense** variants may be milder than **protein-truncating** variants; contributes to imprinting/early developmental failure rather than classic sporadic androgenetic mole biology | Specific c./p. examples were not available in the provided context | Linked to **primary female infertility**, **early embryonic arrest after ART**, and **hydatidiform mole**; should be considered in recurrent/biparental mole differential when NLRP7/KHDC3L testing is unrevealing | (pqac-00000018, pqac-00000022) |
| Genotype class | **Diploid biparental HM** | Maternal-effect gene-associated recurrent form | Presence of both maternal and paternal genomes despite complete-mole phenotype; reflects imprinting failure rather than androgenetic conception | Genotype pattern: **diploid biparental** | Strongly enriched in women with **NLRP7/KHDC3L** variants; in the 113-patient study, tissues from mutation-positive patients were **all diploid biparental**, whereas mutation-negative recurrent cases were heterogeneous | (pqac-00000020, pqac-00000024) |
| Genotype class | **Diploid androgenetic HM** | Usually sporadic, non-maternal-effect form | Paternal-only genome, classic complete mole mechanism | Genotype pattern: **diploid androgenetic monospermic** | Seen commonly among mutation-negative recurrent/sporadic cases; generally distinct from biparental recurrent mole syndrome | (pqac-00000024) |
| Genotype class | **Triploid dispermic HM** | Usually sporadic partial mole biology | Diandric triploidy from dispermy; not the classic maternal-effect recurrent biparental mechanism | Genotype pattern: **triploid dispermic** | In mutation-negative recurrent cases, a substantial fraction of tissues were triploid dispermic; these patients tended to have **fewer reproductive losses and more live births** than mutation-positive patients | (pqac-00000022, pqac-00000024) |
| Diagnostic marker | **RB1** | IHC adjunct marker; not a causal gene here | Paternally imprinted/maternally expressed pattern useful for distinguishing CHM from PHM/non-molar abortus when p57 is equivocal | **Positive in 100%** of PHM and non-molar abortuses; positive in only **10.3%** of CHM | Useful adjunct to **p57** in laboratories lacking molecular testing or in equivocal cases | (pqac-00000025) |
| Diagnostic marker | **TSSC3** | IHC adjunct marker; not a causal gene here | Paternally imprinted/maternally expressed pattern useful for distinguishing CHM from PHM/non-molar abortus | **Positive in 100%** of PHM and non-molar abortuses; positive in only **31%** of CHM | Useful adjunct to **p57** for CHM vs PHM/non-molar distinction, especially where molecular genotyping is unavailable | (pqac-00000025) |
| Diagnostic marker | **DOG1** | IHC adjunct evaluated in study | Tested as a possible adjunct marker | **Uniformly negative** in all cell types/case groups in the cited study | Not useful diagnostically in this setting based on available evidence | (pqac-00000025) |
| Diagnostic marker | **DNMT1 / GATA3** | IHC adjuncts evaluated in study | Maternally imprinted marker expression assessed across villous/trophoblastic compartments | Expressed in **all cases except one CHM with negative GATA3** | Less discriminatory than RB1/TSSC3 for routine CHM vs PHM separation in the cited cohort | (pqac-00000025) |


*Table: This table summarizes the main maternal-effect genes and genotype classes implicated in hydatidiform mole, especially recurrent biparental forms, and adds key diagnostic immunohistochemical adjuncts beyond p57. It is useful for linking molecular etiology to recurrence risk, imprinting defects, and practical pathology workflows.*