#3146 Genetic heterogeneity of ADPKD: A total of 21 different genes identified in a population-based ADPKD cohort

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Abstract Background and Aims A significant number of individuals presenting with an ADPKD-like phenotype either harbour pathogenic variants in other cystic genes or genes that mimic ADPKD, or remain genetically unresolved (GUR). Understanding this variability is a key research priority emphasized in the 2025 KDIGO guidelines on ADPKD. Method Genkyst is a population-based cohort including all patients with ADPKD or ADPKD-like phenotype followed in 28 nephrology centers in northwestern France. Inclusion criteria were: 1) Pei-Ravine radiologic criteria in patients with positive family history or proven pathogenic variant in PKD1/PKD2 (N = 3122); 2) >10 bilateral kidney cysts (N = 263). A gene panel including 25 known or candidate cystogenes was employed, and whole exome sequencing (WES) was performed in majority of GUR families. Results Total of 3385 individuals from 2326 families were included (47.8% males) at the median age of 54.8 (16–94). Likely pathogenic or pathogenic variants (LP/P) compatible with cystic phenotype were identified in 91.2% and 87.6% of individuals and families, respectively. While PKD1 and PKD2 LP/P variants were identified in 64.7 and 18.5% of families, respectively, 4.4% of families had atypical forms of ADPKD caused by variants in 19 different genes, the most common being IFT140, ALG8, DNAJB11, COL4A4 and HNF1B (Fig. 1). WES was performed in 266 GUR families leading to precise genetic diagnosis in 56 (21%) of them and revealing some important ADPKD-differentials like heterozygous COL4A4, OFD1 or even biallelic TULP3 with significant clinical implications. Pathogenic variants in a recently identified ADPKD candidate gene, IFT172, were identified in four unrelated patients, further supporting its role in atypical PKD. After this systematic genetic analysis including WES, a total of 299 individuals remained still GUR. Compared to PKD1-PKD2 patients, GUR individuals were more often males (65% vs 46%, P < 0.001), significantly older (65.05 vs 53.0, P < 0.001), more often diagnosed incidentally (40% vs 24%, P < 0.001), less commonly had positive familial history (24% vs 74%, P < 0.001) and developed kidney failure (16% vs 42%, P < 0.001) and had better renal survival [84.6 y (81–91.8) vs 53.9 y (53.1–55) in PKD1-truncating or 78.4 y (73.5–84) in PKD2 individuals]. Of interest, monoallelic predicted loss-of-function variants were detected within 34 different known ciliopathy genes in 58 GUR individuals from 55 families, and causality is being investigated. Conclusion ADPKD is a genetically heterogeneous disease, with in our cohort 12 ADPKD-associated genes and 9 phenocopies. Further genetic heterogeneity is likely, with new candidate genes identified by WES being currently characterized.

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