Distinguishing benign from pathogenic duplications involving GPR101 and VGLL1-adjacent enhancers in the clinical setting with the bioinformatic tool POSTRE.

BACKGROUND

Structural variants (SVs) that disrupt topologically associating domains (TADs) can cause disease by rewiring enhancer-promoter interactions. Duplications involving GPR101 are known to cause X-linked acrogigantism (X-LAG) by enabling aberrant expression of GPR101 through hijacking of enhancers at VGLL1. However, not all GPR101-containing duplications are pathogenic, presenting a diagnostic challenge, especially in the prenatal setting.

METHODS

We evaluated POSTRE, a tool designed to predict the regulatory impact of SVs, to distinguish pathogenic from benign GPR101 duplications. We analyzed six non-pathogenic duplications, and 27 known X-LAG associated pathogenic duplications. Tissue-specific enhancer maps built using H3K27ac ChIP-seq and ATAC-seq data as well as gene expression data derived from human anterior pituitary samples were integrated into POSTRE to enable predictions in a X-LAG relevant tissue context.

RESULTS

POSTRE correctly classified all 33 duplications as benign or pathogenic. In addition, one X-LAG case with mild clinical features (e.g., severe GH hypersecretion in the absence of pituitary tumorigenesis) was found to include only 2/5 VGLL1 enhancers (also predicted to be the weakest enhancers), whereas all 26 typical X-LAG cases had ≥4 enhancers duplicated. This suggests that milder enhancer hijacking at VGLL1 could explain the different clinical features of X-LAG in this individual.

CONCLUSIONS

These findings support the utility of POSTRE to support diagnostic pipelines when interpreting SVs affecting chromatin architecture in pituitary disease. By accurately modelling enhancer adoption in a cell type-specific context, POSTRE could help to reduce uncertainty in genetic counselling and offers a rapid alternative to performing chromatin conformation capture experiments.