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

ABSTRACT: Mutations in genes associated with chromatin remodeling, such as Additional sex combs-like 1 (ASXL1), underlie a spectrum of congenital abnormalities and neurodevelopmental disorders. Pathogenic variants in ASXL1 are classically associated with Bohring–Opitz syndrome (BOS), a severe developmental disorder caused predominantly by de novo truncating mutations. In this study, we present a 14-year-old female with overgrowth, macrocephaly, and normal neurodevelopment, features that diverge from the typical BOS phenotype. This proband was found to carry a paternally-inherited ASXL1 missense mutation (c.4562C>T p.Ala1521Val) in the plant homeodomain (PHD), a variant of unknown significance (VUS). To investigate its functional impact, we performed integrated transcriptomic (RNA-seq) and metabolomic profiling of peripheral blood and patient-derived fibroblasts, with comparison to unaffected controls and previously characterized BOS samples. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE337807 | GEO | 2026/07/11

REPOSITORIES: GEO