Clinical Features and PLCZ1 Gene Variants in Two Cases of Male Infertility: A Case Series and Literature Review

Variations in the PLCZ1 gene can lead to male infertility (MIM #617214), an autosomal recessive disorder characterized by failure or abnormal fertilization of oocytes after intracytoplasmic sperm injection. This condition can be addressed using assisted oocyte activation. Although various mutation types have been reported, our study identified two novel pathogenic variants.

Whole-exome sequencing (WES) was performed to screen for pathogenic variants. Candidate variants were validated using Sanger sequencing and pedigree analysis. Pathogenicity was assessed with bioinformatics tools and the ACMG guidelines. A literature review on PLCZ1 mutations was conducted using PubMed, CNKI, and Wanfang databases.

Our results showed that both patients carried homozygous frameshift pathogenic variants in PLCZ1: c.138_139delCA (p. D46Efs*2) (Family 1, II-2) and c.1087del (p. S363Afs*64) (Family 2, II-2). The parents of family 1 were both heterozygous carriers, which was consistent with the autosomal recessive inheritance pattern. For family 2, the parents were deceased, so validation could not be performed. The clinical intervention results of the two patients showed that almost all fertilizations failed in the first cycle, and after assisted oocyte activation in the second cycle, the normal fertilization rates increased to 72.7% and 80.0% respectively, and both couples eventually gave birth to healthy offspring. In the retrospective analysis of the literature, 24 studies and 77 patients with 46 different genetic variants were included. Missense mutations were the most common 63.1% (65/103), and exon 6 was the mutation hotspot 31.0% (32/103).

This study reported for the first time that homozygous frameshift mutations in the PLCZ1 gene led to fertilization failure. These newly discovered mutations expanded the range of pathogenic variants in the PLCZ1 gene, confirming that ICSI combined with assisted oocyte activation can effectively overcome such male factor infertility, providing a theoretical basis for genetic counseling and reproductive intervention for such patients.