A priori clinical diagnosis of CKD is defined as pre-WES clinical diagnosis per referral by primary nephrologist. CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; ESKD, end-stage kidney disease; GN, glomerulonephritis; SRNS, steroid-resistant nephrotic syndrome; TIKD, tubulointerstitial kidney disease; WES, whole exome sequencing. a Age at first presentation to medical services with evidence of CKD. b Age at start of renal replacement therapy, i.e., dialysis or kidney transplantation. DM Connaughton et al.: Monogenic causation of chronic kidney disease in Ireland c l i n i c a l i n v e s t i g a t i o n Kidney International (2019) 95, 914-928 DM Connaughton et al.: Monogenic causation of chronic kidney disease in Ireland c l i n i c a l i n v e s t i g a t i o n

We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most frequent birth defects and represent the most common cause of chronic kidney disease in the first three decades of life. Despite the discovery of dozens of monogenic causes of CA-KUT, most pathogenic pathways remain elusive. We performed whole-exome sequencing (WES) in 551 individuals with CAKUT and identified a heterozygous de novo stop-gain variant in ZMYM2 in two different families with CAKUT. Through collaboration, we identified in total 14 different heterozygous loss-of-function mutations in ZMYM2 in 15 unrelated families. Most mutations occurred de novo, indicating possible interference with reproductive function. Human disease features are replicated in X. tropicalis larvae with morpholino knockdowns, in which expression of truncated ZMYM2 proteins, based on individual mutations, failed to rescue renal and craniofacial defects. Moreover, heterozygous Zmym2-deficient mice recapitulated features of CAKUT with high penetrance. The ZMYM2 protein is a component of a transcriptional corepressor complex recently linked to the silencing of developmentally regulated endogenous retrovirus elements. Using protein-protein interaction assays, we show that ZMYM2 interacts with additional epigenetic silencing complexes, as well as confirming that it binds to FOXP1, a transcription factor that has also been linked to CAKUT. In summary, our findings establish that loss-of-function mutations of ZMYM2, and potentially that of other proteins in its interactome, as causes of human CAKUT, offering new routes for studying the pathogenesis of the disorder.