P1799genotype-Phenotype Correlation in a Pediatric Adpkd Cohort

Abstract

Background and Aims The correlation between genotype and phenotype is well described in ADPKD adults. PKD2 is milder than PKD1 disease, with end stage kidney disease (ESKD) occurring on average 20 years later, and patients with PKD1 truncating mutations having a more severe outcome than PKD1 non-truncating mutations. Still, large differences in outcome occur even within families carrying the same gene variation. Only a few cases series reported the genetic profile of severely affected ADPKD children and suggest an additional effect of hypomorphic genes. We therefore aim to analyse the geno-phenotype profile in a well characterized pediatric ADPKD cohort. Method Clinical, familial, biological and imaging data were collected longitudinally in children diagnosed with ADPKD. Genotypic analysis was done using a custom Agilent SureSelect gene panel containing 136 ciliopathy-associated genes, including PKD1 and PKD2. Mutations and/or variants identified were individually evaluated for pathogenicity. Results 57 ADPKD children from 44 families were diagnosed at a mean (± SD) age of 4.1 (±4.8) years. ADPKD diagnosis was made in 32 children (56%) because of asymptomatic screening as requested by the family; 7 (12%) due to presenting symptoms (6 due to urinary tract infection and 1 due to post-traumatic macroscopic hematuria); 9 (16%) due to a coincidental finding of renal cysts on US performed for another reason and in 9 cases (16%) a prenatal diagnosis was performed. Twenty-nine children (51%) met the definition of very-early onset (VEO) disease. We identified pathogenic mutations in 100% of our patients, in which the prevalence of PKD1 truncating, PKD1 non-truncating, PKD2 and GANAB mutations was 75%, 19%, 4%, and 2%, respectively. Four cases (7%) were due to a de novo mutation. Interestingly, in 29 patients (51%) the germline mutation was the only identified mutation. However, in the rest of the subjects additional variants were identified in other ciliopathy-associated genes. In 12 cases (21%) the additional identified variants found in either the PKD, PMM2, HNF1B, DNAJC1, CEP290, NEK1, MKKS, NPHP4 or PKHD1 genes were scored to have a potential phenotypic effect, which will be evaluated by continued follow-up of this cohort. Conclusion We report the first large cohort of genotyped ADPKD children, including an extensive panel of ciliopathy genes next to the PKD genes. Interestingly, we found a high prevalence of additional and potentially modifying variants in this young population.