The Relation Between Genotype and Behavioral Phenotype in Children and Adolescents With Neurofibromatosis Type 1

Objective Children with the autosomal dominant disorder Neurofibromatosis 1 (NF1) exhibit a high prevalence of both attention-deficit/hyperactivity disorder (ADHD) (up to 40%) and autism (up to 11%). The genetic mechanisms underlying these behavioral phenotypes are largely unexplored. This study examines the associations between various NF1 genotypes and NF1 behavioral phenotypes. Method A retrospective cohort study was carried out in children and adolescents with NF1 from three national referral centers for NF1 (the Netherlands, the UK and Belgium). Anonymized data was collected on five primary outcomes to characterize the behavioral phenotype in NF1: autistic traits (Social Responsiveness Scale 2 [SRS-2] Total T-score and Autism Diagnostic Observation Schedule [ADOS] Calibrated Severity Score); attention-deficit/hyperactivity disorder characteristics (Conners Inattention and Hyperactivity T-score) and global behavioral/emotional problems (Child Behavior Checklist [CBCL] Total Problems T-score). Genotypes were categorized based on three types of NF1 variant definitions: (1) coding variant type, (2) variant effect (truncating vs. non-truncating variants), and (3) the location within the gene. Results In total, 408 children and adolescents with NF1 were included, of which 187 (46%) were female. Range of median age at assessment across all outcomes was 6.0-8.4 years. Behavioral outcomes were not associated to any of the NF1 genotypes categories examined. Conclusion In this large cohort, autism traits, ADHD characteristics or global behavioral/emotional problems were not associated with NF1 variant type, effect or location. These findings indicate that the NF1 variant classes examined here do not differentially influence the NF1 behavioral phenotype, although genotype–phenotype associations at the single codon level cannot be ruled out.