Abstract Introduction Structural variants (SVs) are genomic rearrangements ≥ 50 bp that alter copy number, orientation, or chromosomal location, and complex chromosomal rearrangements (CCRs) represent a rare SV subset characterized by three or more chromosomal breakpoints, often involving multiple chromosomes. Aim of the study To evaluate the diagnostic utility of an integrated cytogenomic workflow in characterizing rare SVs and CCRs within a tertiary genetic center cohort. Results In this study, a retrospective case series from a diagnostic cohort of 7508 individuals who applied to our center were reviewed. We identified four cases where standard single-modality testing was insufficient. The integration of karyotyping, FISH, CMA, and Optical Genome Mapping (OGM) allowed for the step-by-step resolution of complex puzzles, including a possible chromoanagenesis-related ring 18, a technically elusive ATAD3 deletion, an intrachromosomal CCR and one with a rare sex chromosomal rearrangement detected incidentally. Conclusion All four patients presented with genomic variants that could not be fully resolved using a single routine diagnostic approach. The integrated use of cytogenetics technologies remains essential for the accurate diagnosis and interpretation of complex genomic variation in clinical practice.
Kocagil et al. (2026) studied this question.