The spectrum of diseases, genetic landscape and new mutation sites of hereditary cystic kidney disease.

Background: Cystic kidney disease is common. Beyond autosomal dominant polycystic kidney disease (ADPKD), knowledge of other hereditary forms of cystic kidney disease remains limited. This study aimed to retrospectively analyse 702 patients with multiple renal cysts from the Chinese PLA General Hospital (September 2015-December 2023). Methods: Patients suspected of having hereditary cystic kidney disease underwent next-generation sequencing (NGS) and subsequent bioinformatics analysis. Variations were assessed for pathogenicity in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines. Moreover, the ClinVar and Mastermind databases were used to identify novel mutation sites. Statistical analysis was performed using SPSS 25.0 software. Results: Of 702 patients, 96 (13.7%) lacked gene mutations associated with cystic kidney disease. In contrast, 606 patients (86.3%) were found to have gene mutations associated with renal cyst phenotypes, involving 23 unique mutated genes. Among these, mutations in 158 patients were categorized as variants of uncertain significance. The remaining 448 patients harboured mutations predicted by the ACMG guidelines to be pathogenic or likely pathogenic, enabling a diagnosis of hereditary cystic kidney disease. These mutations were linked to seven diseases and 10 genes. The most common was ADPKD [434 cases (96.9%)], followed by autosomal dominant tubulointerstitial kidney disease [ADTKD; six cases (1.3%)], autosomal recessive polycystic kidney disease [ARPKD; five cases (1.1%)] and tuberous sclerosis complex [two cases (0.4%)]. One case each was found for autosomal dominant polycystic liver disease, Conclusion: In this study we identified 23 mutated genes linked to renal cyst phenotypes, 10 of which had pathogenic or likely pathogenic variants. These findings facilitated the diagnosis of seven hereditary cystic kidney diseases, including ADPKD, ADTKD, ARPKD and others. Furthermore, 63 novel pathogenic or likely pathogenic variants were identified.