Mutations in NLRP7 are associated with diploid biparental hydatidiform moles, but not androgenetic complete moles.
BACKGROUND
NLRP7 (NALP7) has been identified as the major gene involved in the inherited predisposition to recurrent molar pregnancies, a rare recessive condition in which affected individuals have complete hydatidiform moles of diploid biparental origin (BiCHM). The role of NLRP7 in other types of molar pregnancy and reproductive wastage has not been conclusively demonstrated. The purpose of this study was to clarify this by identifying NLRP7 variation in two clinically well-defined groups of patients: women with recurrent BiCHM, and women with three or more recurrent complete hydatidiform moles of proven androgenetic origin (AnCHM).


METHODS
Fluorescent microsatellite genotyping of molar tissue was used to establish a diagnosis of recurrent BiCHM (four novel cases) or recurrent AnCHM (nine women with multiple CHM). These two groups were subsequently screened for mutations in NLRP7 using DNA sequencing. Additional screening for non-pathological variants was performed in 21 previously published cases of recurrent BiCHM. Taqman genotyping was used to determine the frequency of novel NLRP7 variants in two control cohorts of Caucasian and Asian women with no adverse reproductive outcomes.


RESULTS
Of the four novel cases with recurrent BiCHM, two were homozygous for mutations in NLRP7 while one was a compound heterozygote for a nonsense mutation and a pathological variant. No NLRP7 mutations or pathological variants were identified in the fourth case. None of the women with AnCHM carried any mutations or pathological variants of NLRP7. A single case of AnCHM was found to be heterozygous for a novel variant (R413Q).


CONCLUSIONS
NLRP7 mutations do not represent a major cause of AnCHM.
Gestational Trophoblastic Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, Hammersmith Campus, London, UK.
Peter H
PH
Dixon
Pirada
P
Trongwongsa
Shadi
S
Abu-Hayyah
Sze Hwei
SH
Ng
Syed Ali
SA
Akbar
Nuzhat P
NP
Khawaja
Michael J
MJ
Seckl
Philip M
PM
Savage
Rosemary A
RA
Fisher
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004171:Diploidy; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics*; D020125:Mutation, Missense; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy
D048868:Adaptor Proteins, Signal Transducing; C502448:NLRP7 protein, human