Congenital anomalies of the kidney and urinary tract (CAKUT) comprise a broad spectrum of renal malformations. The underlying genetics is complex: a number of monogenic causes exist but can have pleiotropic manifestations. A substantial number of patients also carry copy number variants (CNVs), many of which are associated with genomic disorders (GDs). A new, large-scale study of CNVs has now helped researchers to define distinct genetic landscapes of CAKUT phenotypes.

To assess the contribution of CNVs to CAKUT phenotypes, Simone Sanna-Cherchi and colleagues genotyped rare, large CNVs in 2,824 patients with CAKUT and 21,498 controls. “In addition to demonstrating a high burden of rare CNVs in CAKUT we also defined unique features for CAKUT subcategories,” says Sanna-Cherchi. Patients with kidney anomalies had the largest burden of rare CNVs, which were mostly deletions and encompassed known GDs; patients with vesicoureteral reflux had a high burden of CNVs, which were mostly duplications, but a lower burden of GDs; and patients with obstructive uropathy had an intermediate burden of GDs and rare CNVs. “These data indicate that, from a CNV standpoint, different CAKUT categories are genetically distinct,” says Miguel Verbitsky, the first author on the paper. “Furthermore, we identified 45 GDs at 37 independent loci, supporting high genetic heterogeneity for CAKUT; however, six of these loci accounted for about 65% of cases with a GD, thus identifying major regions that are likely to encompass critical regulators of kidney and urinary tract development.” Finally, using a mouse allelic series the researchers identified TBX6 as a major driver of CAKUT phenotypes in patients with 16p11.2 microdeletion syndrome — one of the most common genetic causes of autism.

Sanna-Cherchi explains that the identification of variants with incomplete penetrance and variable expressivity of phenotypes provides a framework for studying these fundamental aspects of human genetics. “By understanding these complex aspects we can understand the mechanisms by which certain individuals can compensate and tolerate mutations, whereas others progress to end-stage renal disease, and envision the development of novel tools to mitigate the effect of human mutations,” he says.