Chromoanagenesis encompasses catastrophic genomic rearrangements, with chromoanasynthesis referring to unbalanced germline events involving one or multiple chromosomes, distinct from the mostly balanced rearrangements seen in cancer-associated chromothripsis and chromoplexy. Initially identified via chromosomal microarray analysis (CMA) and custom high-density arrays, chromoanasynthesis detection and delineation was improved by next-generation sequencing (NGS). However, the short read-lengths and read-depth variations of NGS limit its fine-mapping capabilities. While third-generation sequencing (TGS) offers higher accuracy than that of NGS by providing long read sequences, it remains costly. Accurate characterization of rearrangement patterns is crucial for understanding disease pathogenicity, as small copy-number variations (CNVs) near breakpoints can significantly alter diagnostic interpretations. To overcome the limitations of CMA and regular NGS, we developed a mate-pair library construction method using large DNA inserts (~5 kb) and low-pass genome sequencing (GS) to identify CNVs, structural variants (SVs), and absence of homozygosity (AOHs), as well as to assemble the genomic organization. This methodology, illustrated through a chromoanasynthesis case study, enhances our ability to efficiently and cost-effectively characterize complex genomic rearrangements, addressing both technical challenges and clinical diagnostic needs.