Clinical and genetic factors associated with regression in children with autism spectrum disorders

Background 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 ( _reg ASD), characterized by the acute loss of previously acquired skills. The mechanisms, predictors, and molecular basis of _reg ASD remain poorly understood. Methods 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. Results Developmental regression was detected in 74 children (15%). Prior to regression, _reg ASD children exhibited more favorable neurodevelopmental profiles, including lower rates of prematurity, higher birth weight and height, and earlier acquisition of first words, compared with non-regressive ASD (non- _reg ASD) peers. However, after regression, _reg ASD 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 _reg ASD 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- _reg ASD genetic profiles. Conclusions Our findings support the hypothesis that _reg ASD represents a distinct clinical and molecular subgroup within ASD. The unique molecular signatures identified in _reg ASD implicate immune and synaptic pathways, highlighting the need for targeted research and potential therapeutic interventions for this subgroup.