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Original Investigation
December 2016

Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1A Study of the International NF1-ASD Consortium Team (INFACT)

Author Affiliations
  • 1Department of Neurology, Washington University School of Medicine, St Louis, Missouri
  • 2Center for Neuroscience and Behavioral Medicine at Children’s National Health System, Washington, DC
  • 3Institute of Brain Behavior and Mental Health, The University of Manchester, Manchester, England
  • 4Manchester Academic Health Sciences Centre, Manchester, England
  • 5Central Manchester University NHS Foundation Trust, Manchester, England
  • 6Department of Human Genetics, Laboratory for Neurofibromatosis Research, Katholieke Universiteit Leuven, Leuven, Belgium
  • 7Murdoch Children’s Research Institute, Royal Children’s Hospital, Melbourne, Australia
  • 8Department of Paediatrics, University of Melbourne, Melbourne, Australia
  • 9Center for Pediatric Behavioral Health, Pediatric Institute, Cleveland Clinic, Cleveland, Ohio
  • 10Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco
  • 11Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
  • 12Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri
JAMA Psychiatry. 2016;73(12):1276-1284. doi:10.1001/jamapsychiatry.2016.2600
Key Points

Question  What is the nature of autistic symptomatology in neurofibromatosis type 1 (NF1)?

Findings  In this analysis of pooled, individual-level primary data from 531 individuals, males and females with NF1 exhibited a significant burden of autistic traits and symptoms in a continuous distribution that encompassed the full range of mild (subclinical) to severe (clinical). When NF1 was inherited, there was a high degree of within-family association for the severity of autistic traits.

Meaning  Autistic symptoms represent a variable, mutation-specific component of the neurodevelopmental impairments in this monogenic syndrome and establish NF1 as a quantitative trait locus for autism.


Importance  Recent reports have demonstrated a higher incidence of autism spectrum disorder (ASD) and substantially elevated autistic trait burden in individuals with neurofibromatosis type 1 (NF1). However, important discrepancies regarding the distribution of autistic traits, sex predominance, and association between ASD symptoms and attentional problems have emerged, and critical features of the ASD phenotype within NF1 have never been adequately explored. Establishing NF1 as a monogenic cause for ASD has important implications for affected patients and for future research focused on establishing convergent pathogenic mechanisms relevant to the potential treatment targets for ASD.

Objective  To characterize the quantitative autistic trait (QAT) burden in a pooled NF1 data set.

Design, Setting, and Participants  Anonymized, individual-level primary data were accumulated from 6 tertiary referral centers in the United States, Belgium, United Kingdom, and Australia. A total of 531 individuals recruited from NF1 clinical centers were included in the study.

Main Outcomes and Measures  Distribution of ASD traits (Social Responsiveness Scale, second edition [SRS-2], with T scores of ≥75 associated with a categorical ASD diagnosis); attention-deficit/hyperactivity disorder (ADHD) traits (4 versions of Conners Rating Scale, with T scores of ≥65 indicating clinically significant ADHD symptoms); ASD symptom structure, latent structure, base rate derived from mixture modeling; and familiality.

Results  Of the 531 patients included in the analysis, 247 were male (46.5%); median age was 11 years (range, 2.5-83.9 years). QAT scores were continuously distributed and pathologically shifted; 13.2% (95% CI, 10.3%-16.1%) of individuals scored within the most severe range (ie, above the first percentile of the general population distribution) in which the male to female ratio was markedly attenuated (1.6:1) relative to idiopathic ASD. Autistic symptoms in this NF1 cohort demonstrated a robust unitary factor structure, with the first principal component explaining 30.9% of the variance in SRS-2 scores, and a strong association with ADHD symptoms (r = 0.61). Within-family correlation for QAT burden (intraclass correlation coefficient, 0.73 in NF1-affected first-degree relatives) exceeded that observed in the general population and ASD family samples.

Conclusions and Relevance  This study provides confirmation that the diversity of mutations that give rise to NF1 function as quantitative trait loci for ASD. Moreover, the within-family correlation implicates a high degree of mutational specificity for this associated phenotype. Clinicians should be alerted to the increased frequency of this disabling comorbidity, and the scientific community should be aware of the potential for this monogenic disorder to help elucidate the biological features of idiopathic autism.