p70 ribosomal protein S6 Kinase (p70S6K) as a potential peripheral biomarker for autistic symptoms in 16p11.2 deletion and duplication syndromes

Abstract

Neurodevelopmental disorders (NDDs) encompass cognitive, motor, and psychiatric manifestations that require extensive assessments spanning different clinical domains. Individuals with syndromes caused by micro-deletions and -duplications in the proximal region of 16p11.2 have increased likelihood of neurodevelopmental and mental health symptoms, as well as cardiometabolic disorder. However, considerable phenotypic variability complicates prediction of risk, disease trajectory and treatment response. The identification of biomarkers in easily accessible tissues, such as Peripheral Blood Mononuclear Cells (PBMCs), could help 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 NDDs of both idiopathic and genetic origin. Here, using a hypothesis-driven approach, we examined candidate peripheral biomarkers in individuals with 16p11.2 proximal deletion and duplication syndromes. We established increased psychopathology and cognitive deficits in individuals with 16p11.2 deletion and duplication syndromes, compared to sibling controls. Furthermore, we identified a significant reduction of p70 S6 kinase (p70S6K) levels in PBMCs across both genotypes compared to controls. Notably, the magnitude of p70S6K reduction correlated with the severity of autistic symptoms independent of CNV genotype. In contrast, MAPK3/ERK1 protein levels mirrored the gene dosage, showing increased expression in individuals with the duplication and reduced levels in those with the deletion. These findings suggest that peripheral alterations in p70S6K may relate to variation in autism-related traits within individuals with 16p11.2 deletion and duplication syndromes, indicating that it may repreesent a potential biomarker of autism-associated symptom severity in this genetically at-risk group.