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An increasing amount of evidence indicates the critical role of the <i>NSD1</i> gene in Sotos syndrome (SoS), a rare genetic disease, and in tumors. Molecular mechanisms affected by <i>NSD1</i> mutations are largely uncharacterized. In order to assess the impact of <i>NSD1</i> haploinsufficiency in the pathogenesis of SoS, we analyzed the gene expression profile of fibroblasts isolated from the skin samples of 15 SoS patients and of 5 healthy parents. We identified seven differentially expressed genes and five differentially expressed noncoding RNAs. The most upregulated mRNA was stratifin (<i>SFN</i>) (fold change, 3.9, Benjamini–Hochberg corrected <i>p</i> < 0.05), and the most downregulated mRNA was goosecoid homeobox (<i>GSC</i>) (fold change, 3.9, Benjamini–Hochberg corrected <i>p</i> < 0.05). The most upregulated lncRNA was lnc-C2orf84-1 (fold change, 4.28, Benjamini–Hochberg corrected <i>p</i> < 0.001), and the most downregulated lncRNA was Inc-C15orf57 (fold change, −0.7, Benjamini–Hochberg corrected <i>p</i> < 0.05). A gene set enrichment analysis reported the enrichment of genes involved in the KRAS and E2F signaling pathways, splicing regulation and cell cycle G2/M checkpoints. Our results suggest that <i>NSD1</i> is involved in cell cycle regulation and that its mutation can induce the down-expression of genes involved in tumoral and neoplastic differentiation. The results contribute to defining the role of <i>NSD1</i> in fibroblasts for the prevention, diagnosis and control of SoS.