Sources of Phenotypical Variability in Autism Spectrum Disorder and Their Effects on Treatment
Sources of Phenotypical Variability in Autism Spectrum Disorder and Their Effects on Treatment

Summary/Abstract: Autism Spectrum Disorder (ASD) is a clinically and etiologically heterogeneous neurodevelopmental disorder. Approaching ASD as a single categorical diagnosis without addressing heterogeneity may limit intervention efficacy. A narrative, critical review was conducted using the PubMed database for studies between 2020-2025 and using “autism” AND “heterogeneity” (n= 3869) and “ASD” AND “heterogeneity” (n= 2391). A total of 435 references were selected based on titles, 167 based on abstracts, and 89 based on text reviews. Finally, 59 studies were reviewed. The DSM-5 criteria and their evolution, genetics, gender, environmental/epigenetic risk factors, comorbidities, development, syndromic vs. non-syndromic presentations, simplex vs. multiplex families, and autistic regression were the main sources of heterogeneity in the studies. The “deficit” term in the DSM-5 should be operationalized in conjunction with disability levels. ASD should be better characterized in female samples. Studies on genetic, environmental, and epigenetic risk factors should model these interactions. Protective factors should also be evaluated in future studies. Comorbidities may be grouped according to type (psychiatric vs. medical) and degree (symptom vs. syndrome), and temporal changes in symptoms can be modelled. Incident ASD cases should be screened using genetic tests and evaluated for dysmorphology. International databases of simplex/multiplex families and regressive ASD cases may help better characterize samples.

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