Exome-wide analysis of congenital kidney anomalies reveals new genes and shared architecture with developmental disorders

Abstract

Kidney anomalies (KA) are developmental disorders that commonly cause pediatric chronic kidney disease and mortality. We examined rare coding variants in 248 KA trios and 1,742 singleton KA cases and compared them to 22,258 controls. Diagnostic and candidate diagnostic variants were detected in 14.1% of cases. We detected a significant enrichment of rare damaging variants in constrained genes expressed during kidney development and in genes associated with other developmental disorders, suggesting phenotype expansion. Consistent with these data, 18% of KA patients with diagnostic variants had neurodevelopmental or cardiac phenotypes. Extrarenal developmental phenotypes were associated with a higher burden of rare variants. Statistical analyses identified 40 novel candidate genes, 2 of which were confirmed as new KA genes: ARID3A and NR6A1. This study suggests that many yet-unidentified syndromes would be discoverable with larger cohorts and cross-phenotype analysis, leading to clarification of the genetic and phenotypic spectrum of developmental disorders.