Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent genetic kidney disorder, characterized by the development of cysts within the kidneys. ADPKD is primarily caused by mutations in the polycystic kidney disease genes 1 or 2 (PKD1 or PKD2), and less commonly by variants in other genes such as glucosidase II alpha subunit (GANAB), which have been associated with milder renal phenotypes and concurrent polycystic liver disease. Therefore, preimplantation genetic testing for monogenic disorders (PGT-M) offers a promising strategy for preventing the transmission of ADPKD-related mutations to offspring. When combined with preimplantation genetic testing for aneuploidy (PGT-A), this approach enhances the selection of genetically unaffected and chromosomally normal embryos, thereby improving implantation and live birth outcomes in affected couples. Here, we present a 28-year-old woman with ADPKD. In 2016, she delivered a male infant by cesarean section who was diagnosed with a more severe, early-onset form of PKD and sadly died at one year of age due to disease-related complications. In 2019, her renal function declined, necessitating a kidney transplant and subsequent immunosuppression. Three years later, after intrauterine device (IUD) removal, she experienced 1.5 years of secondary infertility before seeking fertility treatment. In 2022, she underwent an antagonist protocol after consulting a nephrology staff member. Subsequently, hormone replacement therapy was initiated for frozen embryo transfer, with endometrial preparation completed by day 20 of her cycle. Genetic counseling and a detailed pedigree-based family history were obtained. Genetic testing using targeted next-generation sequencing (NGS) was performed and revealed a novel in-frame deletion-insertion variant in the PKD2 gene (NM_000297.4:c.278_284delinsAGGAGGAGGTTATCCTCCTCCTCCCCGC) in a heterozygous state. The variant was classified as a variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines, and is associated with ADPKD with or without polycystic liver disease. Database (ClinVar, gnomAD, Varsome) comparison confirmed its novelty and absence in population datasets. Despite uncertain pathogenicity, the strong genotype-phenotype correlation with classical ADPKD manifestations and the patient's kidney transplant support its potential clinical relevance. The patient underwent combined PGT-M and PGT-A to exclude embryos carrying the PKD2 variant. Among the four embryos analyzed, one unaffected euploid female embryo was selected for transfer. Fourteen days later, a positive pregnancy test and subsequent ultrasound confirmed a single intrauterine gestation, culminating in a successful pregnancy and the delivery of a healthy newborn.