022 Genetic investigations in renal tubulopathies

We have established the only specialised clinic for renal tubulopathies in children. The clinical diagnosis of these disorders can be challenging, as they are rare and characterized by significant phenotypic variability. Advances in sequencing technologies facilitate the establishment of a molecular diagnosis. We aimed to investigate the diagnostic yield of a next-generation sequencing panel assessing relevant disease genes in children with a clinical diagnosis of a renal tubulopathy followed through three national networks. DNA was amplified with a kit provided by the European Consortium for High-Throughput Research in Rare Kidney Diseases with 9 multiplex PCR reactions producing 571 amplicons to cover 37 genes associated with tubulopathies, followed by massively parallel sequencing and bioinformatic interpretation. Identified mutations were confirmed by Sanger sequencing. Overall, we assessed 384 index patients and 16 siblings. Most common clinical diagnoses were Bartter/Gitelman syndrome (n=174) and distal renal tubular acidosis (n=76). A total of 269 different variants were identified in 27 genes, of which 95 were considered likely and 136 definitely pathogenic and 100 had not been described at annotation. These mutations established a genetic diagnosis in 245 (64%) of the index patients. Genetic testing changed the clinical diagnosis in 16 (4%) of cases and provided insights into the phenotypic spectrum of the respective disorders. Our results demonstrate a high diagnostic yield of genetic testing in children with a clinical diagnosis of a renal tubulopathy, consistent with a predominantly genetic aetiology in known disease genes. Genetic testing helped establish a definitive diagnosis in almost two-thirds of patients and thereby informed prognosis, management and genetic counselling.