Fig. 2

Quantitative phenotype-driven clustering analysis of PAX2-associated phenotypes. The clinical features assessed are labeled on the x-axis. Ninety reported pathogenic variants in the available literature from 234 patients with PAX2-related kidney disease were enrolled in the clustering analysis. Heat map generated using Manhattan distance with dendrogram and PAX2 variants shown (right panel). All reported pathogenic missense variants in PAX2 (white) and a size-matched cohort of likely/presumed gene disruptive (LGD) variants (MediumAquamarine; deletion, truncating, nonsense and frameshift variants with predicted nonsense-mediated decay) were clustered according to phenotypic features using the R packages cluster and gplots, and function heatmap (Red, renal coloboma syndrome, RCS; Yellow, CAKUT, Blue, nephrosis, NavajoWhite, CKD of unknown etiology, CKDu). The clustering reveals that LGD variants are predominantly associated with RCS, whereas missense variants have a wider phenotypic spectrum that includes distinct clusters of CAKUT or nephrosis or CKD of unknown etiology phenotypes. Detailed versions of the phenotyping data set used for clustering analysis and the heat map, with all of the missense and LGD variants labeled, are available (Additional file 1: Table S1)