{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:59:29Z","timestamp":1768571969862,"version":"3.49.0"},"posted":{"date-parts":[[2025,6,30]]},"group-title":"Genetic and Genomic Medicine","reference-count":41,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T00:00:00Z","timestamp":1751241600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Structural variants (SVs) that disrupt topologically associating domains (TADs) can cause disease by rewiring enhancer-promoter interactions. Duplications involving\n                    <jats:italic>GPR101<\/jats:italic>\n                    are known to cause X-linked acrogigantism (X-LAG) by enabling aberrant expression of\n                    <jats:italic>GPR101<\/jats:italic>\n                    through hijacking of enhancers at\n                    <jats:italic>VGLL1<\/jats:italic>\n                    . However, not all\n                    <jats:italic>GPR101<\/jats:italic>\n                    -containing duplications are pathogenic, presenting a diagnostic challenge, especially in the prenatal setting.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We evaluated POSTRE, a tool designed to predict the regulatory impact of SVs, to distinguish pathogenic from benign\n                    <jats:italic>GPR101<\/jats:italic>\n                    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.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:italic>VGLL1<\/jats:italic>\n                    enhancers (also predicted to be the weakest enhancers), whereas all 26 typical X-LAG cases had 24 enhancers duplicated. This suggests that milder enhancer hijacking at\n                    <jats:italic>VGLL1<\/jats:italic>\n                    could explain the different clinical features of X-LAG in this individual.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.06.27.25329768","type":"posted-content","created":{"date-parts":[[2025,6,30]],"date-time":"2025-06-30T14:00:15Z","timestamp":1751292015000},"source":"Crossref","is-referenced-by-count":0,"title":["Distinguishing benign from pathogenic duplications involving\n                  <i>GPR101<\/i>\n                  and\n                  <i>VGLL1<\/i>\n                  -adjacent enhancers in the clinical setting with the bioinformatic tool 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