Le podocitopatie: analisi di varianti genetiche in forme familiari e sporadiche

Background and aims. The understanding of proteinuric glomerular diseases has greatly expanded in recent years, thanks to the advances in the filed of molecular biology. An increased number of podocyte-expressed genes have been identified, placing glomerular epithelial cell (podocyte) at the centre of the disease mechanisms of podocitopathies. Podocitopathies include a variety of causes and histopathologic findings, despite similar clinical presentation. Even though the development of the glomerulopathy that leads to proteinuria may not only be explained by a genetic alteration, the identification of a genetic disease may be essential to define a patient-tailored therapy (aimed to avoid unnecessary and potentially detrimental drugs, as immunosuppressants) and long-term prognosis (progression to end stage renal disease, risk of post-transplantation recurrence and necessity of specific therapy, possibility of living-related transplantation). Patients and methods. Genetic testing by direct sequencing of the genes more frequently associated with podocitopathies (NPHS2, WT1, PLCE1, NPHS1) and Next Generation Sequencing (including 46 genes) were carried out in 40 children affected by familial or sporadic podocitopathy. Clinical and histopathological features, as well as outcomes, were also retrospectively and prospectively analysed. Results. A genomic alteration was found in 20/40 patients (50%): 6/40 children (15%) had a variation in NPHS2 gene (associated with focal segmental glomerulosclerosis - FSGS); in 4/6 cases, the detected sequence variant was novel. 11 patients (27.5%) carried a mutation in WT1 gene (associated with FSGS in 6 and with diffuse mesangial sclerosis – DMS - in 5 children); in 4/11 cases, the detected variation was novel. 3 children had novel sequence variations in PLCE1 gene (the histological picture was FSGS in 2 and DMS in 1). The detected alterations were found to be pathogenetic in 18/20 patients. Genetic analysis was extended to parents in 12/20 cases. Conclusions. The high frequency of mutation in our series of children affected by podocitopathies confirms the importance of genetic alterations in the pathogenesis of these diseases. Therefore, a correct diagnostic pathway cannot exclude a genetic screening, at least for genes more frequently associated with proteinuria and nephrotic syndrome (namely, NPHS2, WT1 e PLCE1). In clinical practice, the ethiological diagnosis is essential to an accurate work up of the patient (with direct outcomes on therapeutic strategies and prognosis) and may contribute to the optimization of health resources.