L'analisi genomica per la diagnosi e il trattamento delle anomalie congenite dei reni e delle vie urinarie (CAKUT)

Congenital anomalies of the kidneys and urinary tract are the leading cause of end stage renal disease (ESRD) in children and young adults. CAKUT diagnosis is currently based on imaging studies and It is classified using descriptive anatomic criteria which omit the underlying pathogenetic and molecular mechanisms. Studies from our group indicate that a large fraction of CAKUT is attributable to rare genetic variants with large effect size. In particular, both point mutations and structural genomic variants (copy number variations, CNVs), detectable by whole exome sequencing (WES) or DNA microarrays, respectively, account for 10 to 30% of the cases. Nevertheless, genetic tests are often not performed or not clinically indicated, thus limiting prognosis and medical management. Here we present a new multi-institutional Italian study group on CAKUT, composed of a network of clinical and basic investigators in adult and pediatric nephrology and urology. The group aims at the recruitment and clinical characterization of 5,000 patients affected by CAKUT to conduct detailed clinical characterization and perform research DNA microarrays and WES in all patients (in collaboration with Columbia University). To date, 30 Italian centers have an approved IRB are actively enrolling for these studies or they are in the process of submitting or activating the IRB in order to start enrolling patients. We currently recruited and characterized 1,482 independent index patients. We plan to reach the target goal of 5,000 patients in four years. The deep clinical and phenotypic characterization will allow precise anatomical classification of disease. Genetic data will be use to guide deep phenotyping (ex imaging studies, metabolic tests, neurodevelopmental tests). The longitudinal design will allow identification of both genetic and non genetic prognostic factors. Finally, this project aims at a reclassification of CAKUT based on underlying molecular genetics mechanisms, in order to improve renal and overall patient outcome