Clinical diagnostic workflows have been focused on exome sequencing and the detection of small protein-coding variants (single-nucleotides, short insertions, and deletions) often overlooking complex genomic rearrangements (CGR). Indeed, detection of CGRs required genome rather than exome sequencing and development of advanced analytical tools. Among the available technologies for genome sequencing, short-read whole genome sequencing (srWGS) is currently the most cost-efficient technology for detecting variants as it covers most of the genome and theoretically allows the detection of the whole spectrum of genomic variations. To develop and assess new workflows for accurate detection of CGRs with srWGS, model organisms such as Caenorhabditis elegans (C. elegans) constitute an excellent biological tool that could be used in a tractable fashion. Indeed, many C. elegans strains called balancers are known to carry CGRs used to balance genomic loci. Balancer C. elegans genomes constitute then a source of known CGRs to assess analytical methods and the compact genome of C. elegans allows reduced sequencing and experimental validation costs but also reduced computational burden while testing computational approaches. Here, we present a complete workflow to detect and validate CGR breakpoints as well as guidelines to interpret their structure using srWGS developed on C. elegans balancers strains.