Position effect at the SOX3 locus by an interchromosomal insertion causes hereditary spastic paraplegia.

A 149-kb interchromosomal insertion at Xq27.1 originating from 4q24, causing a position effect: rewiring of the 3D architecture of the SOX3 TAD, reduced ability of upstream cis-regulatory elements to activate SOX3, and dysregulation dependent on CTCF-binding sites within the insertion.

Pathogenic rewiring of 3D genome architecture is increasingly recognised as a cause of genetic disease, but recognising the cis-regulatory effects of structural variation remains challenging. In a large Danish family with X-linked recessive complex spastic paraplegia, the authors identified segregation of a 149-kb interchromosomal insertion at Xq27.1 originating from 4q24. Using patient-derived iPSCs, they combined CRISPR perturbation, neural differentiation, Hi-C and transcriptomic analyses and demonstrated 3D regulatory rewiring of SOX3 with transcriptional dysregulation of its targets in iPSC-derived neurons. Experiments show that upstream cis-regulatory elements have a reduced ability to activate SOX3 and that the observed dysregulation depends on CTCF-binding sites within the insertion.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

An exemplary mechanistic demonstration: from family segregation to proof that the CTCF-binding sites carried by the insertion are what dysregulate SOX3. It is a concrete reminder that WGS alone is not enough — an interchromosomal insertion of this kind can be detected without being interpretable, and iPSCs, Hi-C and CRISPR were needed to classify it. Only one family: the value is methodological and conceptual rather than directly transferable to routine, but the Xq27.1 insertion hotspot is worth knowing.

Analysis by Dr Thibaut Benquey