Atypical ADPKD Due to Complex Genotypes of Both PKD1 and HNF1B Pathogenic Variants: An Educational Case Report

Introduction: ADPKD is the most common genetic cause of renal failure in adults. Advances in next-generation sequencing have revealed complex genotypes, including mosaicism, digenic inheritance, diallelic variants, and genetic modifiers. Understanding the phenotypes associated with variants is crucial for clinicians, as genetic variability significantly influences the severity of ADPKD. Case Description: A 33-year-old Han Chinese male presented with enlarged kidneys, numerous small cysts, deteriorating renal function, early-onset diabetes mellitus, proteinuria, and a family history of CKD and renal cysts. His mother and sister had multiple renal cysts consistent with ADPKD but only moderately enlarged kidneys and normal renal function. This suggested an atypical ADPKD form, with rapid cyst development, renal decline, and early-onset diabetes, lacking common ADPKD-associated extra-renal manifestations. Whole-exome sequencing identified a heterozygous PKD1 variant (c.9618G>T, p.Q3206H), inherited from his mother and confirmed in his sister, classified as likely pathogenic. Additionally, a heterozygous deletion of exons 1-9 in the HNF1B gene, absent in his pedigree, was confirmed by real-time quantitative PCR. A comprehensive treatment strategy was implemented, including insulin therapy, blood pressure control, and symptom management. At latest follow-up, proteinuria had decreased, but renal function continued to decline slowly. Discussion: Distinguishing HNF1B-related cystic kidney disease from PKD1/PKD2 variants is crucial. HNF1B-related disease typically features small cysts, normal kidney size, progressive CKD, and early-onset diabetes, overlapping with ADTKD. However, its presentation, prognosis, and pathogenesis differ significantly from PKD1/PKD2-related ADPKD. Genetic testing is recommended for patients with atypical ADPKD features, which is important for diagnosis, genetic counseling, and prognosis. Further research on ADTKD variants in unexplained ADPKD cases is valuable.