Abstract
PURPOSE: Successful reproduction in humans requires maturation and fertilization of gametes as well as early embryonic development. Any deviation from these processes leads to infertility. Early embryonic arrest (EEA) is common in female infertility and is primarily attributed to genetic factors. Mutations in the NLRP2 gene have been identified as the causative factors for EEA. In the present study, a novel mutation identified in NLRP2 underscored the novel homozygous variant and phenotypes that might contribute to its inclusion in the genetic counseling of infertile patients. METHODS: We recruited a proband from a consanguineous family with a diagnosis of EEA. Peripheral blood samples were collected from the proband and family members for whole-exome sequencing to identify the genes and inheritance patterns associated with infertility; the results were substantiated by Sanger sequencing. All genetic variants and protein structures were analyzed based on computational predictions. Wild-type and mutant plasmids were constructed and transfected into HeLa cells. Subsequent in vitro analyses elucidated the functional impact of the variant. RESULTS: A novel homozygous mutation in NLRP2 was identified in the proband. The patient harbored a frameshift deletion mutation (c.195delC: p.Tyr66Thrfs*32) in the pyrin structural domain. This genetic alteration resulted in the down-regulation of NLRP2 mRNA expression, truncation of the protein structure, and altered protein localization in cells. CONCLUSIONS: The current findings broaden the spectra of NLRP2 variants, especially concerning EEA. Also, potential diagnostic markers for patients experiencing recurrent IVF/ICSI failure were identified, and a solid foundation was laid for genetic counseling for female infertility.