A Compound Heterozygous Pathogenic Variant in ZP2 Gene Causes Female Infertility.

The oocyte maturation defect 6 is an autosomal recessive hereditary disease caused by a homozygous variant in ZP2 gene. It is characterized by female primary infertility due to an abnormally thin zona pellucida (ZP) and defective sperm binding. Here we identified a compound heterozygous variant (c.1924C > T and c.1695-2A > G) in ZP2 gene in a Chinese Han family. Quantitative real-time PCR showed that the variant c.1924C > T significantly decreased the expression of truncated ZP2 message RNA by the nonsense-mediated decay pathway. Minigene assays showed the c.1695-2A > G variant led to an extra-61-nt preservation of intron 15 at the junction between exons 15 and 16 during transcription. Both variants (c.1924C > T and c.1695-2A > G) resulted in truncated ZP2 proteins (p.R642X and p.C566Hfs*2) that lost the transmembrane domain, which prevented the secretion of the mutant ZP2 proteins and produced a structurally abnormal ZP, thus resulting in female infertility. This study further elucidated the pathogenic mechanism of these two variants and provided new support for the genetic diagnosis of female infertility.