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Chromatin, transcriptional and immune dysregulation in children with neurodevelopmental regression

Nishida, H.; Han, V. X.; Keating, B. A.; Zyner, K. G.; Gloss, B.; Aryamanesh, N.; Dey, P.; Marshall, L. L.; Tsang, E.; Alshammery, S.; Lau, X.; Dissanayake, R.; Mohammad, S.; Graham, M.; Patel, S.; Dale, R. C.

2025-03-06 neurology
10.1101/2025.03.05.25322433 medRxiv
Show abstract

Neurodevelopmental including autistic regression in children is often associated with inconclusive diagnostic investigations, leaving the underlying pathophysiology largely unexplored and poorly understood. To address this, we conducted peripheral blood multi-omics profiling in 15 children with neurodevelopmental regression (median age 9 (4-14) years, 60% males), and 15 healthy controls (median age 12 (7-16) years, 60% males). Our comprehensive analysis included bulk RNA sequencing (8 regression vs. 8 controls), single-cell RNA sequencing (two cohorts of 4 regression vs. 4 controls), bulk proteomics (4 regression vs. 4 controls), and phosphoproteomics (4 regression vs. 4 controls). Despite clinical heterogeneity, we identified convergent pathophysiological processes, including dysregulated pathways in epigenetic pathways (chromatin remodelling, histone modifications, transcription factors) and immune responses, as well as downregulated ribosomal and translational pathways. These disruptions in epigenetic, immune and translational processes may arise from complex genetic and environmental interactions, offering opportunities for therapeutic interventions that specifically target these pathways.

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