Novel Genetic Variants in 2 Corresponding to Different Clinical Phenotypes of Female Infertility.

PATL2, an RNA-binding protein and a translational repressor, plays a crucial role in maintaining mRNA homeostasis during female gametogenesis and early development of embryos. Rare pathogenic variants of its encoding gene have been implicated as causative factors for oocyte, zygote, and embryo maturation arrest (OZEMA), which results in female primary infertility and failed IVF or ICSI attempts. In this study, we identified multiple 2 variants carried by three patients from two unrelated families: compound heterozygous missense variants comprising novel c.1373T>C (p.I458T), and reported c.877G>T (p.D293Y); unprecedented homozygous missense variants of recurrent c.839G>A (p.R280Q). Molecular dynamics simulations revealed that variants I458T and D293Y severely damaged structural integrity of the PATL2 protein, strongly suggesting a more pronounced functional impairment than the other variant, R280Q. These computational results are in a good consistency with the corresponding clinical phenotypes and offer a plausible explanation for previously observed decrease of protein abundancy associated with the reported variants in 2. Our findings provide more insights into the significant impacts of both novel and recurrent 2 variants on female infertility and failed assisted reproduction.