Compound heterozygous variants in PATL2 cause oocyte germinal vesicle arrest associated with primary infertility: a...

This study aims to explore the clinical characteristics, genetic etiology, and individualized treatment strategies of patients with PCOS complicated by oocyte maturation disorders caused by novel compound heterozygous variants of the PATL2 gene, and to expand the mutation and phenotypic spectrum of the PATL2 gene.

Clinical data and two cycles of controlled ovarian hyperstimulation (COH) were collected from a 34-year-old patient with primary infertility and PMOS. Genetic analysis was performed using whole-exome sequencing (WES), and variant pathogenicity was predicted by bioinformatics tools. An individualized COH protocol was designed and implemented based on the genetic diagnosis.

The patient had 8 years of primary infertility. In the first cycle, 10 oocytes were retrieved after COH with an antagonist protocol, all arrested at the germinal vesicle (GV) stage. WES revealed compound heterozygous variants in the PATL2 gene (OMIM: 617743): NM_001145112.1: c.1225-2A > G (splice-site variant) and c.1382 T > C (p.Leu461Pro, missense variant), consistent with autosomal recessive inheritance. Both variants were predicted to be deleterious, and c.1382 T > C was a novel unreported variant. In the second cycle, a long follicular protocol, delayed trigger, segmented oocyte retrieval, and indomethacin for spontaneous ovulation prevention were applied. A total of 24 oocytes were retrieved; however, all remained arrested at the GV stage after in vitro culture, and no mature oocytes were obtained.

Compound heterozygous variants c.1225-2A > G and c.1382 T > C in PATL2 are the core genetic cause of GV-stage oocyte arrest in this patient. GV arrest caused by PATL2 defects cannot be overcome by conventional or optimized IVF protocols even with individualized COH. WES provides critical evidence for etiological clarification, avoidance of ineffective treatment, and genetic counseling. Donor-oocyte IVF remains the ultimate effective strategy for pregnancy in such patients.