1. Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.
- Author
-
Han JC, Thurm A, Golden Williams C, Joseph LA, Zein WM, Brooks BP, Butman JA, Brady SM, Fuhr SR, Hicks MD, Huey AE, Hanish AE, Danley KM, Raygada MJ, Rennert OM, Martinowich K, Sharp SJ, Tsao JW, and Swedo SE
- Subjects
- Adolescent, Adult, Aniridia complications, Aniridia genetics, Autistic Disorder genetics, Autistic Disorder psychology, Behavior physiology, Brain pathology, Child, Child Behavior Disorders etiology, Child Behavior Disorders psychology, Child, Preschool, Chromosome Deletion, Chromosome Mapping, Chromosomes, Human, Pair 11 genetics, Cognition physiology, Cognition Disorders physiopathology, Cohort Studies, Corpus Callosum pathology, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuropsychological Tests, Vision Tests, Visual Acuity, Young Adult, Adaptation, Psychological physiology, Brain-Derived Neurotrophic Factor deficiency, Cognition Disorders genetics, Cognition Disorders psychology, Haploinsufficiency genetics, Haploinsufficiency physiology, WAGR Syndrome genetics
- Abstract
In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6-28 years), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7-54 years), and 20 healthy controls (4-32 years) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high-resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/- subjects (n = 15), compared with BDNF intact (+/+) subjects (n = 13), had lower adaptive behaviour (p = .02), reduced cognitive functioning (p = .04), higher levels of reported historical (p = .02) and current (p = .02) social impairment, and higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgement, 3 subjects (2 BDNF+/- and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development., (Published by Elsevier Ltd.)
- Published
- 2013
- Full Text
- View/download PDF