Using transcription modules to identify expression clusters perturbed in Williams-Beuren Syndrome


The genetic dissection of the phenotypes associated with Williams-Beuren Syndrome (WBS) is advancing thanks to the study of individuals carrying typical or atypical structural rearrangements, as well as in vitro and animal studies. However, no global assessment of the dysregulations caused by the WBS deletion exists to date. We profiled the transcriptomes of skin fibroblasts from WBS patients and compared them to matched controls. We identified 868 differentially expressed genes that were significantly enriched in extracellular matrix genes, major histocompatibility complex (MHC) genes, as well as genes the products of which localize to the postsynaptic membrane. We then used public expression datasets from human fibroblasts to establish sets of genes coexpressed in this cell type. We then identified those sets whose average gene expression was altered in WBS samples. Dysregulated modules are often interconnected and share multiple common genes, suggesting that intricate regulatory networks connected by a few central genes are disturbed in WBS. This modular approach increases the power to identify pathways which are dysregulated in WBS patients, thus providing additional candidates for genes and their interactions that modulate the WBS phenotypes. Notably, our results emphasize the role of the extracellular space in the pathophysiology of WBS and provide novel clues about other affected processes.



Charlotte N. Henrichsen, Gábor Csárdi, Marie-Thérèse Zabot, Carmela Fusco, Sven Bergmann, Giuseppe Merla and Alexandre Reymond: Using transcription modules to identify pathways perturbed in Williams-Beuren Syndrome.