Expanding the ASXL1 Mutation Spectrum: Transcriptomic and Metabolic Dysregulation Underlying Overgrowth Phenotype in Inherited ASXL1 Missense Mutations

Transcriptomic analysis demonstrated that ASXL1 missense carriers exhibit a gene expression profile distinct from BOS. Cross-tissue integration identified 104 shared differentially expressed genes, significantly enriched for oxidative phosphorylation pathways. Notably, mitochondrial genes were downregulated in blood but upregulated in fibroblasts, suggesting tissue-specific metabolic adaptation.

Metabolomic profiling revealed depletion of glycolytic intermediates and reduced levels of key energy carriers, including NAD⁺ and NADPH, indicating impaired energy metabolism. In contrast to BOS, which is characterized by transcriptional de-repression and increased glycolytic activity, ASXL1 missense cells demonstrated a predominantly repressive transcriptional profile and diminished bioenergetic capacity. These findings define a distinct molecular and metabolic signature associated with ASXL1 missense variation and support an expanded phenotypic spectrum beyond classical BOS.