Case Report: Functional validation of a PKD1 c.7489 + 5G>A variant in an ADPKD family

Abstract

Background Autosomal dominant polycystic kidney disease (ADPKD) is most commonly caused by pathogenic variants in PKD1. Here, we reported the functional characterization of an intronic PKD1 variant identified in an ADPKD-affected family and its subsequent application in preimplantation genetic testing for monogenic disorders (PGT-M). Case presentation A three-generation ADPKD family was enrolled. Whole-exome sequencing revealed a heterozygous PKD1 c.7489 + 5G>A variant, which co-segregated with the disease and was initially classified as a variant of uncertain significance. A minigene assay demonstrated that the variant induced skipping of exon 18, leading to a frameshift (p.Arg2404Valfs*123), supporting its reclassification as pathogenic. The couple underwent PGT-M using trophectoderm biopsy, haplotype linkage analysis, and direct mutation detection. An unaffected pregnancy was achieved, and subsequent prenatal diagnosis confirmed the absence of the variant and a normal chromosomal karyotype. Conclusion We validated a pathogenic splicing variant in PKD1 and successfully applied PGT-M to prevent disease transmission, resulting in an unaffected pregnancy.