Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure in adult life. Rarely, ADPKD can be diagnosed in utero or in infancy, and the genetic mechanism underlying such severe presentation has been shown to be related to reduced gene dosage. Biallelic PKD1 variants are often identified in early onset ADPKD, with one main pathogenic variant and a modifier hypomorphic variant showing an in trans configuration. We describe two unrelated individuals with early onset cystic kidney disease and unaffected parents, where a combination of next-generation sequencing of cystic genes including PKHD1, HNF1B and PKD1 allowed the identification of biallelic PKD1 variants. Furthermore, we review the medical literature in order to report likely PKD1 hypomorphic variants reported to date and estimate a minimal allele frequency of 1/130 for this category of variants taken as a group. This figure could help to orient genetic counseling, although the interpretation and the real clinical impact of rare PKD1 missense variants, especially if previously unreported, remain challenging.

Key Points: The Mayo clinic imaging classification and the predicting renal outcome in polycystic kidney disease score are used to assess the risk of progression to kidney failure in autosomal dominant polycystic kidney disease. Mayo imaging classification and predicting renal outcome in polycystic kidney disease show little concordance; combined use increased the ability to identify rapid progression especially among intermediate risk patients. Accurate risk prediction is key for determining indication for specific treatment. Background: Autosomal dominant polycystic kidney disease is the most common genetic cause of kidney failure. Specific treatment is indicated on observed or predicted rapid progression. For the latter, risk stratification tools have been developed independently based on either total kidney volume or genotyping as well as clinical variables. This study aimed to improve risk prediction by combining both imaging and clinical-genetic scores. Methods: We conducted a retrospective multicenter cohort study of 468 patients diagnosed with autosomal dominant polycystic kidney disease. Clinical, imaging, and genetic data were analyzed for risk prediction. We defined rapid disease progression as an eGFR slope ≥3 ml/min per 1.73 m² per year over 2 years, Mayo imaging classification (MIC) 1D–1E, or a predicting renal outcome in polycystic kidney disease (PROPKD) score of ≥7 points. Using MIC, PROPKD, and rare exome variant ensemble learner scores, several combined models were designed to develop a new classification with improved risk stratification. Primary endpoints were the development of advanced CKD stages G4–G5, longitudinal changes in eGFR, and clinical variables such as hypertension or urological events. Statistically, logistic regression, survival, receiver operating characteristic analyses, linear mixed models, and Cox proportional hazards models were used. Results: PKD1-genotype (P < 0.001), MIC class 1E (P < 0.001), early-onset hypertension (P < 0.001), and early-onset urological events (P = 0.003) correlated best with rapid progression in multivariable analysis. While the MIC showed satisfactory specificity (77%), the PROPKD was more sensitive (59%). Among individuals with an intermediate risk in one of the scores, integration of the other score (combined scoring) allowed for more accurate stratification. Conclusions: The combined use of both risk scores was associated with higher ability to identify rapid progressors and resulted in a better stratification, notably among intermediate risk patients.

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a late-onset cilia-related disorder, characterized by progressive cystic enlargement of the kidneys. It is genetically heterogeneous with PKD1 and PKD2 pathogenic variants identified in approximately 78% and 15% of families, respectively. More recently, additional ADPKD genes, such as DNAJB11, have been identified and included in the diagnostic routine test for renal cystic diseases. However, despite recent progress in ADPKD molecular approach, approximately ~7% of ADPKD-affected families remain genetically unresolved. We collected a cohort of 4 families from our center, harboring heterozygous variants in the DNAJB11 gene along with clinical and imaging findings consistent with previously reported features in DNAJB11 mutated patients. Mutations were identified as likely pathogenetic (LP) in three families and as variants of uncertain significance (VUS) in the remaining one. One patient underwent to kidney biopsy and showed a prevalence of interstitial fibrosis that could be observed in ~60% of the sample. The presence in the four families from our cohort of ADPKD characteristics together with ADTKD features, such as hyperuricemia, diabetes, and chronic interstitial fibrosis, supports the definition of DNAJB11 phenotype as an overlap disease between these two entities, as originally suggested by the literature.

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a monogenic disease having a prevalence of 1:400–1000 live births. Depending on kidney imaging, patients can be subdivided into Class 1 (typical) and Class 2 (atypical). The present study aims to provide better assessment of Class 2 patients to help define their family history, together with their clinical and radiological characteristics. Methods: One hundred twenty-four PKD patients with abdominal Magnetic Resonance Imaging (MRI) for the staging of ADPKD, were retrospectively analyzed, aiming to focus on Class 2 ADPKD patients. Total kidney volume and total cyst volume were evaluated, while also assessing their clinical and genetic characteristics. Results: Twelve patients fulfilled the Mayo criteria for Class 2 ADPKD (two Class 2B and ten Class 2A). Extrarenal involvement was observed in 66.7% of cases, but only two subjects presented an estimated Glomerular Filtration Rate (eGFR) < 60 mL/min/1.73 m ² . A positive family history for cystic disease was more frequent compared to other published cohorts. Only 8.3% tested positive for a likely pathogenic mutation in the PKD 1 gene. Class 2B patients showed a lower height-adjusted total kidney volume, with a lower percentage of total cyst volume. Conclusion: Based on our results, atypical ADPKD does not represent an uncommon condition, being present in about 10% of MRI-evaluated patients diagnosed with ADPKD. Genetic tests are frequently negative for PKD1/PKD2 , and total cyst volume and residual tissue volume do not increase the prognostic value of MRI in patients with these radiological characteristics. Other tools are needed to better characterize their kidney prognosis. Graphical