Designer nuclease-associated genotoxicity, such as off-target activity and chromosomal translocations, poses a risk that must be carefully evaluated before clinical application of any gene editing product. We recently described CAST-Seq, a diagnostic assay that detects CRISPR-Cas-induced chromosomal aberrations in a genome-wide manner in clinically relevant cells. CAST-Seq relies on target-specific bait and decoy primers to identify rearrangements between the on-target site and genomic regions that harbor either an off-target site or sequences with high homology to the target site. While CAST-Seq is highly sensitive, the design of effective bait and decoy primers can be cumbersome and, in rare cases, unfeasible. Here, we describe universal (U)CAST-Seq, a method to detect genome-wide off-target effects of CRISPR-Cas nucleases without the need to optimize primers. UCAST-Seq is based on the fact that any nuclease-induced DNA double strand break can serve as an ‘anchor’ to capture off-target events triggered by a second nuclease. Upon adaptation of the bioinformatics pipeline to strain off events triggered by the ‘anchor nuclease’, we provide proof that UCAST-Seq is able to nominate off-target sites and identify nuclease-triggered chromosomal rearrangements of various CRISPR-Cas nucleases for which, in part, target-specific amplicons could not be produced. Executing UCAST-Seq with CRISPR-Cas nucleases targeting reference genes, like VEGFA, confirmed that the results generated by UCAST-Seq were comparable to conventional CAST-Seq both quantitatively and qualitatively. Because the method can be performed with established universal bait and decoy primers, UCAST-Seq saves costs and time, and is particularly well suited for screening designer nucleases in early development.