Clinical and Genetic Factors Associated With Regression in Children With Autism Spectrum Disorders.

Abstract

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with complex genetic and environmental underpinnings. A clinically significant subset of children with ASD experience developmental regression (regASD), characterized by the acute loss of previously acquired skills. The mechanisms, predictors, and molecular basis of regASD remain poorly understood. We retrospectively and prospectively analyzed a cohort of 505 children diagnosed with ASD at the Center of Excellence for Autism and Neurodevelopmental Disorders (Paris, France) between 2017 and 2023. Clinical, neurodevelopmental, and genetic data were collected, including detailed developmental histories, standardized diagnostic assessments (ADI-R, ADOS-2, VABS), and chromosomal microarray analysis (CMA). Statistical analyses included classification tree algorithms and principal component analysis to identify clinical predictors of regression, and gene ontology enrichment to explore molecular pathways. Developmental regression was detected in 74 children (15%). Prior to regression, regASD children exhibited more favorable neurodevelopmental profiles, including lower rates of prematurity, higher birth weight and height, and earlier acquisition of first words, compared with nonregressive ASD (non-regASD) peers. However, after regression, regASD children had significantly more severe neurodevelopmental impairments across cognitive, adaptive, and social domains (p < 0.001). Routine clinical variables did not reliably predict the onset of regression. CMA revealed that regASD is associated with distinct genetic deletions enriched in immune, inflammatory (particularly Type I interferon), oxidative stress, angiogenesis, and synaptic pathways, with minimal overlap with non-regASD genetic profiles. Our findings are consistent with the hypothesis that regASD may represent a distinct clinical and molecular subgroup within ASD. The molecular signatures identified in regASD suggest involvement of immune and synaptic pathways, highlighting the need for further targeted research to clarify their potential therapeutic implications for this subgroup.