Abstract

Neurodevelopmental disorders (NDDs) encompass heterogeneous cognitive, motor, and psychiatric manifestations that typically require extensive behavioural assessments for characterization. Individuals carrying 16p11.2 copy number variations (CNVs), including both deletions and duplications, represent a relatively common NDD subgroup marked by wide variability in psychiatric symptoms, as well as metabolic and peripheral abnormalities, complicating prediction of disease trajectory and treatment response. The identification of biomarkers in easily accessible tissues, such as peripheral blood mononuclear cells (PBMCs), could provide valuable tools for diagnosis and prognosis, yet remains an unmet clinical need. Converging evidence implicates dysregulation of ubiquitous signalling pathways, including ERK and mTOR cascades, in altered protein synthesis across both idiopathic and genetic NDDs. Here, using a hypothesis-driven screening approach, we examined candidate peripheral biomarkers in individuals with 16p11.2 deletions and duplications. We identified a significant reduction of ribosomal protein S6 kinase (p70S6K) levels in PBMCs across both genotypes. Notably, the magnitude of p70S6K reduction correlated with the severity of autistic symptoms independently of CNV genotype. In parallel, MAPK3/ERK1 protein levels mirrored gene dosage, showing increased expression in duplication carriers and reduced levels in deletion carriers, in accordance with the genotype. Collectively, these findings indicate that peripheral molecular alterations may support clinical stratification and suggest that p70S6K represents a promising biomarker for symptom severity and potentially treatment responsiveness in NDD patients carrying 16p11.2 CNVs.