The genetic puzzle of vesicoureteral reflux: What are we missing?

Vesicoureteral reflux (VUR) is a common congenital anomaly of the urinary tract and a recognized risk factor for recurrent febrile urinary tract infections, renal scarring and, in some patients, long-term renal morbidity. Its clustering in siblings and across generations leaves little doubt that primary VUR has a substantial genetic component. Even so, more than three decades of research have not identified a gene or locus that accounts for most isolated cases. Early linkage studies pointed to marked genetic heterogeneity, and candidate-gene studies identified variants in developmental regulators such as PAX2, ROBO2 and SOX17 in only small subsets of patients. Genome-wide association studies, copy-number analyses and whole-exome sequencing have since broadened the list of implicated genes and loci, including WNT5A, WDPCP, KIF26B, LIFR and LAMC1. Rather than converging on a single cause, these findings place VUR within a network of processes governing ureteric bud position and branching, ureteral differentiation and formation of the ureterovesical junction. Important gaps remain: incomplete penetrance, variable expressivity, inconsistent phenotyping, non-coding and structural variation, epigenetic regulation and gene–environment interactions remain poorly understood. This review assesses the genetic evidence for VUR, considers why earlier approaches have provided limited answers and outlines genomic and developmental strategies that may move the field forward. The central challenge is now less about identifying one additional candidate gene than about explaining how multiple modest disturbances combine to produce reflux.