Exome Reanalysis Identifies Novel Candidate Genes Associated with Congenital Anomalies of the Kidney and Urinary Tract in China

Abstract

Congenital anomalies of the kidney and urinary tract (CAKUT) are the primary cause of pediatric kidney failure, yet the genetic etiologies remain elusive for most affected individuals. Reanalysis of trio exome sequencing data from 80 Chinese CAKUT patients identified 32 rare, predicted deleterious variants. Replication in unrelated families from a national multicenter database prioritized four novel candidate genes--DOCK11, MIB1, TENM2, and TNS1. These candidates are involved in both well-characterized developmental pathways and more under-explored biological processes relevant to renal and ureteric morphogenesis. CRISPR-Cas9-mediated zebrafish knockout studies were employed to validate the potential association of these genes with kidney abnormalities including significant pericardial edema, malformed renal tubules, and impaired glomerular filtration. These findings offer potential genetic diagnoses for 10% of CAKUT probands, and demonstrate that exome reanalysis can substantially improve diagnostic yield and inform personalized clinical management. Overall, this study expands the known genetic landscape of CAKUT.