Zooming into rearranged genome: applying pipeline of cytological, genomic, and transcriptomic methods for structural variant interpretation

Recent advances in genomic technologies have greatly enhanced our understanding of genotype-phenotype relationships and improved the diagnosis of genetic diseases. However, the dissection of complex structural variants (SVs) remains challenging due to the limitations of current methods in resolving their breakpoints and interpreting phenotypes involving multiple disrupted genes. In this study, we demonstrate how an integrative approach-combining molecular cytogenetic, genomic, and transcriptomic methods-enables the detection and structural and functional characterization of complex SVs affecting the MBD5, USP34, and XPO1 genes. Our findings underscore the utility of the Exo-C, a modified chromosome conformation capture technique in resolving complex rearrangements. We also report, for the first time, a composite neurodevelopmental phenotype resulting from the combined effects of MBD5-associated intellectual disability and 2p15p16.1 microdeletion syndromes.