The genetics and pathogenesis of CAKUT

Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a large variety of malformations that arise from defective kidney or urinary tract development and frequently lead to kidney failure. The clinical spectrum ranges from severe malformations, such as renal agenesis, to potentially milder manifestations, such as vesicoureteral reflux. Almost 50% of cases of chronic kidney disease that manifest within the first three decades of life are caused by CAKUT. Evidence suggests that a large number of CAKUT are genetic in origin. To date, mutations in ~54 genes have been identified as monogenic causes of CAKUT, contributing to 12–20% of the aetiology of the disease. Pathogenic copy number variants have also been shown to cause CAKUT and can be detected in 4–11% of patients. Furthermore, environmental and epigenetic factors can increase the risk of CAKUT. The discovery of novel CAKUT-causing genes is challenging owing to variable expressivity, incomplete penetrance and variable genotype–phenotype correlation. However, such a discovery could ultimately lead to improvements in the accurate molecular genetic diagnosis, assessment of prognosis and multidisciplinary clinical management of patients with CAKUT, potentially including personalized therapeutic approaches.