The arrangement of chromatin inside the nucleus has long been recognized as a key element in genomic stability and an active participant in transcriptional control. With the development and diverse adaptations of the chromosome conformation capture technique (3C), it has become possible to discover many organizational units of the chromatin fiber at the sub-chromosomal and chromosomal scale. Among the most important of these structures are the topologically associating domains (TADs), regions of ~1Mb in size that partition chromosomes into modular structures which are remarkably evolutionarily conserved. Besides their DNA packaging contribution, TADs are recognized as safekeepers of transcriptional control by limiting enhancer-promoter interactions within a defined region, and avoiding awry activation or repression of genes outside the domains.
In this exciting era of “Next-Gen Cytogenetics”, integration of genomic sequencing into the clinical diagnostic setting can provide precise delineation of chromosomal structural rearrangements at nucleotide level. Given the increased risk for congenital abnormalities with de novo balanced chromosome rearrangements, comprehensive interpretation of breakpoints may substantially improve prediction of phenotypic outcomes. A systematic approach for evaluating sequencing results of chromosome rearrangements can be undertaken in light of regulatory chromatin domains: in addition to genes directly located at the breakpoints, dysregulated protein coding genes and non-coding regions can be assessed in relation to TADs, given their role in pathologic rewiring of the human genome through structural rearrangements. Convergent genomic evidence and predicted probability of exhibiting haploinsufficiency is analyzed through publicly available databases including the Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources (DECIPHER) and Developmental Disorders Genotype-Phenotype Database (DDG2P). Our analyses highlight the important interplay between chromosome organization and disease, and further demonstrate the feasibility of utilizing topological information to predict pathogenic gene-dosage effects. Such analyses can further aid in clinical diagnosis of "n-of-one" samples of non-coding chromosome rearrangements, complementing and enhancing interpretation of current sequencing and array results.