Exploring the genetic basis of early-onset chronic kidney disease

Genetic studies over the past few years have led to the discovery that a monogenic cause of disease can be detected in ∼20% of individuals with early-onset chronic kidney disease (CKD). In this Review, Vivante and Hildebrandt discuss some of the known single-gene causes of early-onset CKD and the implication of next-generation sequencing for genetic diagnosis. They describe how the discovery of novel causative genes has led to opportunities for delineating the pathomechanisms of disease and potential treatment approaches. The primary causes of chronic kidney disease (CKD) in children differ from those of CKD in adults. In the USA the most common diagnostic groups of renal disease that manifest before the age of 25 years are congenital anomalies of the kidneys and urinary tract, steroid-resistant nephrotic syndrome, chronic glomerulonephritis and renal cystic ciliopathies, which together encompass >70% of early-onset CKD diagnoses. Findings from the past decade suggest that early-onset CKD is caused by mutations in any one of over 200 different monogenic genes. Developments in high-throughput sequencing in the past few years has rendered identification of causative mutations in this high number of genes feasible. Use of genetic analyses in patients with early onset-CKD will provide patients and their families with a molecular genetic diagnosis, generate new insights into disease mechanisms, facilitate aetiology-based classifications of patient cohorts for clinical studies, and might have consequences for personalized approaches to the prevention and treatment of CKD. In this Review, we discuss the implications of next-generation sequencing in clinical genetic diagnostics and the discovery of novel genes in early-onset CKD. We also delineate the resulting opportunities for deciphering disease mechanisms and the therapeutic implications of these findings.