Trivellin Giampaolo, Sánchez-Gaya Víctor, Grasso Alexia, Pasińska Magdalena, Stratakis Constantine A, Milnes Di, Kirk Edwin P, Beckers Albert, Lania Andrea G, Pétrossians Patrick, Rada-Iglesias Alvaro, Franke Martin, Daly Adrian F
Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.
IRCCS Humanitas Research Hospital, Translational Endocrinology and Metabolism Lab, via Manzoni 56, 20089 Rozzano, Milan, Italy.
medRxiv. 2025 Jul 10:2025.06.27.25329768. doi: 10.1101/2025.06.27.25329768.
Structural variants (SVs) that disrupt topologically associating domains (TADs) can cause disease by rewiring enhancer-promoter interactions. Duplications involving are known to cause X-linked acrogigantism (X-LAG) by enabling aberrant expression of through hijacking of enhancers at . However, not all -containing duplications are pathogenic, presenting a diagnostic challenge, especially in the prenatal setting.
We evaluated POSTRE, a tool designed to predict the regulatory impact of SVs, to distinguish pathogenic from benign 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.
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 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 could explain the different clinical features of X-LAG in this individual.
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.
破坏拓扑相关结构域（TADs）的结构变异（SVs）可通过重新连接增强子-启动子相互作用导致疾病。已知涉及的重复通过在处劫持增强子使异常表达而导致X连锁肢端巨大症（X-LAG）。然而，并非所有包含的重复都是致病的，这带来了诊断挑战，尤其是在产前环境中。
我们评估了POSTRE，这是一种旨在预测SVs调控影响的工具，以区分良性和致病的重复。我们分析了6个非致病重复和27个已知的与X-LAG相关的致病重复。使用H3K27ac ChIP-seq和ATAC-seq数据构建的组织特异性增强子图谱以及来自人垂体前叶样本的基因表达数据被整合到POSTRE中，以便在与X-LAG相关的组织背景下进行预测。
POSTRE正确地将所有33个重复分类为良性或致病。此外，发现1例具有轻度临床特征（例如，在无垂体肿瘤发生的情况下严重生长激素分泌过多）的X-LAG病例仅包含2/5个增强子（也被预测为最弱的增强子），而所有26例典型的X-LAG病例都有≥4个增强子被重复。这表明在处较轻的增强子劫持可以解释该个体中X-LAG的不同临床特征。
这些发现支持POSTRE在解释影响垂体疾病染色质结构的SVs时对诊断流程的实用性。通过在细胞类型特异性背景下准确模拟增强子的采用，POSTRE有助于减少遗传咨询中的不确定性，并提供一种快速替代染色质构象捕获实验的方法。
