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Abstract Background Existing research has demonstrated elevated autistic behaviours in children with neurofibromatosis type 1 (NF1), but the autistic phenotype and its relationship to other neurodevelopmental manifestations of NF1 remains unclear. To address this gap, we performed detailed characterisation of autistic behaviours in children with NF1 and investigated their association with other common NF1 child characteristics. Methods Participants were drawn from a larger cross-sectional study examining autism in children with NF1. The population analysed in this study scored above threshold on the Social Responsiveness Scale-Second Edition (T-score ≥ 60; 51% larger cohort) and completed the Autism Diagnostic Interview-Revised (ADI-R) and/or the Autism Diagnostic Observation Schedule-Second Edition (ADOS-2). All participants underwent evaluation of their intellectual function, and behavioural data were collected via parent questionnaires. Results The study cohort comprised 68 children (3–15 years). Sixty-three per cent met the ADOS-2 ‘autism spectrum’ cut-off, and 34% exceeded the more stringent threshold for ‘autistic disorder’ on the ADI-R. Social communication symptoms were common and wide-ranging, while restricted and repetitive behaviours (RRBs) were most commonly characterised by ‘insistence on sameness’ (IS) behaviours such as circumscribed interests and difficulties with minor changes. Autistic behaviours were weakly correlated with hyperactive/impulsive attention deficit hyperactivity disorder (ADHD) symptoms but not with inattentive ADHD or other behavioural characteristics. Language and verbal IQ were weakly related to social communication behaviours but not to RRBs. Limitations Lack of genetic validation of NF1, no clinical diagnosis of autism, and a retrospective assessment of autistic behaviours in early childhood. Conclusions Findings provide strong support for elevated autistic behaviours in children with NF1. While these behaviours were relatively independent of other NF1 comorbidities, the importance of taking broader child characteristics into consideration when interpreting data from autism-specific measures in this population is highlighted. Social communication deficits appear similar to those observed in idiopathic autism and are coupled with a unique RRB profile comprising prominent IS behaviours. This autistic phenotype and its relationship to common NF1 comorbidities such as anxiety and executive dysfunction will be important to examine in future research. Current findings have important implications for the early identification of autism in NF1 and clinical management.

Abstract Objective Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism‐based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test‐retest reliability of the measures and the application of data reduction techniques to improve reproducibility. Methods Data were analyzed from the STARS clinical trial (n = 146), a multi‐center double‐blind placebo‐controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra‐class correlation coefficients were generated between pre‐ and post‐performances (16‐week interval) on neuropsychological endpoints in the placebo group to determine test‐retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. Results Test‐retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test‐retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. Interpretation These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test‐retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

We describe the generation and characterisation of four human induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMC) from individuals with neurofibromatosis type (NF1). PBMC reprogramming was performed using a non-integrative Sendai virus containing the reprogramming factors OCT4, SOX2, MYC and KLF4. All iPSC lines exhibited a normal karyotype, and pluripotency was validated by flow cytometry (EPCAM, TRA-1-81, SSEA1 and CD9) and immunofluorescence (OCT4 and Nanog). Differentiation of the cells into the three embryonic germ layers was confirmed using immunofluorescence. These iPSC lines are a valuable pre-clinical resource to study the molecular mechanisms underlying NF1.