title: Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.
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.
authors.affiliation: Unit on Metabolism and Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD, USA; Section on Growth and Obesity, Program in Developmental Endocrinology and Genetics, NICHD, National Institutes of Health, Bethesda, MD, USA. Electronic address: hanjo@mail.nih.gov.
authors.forename: Joan C
authors.initials: JC
authors.lastname: Han
authors.forename: Audrey
authors.initials: A
authors.lastname: Thurm
authors.forename: Christine
authors.initials: C
authors.lastname: Golden Williams
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Joseph
authors.forename: Wadih M
authors.initials: WM
authors.lastname: Zein
authors.forename: Brian P
authors.initials: BP
authors.lastname: Brooks
authors.forename: John A
authors.initials: JA
authors.lastname: Butman
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Brady
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Fuhr
authors.forename: Melanie D
authors.initials: MD
authors.lastname: Hicks
authors.forename: Amanda E
authors.initials: AE
authors.lastname: Huey
authors.forename: Alyson E
authors.initials: AE
authors.lastname: Hanish
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Danley
authors.forename: Margarita J
authors.initials: MJ
authors.lastname: Raygada
authors.forename: Owen M
authors.initials: OM
authors.lastname: Rennert
authors.forename: Keri
authors.initials: K
authors.lastname: Martinowich
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sharp
authors.forename: Jack W
authors.initials: JW
authors.lastname: Tsao
authors.forename: Susan E
authors.initials: SE
authors.lastname: Swedo
mesh_terms: D000223:Adaptation, Psychological / Q000502:physiology*; D000293:Adolescent; D000328:Adult; D015783:Aniridia / Q000150:complications / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics / Q000523:psychology; D001519:Behavior / Q000502:physiology; D001921:Brain / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency*; D002648:Child; D002653:Child Behavior Disorders / Q000209:etiology / Q000523:psychology; D002675:Child, Preschool; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D015331:Cohort Studies; D003337:Corpus Callosum / Q000473:pathology; D005260:Female; D057895:Haploinsufficiency / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D014787:Vision Tests; D014792:Visual Acuity; D017624:WAGR Syndrome / Q000235:genetics*; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C579455:BDNF protein, human
keywords: 11p Deletion; Autism; Brain-derived neurotrophic factor; IQ; WAGR syndrome