Autism in neurofibromatosis type 1: prevalence, phenotype and clinical implications

Monogenic conditions, such as neurofibromatosis type 1 (NF1), provide a unique opportunity to study autism within a known molecular pathway. This study estimated the prevalence of autism in a large international NF1 cohort and examined how autistic traits relate to cognitive, behavioral, and adaptive functioning.

In this cross-sectional study, 202 children with NF1 and 106 typically developing controls (aged 3-15 years) completed standardized cognitive testing and parent-reported behavioral measures. NF1 participants scoring ≥ 60 on the Social Responsiveness Scale-2 were evaluated using the Autism Diagnostic Observation Schedule-2 and Autism Diagnostic Interview-Revised, with DSM-5-TR autism diagnoses established by multidisciplinary consensus. Neurodevelopmental profiles were compared across NF1 subgroups (autism, broader autistic traits, no-autistic-traits) and controls.

Autistic traits were elevated and continuously distributed in NF1. An estimated 28% (95%CI: 21.7%-34.3%) met DSM-5-TR criteria for autism and 22% exhibited a broader autistic phenotype, with comparable rates in males and females. Children classified as autistic and those with broader autistic traits showed similarly marked behavioral and adaptive challenges, whereas NF1 children without autistic traits showed milder difficulties. Findings establish NF1 as a condition in which autism is common and clinically significant. Autistic features in NF1 occur across the cognitive spectrum and are accompanied by overlapping behavioral and functional impairments that challenge categorical diagnostic boundaries.

The cross-sectional design precludes conclusions about developmental trajectories. The absence of genotype data prevented exploration of genotype-phenotype correlations and the influence of polygenic risk factors outside the NF1 locus.

Findings provide strong support for routine, early screening for autism in NF1 and the recognition that subthreshold traits can be similarly impairing. NF1 provides a powerful model for investigating how a monogenic condition contributes to diverse neurodevelopmental profiles and informs precision-medicine approaches in autism.