Clinical and Experimental Reproductive Medicine

The Korean Society for Reproductive Medicine (대한생식의학회)
권호 표지
DOI QR코드

DOI QR Code

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

  • Sills, E. Scott (Reproductive Research Section, Center for Advanced Genetics) ;
  • Obregon-Tito, Alexandra J. (Fulgent Diagnostics) ;
  • Gao, Harry (Fulgent Diagnostics) ;
  • McWilliams, Thomas K. (Genesis Genetics Inc.) ;
  • Gordon, Anthony T. (Genesis Genetics Inc.) ;
  • Adams, Catharine A. (Reproductive Sciences Medical Center) ;
  • Slim, Rima (Department of Human Genetics, McGill University Health Centre Research Institute)
  • Received : 2016.11.07
  • Accepted : 2017.02.28
  • Published : 2017.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Objective: To 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. Methods: A 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. Results: The 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. Conclusion: This 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.

Keywords

References

  1. Hoffner L, Surti U. The genetics of gestational trophoblastic disease: a rare complication of pregnancy. Cancer Genet 2012;205:63-77. https://doi.org/10.1016/j.cancergen.2012.01.004
  2. Judson H, Hayward BE, Sheridan E, Bonthron DT. A global disorder of imprinting in the human female germ line. Nature 2002; 416:539-42. https://doi.org/10.1038/416539a
  3. Al-Ghamdi AA. Recurrent hydatidiform mole: a case report of six consecutive molar pregnancies complicated by choriocarcinoma, and review of the literature. J Family Community Med 2011; 18:159-61. https://doi.org/10.4103/2230-8229.90018
  4. Parry DA, Logan CV, Hayward BE, Shires M, Landolsi H, Diggle C, et al. Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte. Am J Hum Genet 2011;89:451-8. https://doi.org/10.1016/j.ajhg.2011.08.002
  5. Dixon PH, Trongwongsa P, Abu-Hayyah S, Ng SH, Akbar SA, Khawaja NP, et al. Mutations in NLRP7 are associated with diploid biparental hydatidiform moles, but not androgenetic complete moles. J Med Genet 2012;49:206-11. https://doi.org/10.1136/jmedgenet-2011-100602
  6. Fisher RA, Lavery SA, Carby A, Abu-Hayyeh S, Swingler R, Sebire NJ, et al. What a difference an egg makes. Lancet 2011;378:1974. https://doi.org/10.1016/S0140-6736(11)61751-0
  7. Deng L, Zhang J, Wu T, Lawrie TA. Combination chemotherapy for primary treatment of high-risk gestational trophoblastic tumour. Cochrane Database Syst Rev 2013;(1):CD005196.
  8. Ito Y, Maehara K, Kaneki E, Matsuoka K, Sugahara N, Miyata T, et al. Novel nonsense mutation in the NLRP7 gene associated with recurrent hydatidiform mole. Gynecol Obstet Invest 2016;81:353-8. https://doi.org/10.1159/000441780
  9. Sills ES, Alper MM, Walsh AP. Ovarian reserve screening in infertility: practical applications and theoretical directions for research. Eur J Obstet Gynecol Reprod Biol 2009;146:30-6. https://doi.org/10.1016/j.ejogrb.2009.05.008
  10. Sills ES, Schattman GL, Veeck LL, Liu HC, Prasad M, Rosenwaks Z. Characteristics of consecutive in vitro fertilization cycles among patients treated with follicle-stimulating hormone (FSH) and human menopausal gonadotropin versus FSH alone. Fertil Steril 1998;69:831-5. https://doi.org/10.1016/S0015-0282(98)00046-6
  11. Sills ES, Collins GS, Salem SA, Jones CA, Peck AC, Salem RD. Balancing selected medication costs with total number of daily injections: a preference analysis of GnRH-agonist and antagonist protocols by IVF patients. Reprod Biol Endocrinol 2012;10:67. https://doi.org/10.1186/1477-7827-10-67
  12. Palermo G, Joris H, Devroey P, Van Steirteghem AC. Pregnancies after intracytoplasmic injection of single spermatozoon into an oocyte. Lancet 1992;340:17-8. https://doi.org/10.1016/0140-6736(92)92425-F
  13. Vrettou C, Traeger-Synodinos J, Tzetis M, Palmer G, Sofocleous C, Kanavakis E. Real-time PCR for single-cell genotyping in sickle cell and thalassemia syndromes as a rapid, accurate, reliable, and widely applicable protocol for preimplantation genetic diagnosis. Hum Mutat 2004;23:513-21. https://doi.org/10.1002/humu.20022
  14. Kou YC, Shao L, Peng HH, Rosetta R, del Gaudio D, Wagner AF, et al. A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Mol Hum Reprod 2008;14:33-40. https://doi.org/10.1093/molehr/gam079
  15. Gardner DK, Schoolcraft WB. In vitro culture of human blastocysts. In: Jansen R, Mortimer D, editors. Towards reproductive certainty: fertility and genetics beyond 1999. Carnforth: Parthenon Publishing (Lond); 1999. p. 378-88.
  16. Messaed C, Akoury E, Djuric U, Zeng J, Saleh M, Gilbert L, et al. NLRP7, a nucleotide oligomerization domain-like receptor protein, is required for normal cytokine secretion and co-localizes with Golgi and the microtubule-organizing center. J Biol Chem 2011;286:43313-23. https://doi.org/10.1074/jbc.M111.306191
  17. Krishnamoorthy K, Gerkowicz S, Verma U. Viable intrauterine pregnancy and coexisting molar pregnancy in a bicornuate uterus: a rare presentation. J Clin Imaging Sci 2016;6:26. https://doi.org/10.4103/2156-7514.184541
  18. Edwards R, Crow J, Dale S, Macnamee M, Hartshorne G, Brinsden P. Preimplantation diagnosis and recurrent hydatidiform mole. Lancet 1990;335:1030-1. https://doi.org/10.1016/0140-6736(90)91089-S
  19. Akoury E, Zhang L, Ao A, Slim R. NLRP7 and KHDC3L, the two maternal-effect proteins responsible for recurrent hydatidiform moles, co-localize to the oocyte cytoskeleton. Hum Reprod 2015;30:159-69. https://doi.org/10.1093/humrep/deu291
  20. Fisher RA, Hodges MD, Rees HC, Sebire NJ, Seckl MJ, Newlands ES, et al. The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles. Hum Mol Genet 2002;11:3267-72. https://doi.org/10.1093/hmg/11.26.3267
  21. Wang CM, Dixon PH, Decordova S, Hodges MD, Sebire NJ, Ozalp S, et al. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine-rich region. J Med Genet 2009;46:569-75. https://doi.org/10.1136/jmg.2008.064196
  22. Sanchez-Delgado M, Martin-Trujillo A, Tayama C, Vidal E, Esteller M, Iglesias-Platas I, et al. Absence of maternal methylation in biparental hydatidiform moles from women with NLRP7 maternal- effect mutations reveals widespread placenta-specific imprinting. PLoS Genet 2015;11:e1005644. https://doi.org/10.1371/journal.pgen.1005644

Cited by

  1. NLRPs, the subcortical maternal complex and genomic imprinting vol.154, pp.6, 2017, https://doi.org/10.1530/rep-17-0465
  2. Recurrent complete hydatidiform mole: where we are, is there a safe gestational horizon? Opinion and mini-review vol.35, pp.6, 2017, https://doi.org/10.1007/s10815-018-1202-9
  3. Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles vol.26, pp.7, 2018, https://doi.org/10.1038/s41431-018-0141-3
  4. NLRP7 is increased in human idiopathic fetal growth restriction and plays a critical role in trophoblast differentiation vol.97, pp.3, 2019, https://doi.org/10.1007/s00109-018-01737-x
  5. Genomic imprinting disorders: lessons on how genome, epigenome and environment interact vol.20, pp.4, 2019, https://doi.org/10.1038/s41576-018-0092-0
  6. Pregnancy after oocyte donation in a patient with NLRP7 gene mutations and recurrent molar hydatidiform pregnancies vol.37, pp.9, 2017, https://doi.org/10.1007/s10815-020-01861-z
  7. Prospects of Germline Nuclear Transfer in Women With Diminished Ovarian Reserve vol.12, pp.None, 2017, https://doi.org/10.3389/fendo.2021.635370
  8. An Overview of the Role of Long Non-Coding RNAs in Human Choriocarcinoma vol.22, pp.12, 2021, https://doi.org/10.3390/ijms22126506
  9. Reproductive Outcomes from Maternal Loss of Nlrp2 Are Not Improved by IVF or Embryo Transfer Consistent with Oocyte-Specific Defect vol.28, pp.7, 2017, https://doi.org/10.1007/s43032-020-00360-x
  10. Application of next-generation sequencing to preimplantation genetic testing for recurrent hydatidiform mole patients vol.38, pp.11, 2021, https://doi.org/10.1007/s10815-021-02325-8