Pathogenic variant in NLRP7 (19q13.42) associated with recurrent gestational trophoblastic disease: Data from early embryo development observed during in vitro fertilization

Abstract

ObjectiveTo describe in vitro development of human embryos derived from an individual with a homozygous pathogenic variant in NLRP7 (19q13.42) and recurrent hydatidiform mole (HM), an autosomal recessive condition thought to occur secondary to an oocyte defect.MethodsA patient with five consecutive HM pregnancies was genomically evaluated via next generation sequencing followed by controlled ovarian hyperstimulation, in vitro fertilization (IVF) with intracytoplasmic sperm injection, embryo culture, and preimplantation genetic screening. Findings in NLRP7 were recorded and embryo culture and biopsy data were tabulated as a function of parental origin for any identified ploidy error.ResultsThe patient was found to have a pathogenic variant in NLRP7 (c.2810+2T>G) in a homozygous state. Fifteen oocytes were retrieved and 10 embryos were available after fertilization via intracytoplasmic sperm injection. Developmental arrest was noted for all 10 embryos after 144 hours in culture, thus no transfer was possible. These non-viable embryos were evaluated by karyomapping and all were diploid biparental; two were euploid and eight had various aneuploidies all of maternal origin.ConclusionThis is the first report of early human embryo development from a patient with any NLRP7 mutation. The pathogenic variant identified here resulted in global developmental arrest at or before blastocyst stage. Standard IVF should therefore be discouraged for such patients, who instead need to consider oocyte (or embryo) donation with IVF as preferred clinical methods to treat infertility.

NLRP7 plays a functional role in regulating BMP4 signaling during differentiation of patient-derived trophoblasts

“…Thereby, all the cells during the first cell fate decision may be directed to the trophoblast fate which results in abnormal development of placenta. In agreement with this, recent studies on in vitro pre-implantation embryos have verified the requirement of NLRP7 for proper embryo development 13 , 42 . Interestingly, NLRP7 was found to be one of the most upregulated genes in embryonic carcinomas, epiblasts, and naive pluripotent stem cells along with core stem cell markers, such as OCT3/4 and NANOG 43 – 45 in correlation with our results that reprogramming process itself boosts NLRP7 expression and NLRP7 mutant cells tend to lose pluripotency properties when the media is not supplemented with FGF2.…”

NLRP7 Plays A Functional Role in Regulating BMP4 Signaling During Differentiation of Patient-Derived Trophoblasts

“…Thereby, all of the cells during the first cell fate decision may be directed to the trophoblast fate. In agreement with this, recent studies with in vitro pre-implantation embryos have verified the requirement of NLRP7 for proper embryo development (40,41). Interestingly, NLRP7 was found to be one of the most upregulated genes in embryonic carcinomas, epiblasts and naive pluripotent stem cells along with core stem cell markers, such as; OCT3/4, NANOG (42)(43)(44) in correlation with our results that reprogramming process itself boosts NLRP7 expression and NLRP7 deficient cells tend to lose pluripotency properties when the media is not supplemented with FGF2.…”

Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles

“…While it is well-known that the primary defect in patients with RHM and biallelic functional variants in NLRP7 is in their oocytes, the only documentation of how their embryos develop during early stages has been shown in one patient by Sills et al [20]. In this patient, 15 oocytes were retrieved and fertilized, but the resulting embryos were not of good quality and all arrested between day 3 and 6 like those from patients with recessive functional PADI6 variants [10].…”