#662 Characterization of novel gene mutation sites associated with autosomal dominant polycystic kidney disease on 19 chromosomes

Abstract Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is the most common single-gene inherited kidney disorder, affecting approximately 1 in 500-1000 newborns and often leading to end-stage renal disease. It involves cyst formation in various organs, with renal manifestations including cysts, hematuria, kidney stones, proteinuria, and hypertension. Liver, pancreas, seminal vesicles, spleen, and intracranial aneurysms may also be affected. Genetic diagnosis, particularly for patients without a family history or with atypical imaging, is considered the gold standard. ADPKD is associated with several pathogenic genes, such as PKD1 and PKD2, as well as others like HNF-1B, GANAB, DNAJB11, SEC63, ALG8, ALG9, PRKCSH, LRP5, SEC61B, and SEC63. Understanding the genetic basis is crucial for early diagnosis and identifying high-risk individuals. This study, based on genetic data from patients with renal polycystic kidney disease at Zhong Da Hospital Southeast University, identified novel ADPKD gene mutations. It explored structural changes in proteins, predicting effects on phenotype, to contribute to the enrichment of the ADPKD gene database. Method In a single-center cross-sectional retrospective study, patients with renal multiple cysts diagnosed from January 2019 to February 2023 at the Zhong Da Hospital Southeast University were included. Genetic and clinical data of patients and their families were collected. Unreported novel gene mutation sites associated with ADPKD were identified, and AlphaFold v2.3.1 was employed to predict protein structures. Changes in protein structure before and after mutations were compared to explore genotype-phenotype correlations and enrich the ADPKD gene database. Results The study included 96 patients with renal multiple cysts and their relatives from 62 families. Twelve mutated genes associated with renal cysts were detected in 52 families. Nineteen novel gene mutation sites associated with ADPKD were identified (Table 1, Fig. 1) , including 17 mutations in the PKD1 gene (1 splicing mutation, 7 frameshift mutations, 4 nonsense mutations, 1 whole-codon insertion, and 4 missense mutations), 1 ALG9 missense mutation, and 1 chromosomal structural variation. Truncating mutations in the PKD1 gene were correlated with a more severe clinical phenotype, while non-truncating mutations were associated with greater clinical heterogeneity. Conclusion Numerous novel gene mutation sites associated with ADPKD remain unreported. It is essential to analyze the pathogenicity of these novel mutation sites, establish genotype-phenotype correlations, and enrich the ADPKD gene database.