Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome

Joan Han, Audrey Thurm, Christine Golden Williams, Lisa A. Joseph, Wadih M. Zein, Brian P. Brooks, John A. Butman, Sheila M. Brady, Shannon R. Fuhr, Melanie D. Hicks, Amanda E. Huey, Alyson E. Hanish, Kristen M. Danley, Margarita J. Raygada, Owen M. Rennert, Keri Martinowich, Stephen J. Sharp, Jack Tsao, Susan E. Swedo

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2700-2710
Number of pages11
JournalCortex
Volume49
Issue number10
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

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Haploinsufficiency
Psychological Adaptation
Brain-Derived Neurotrophic Factor
WAGR Syndrome
Aniridia
Autistic Disorder
Partial deletion Chromosome 11p
Neuronal Plasticity
Comparative Genomic Hybridization
Human Development
Oligonucleotide Array Sequence Analysis
Intelligence
Visual Acuity
Central Nervous System
Interviews

All Science Journal Classification (ASJC) codes

  • Neuropsychology and Physiological Psychology
  • Experimental and Cognitive Psychology
  • Cognitive Neuroscience

Cite this

Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. / Han, Joan; Thurm, Audrey; Golden Williams, Christine; Joseph, Lisa A.; Zein, Wadih M.; Brooks, Brian P.; Butman, John A.; Brady, Sheila M.; Fuhr, Shannon R.; Hicks, Melanie D.; Huey, Amanda E.; Hanish, Alyson E.; Danley, Kristen M.; Raygada, Margarita J.; Rennert, Owen M.; Martinowich, Keri; Sharp, Stephen J.; Tsao, Jack; Swedo, Susan E.

In: Cortex, Vol. 49, No. 10, 01.11.2013, p. 2700-2710.

Research output: Contribution to journalArticle

Han, J, 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, J & Swedo, SE 2013, 'Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome', Cortex, vol. 49, no. 10, pp. 2700-2710. https://doi.org/10.1016/j.cortex.2013.02.009
Han, Joan ; Thurm, Audrey ; Golden Williams, Christine ; Joseph, Lisa A. ; Zein, Wadih M. ; Brooks, Brian P. ; Butman, John A. ; Brady, Sheila M. ; Fuhr, Shannon R. ; Hicks, Melanie D. ; Huey, Amanda E. ; Hanish, Alyson E. ; Danley, Kristen M. ; Raygada, Margarita J. ; Rennert, Owen M. ; Martinowich, Keri ; Sharp, Stephen J. ; Tsao, Jack ; Swedo, Susan E. / Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. In: Cortex. 2013 ; Vol. 49, No. 10. pp. 2700-2710.
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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.",
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AU - Joseph, Lisa A.

AU - Zein, Wadih M.

AU - Brooks, Brian P.

AU - Butman, John A.

AU - Brady, Sheila M.

AU - Fuhr, Shannon R.

AU - Hicks, Melanie D.

AU - Huey, Amanda E.

AU - Hanish, Alyson E.

AU - Danley, Kristen M.

AU - Raygada, Margarita J.

AU - Rennert, Owen M.

AU - Martinowich, Keri

AU - Sharp, Stephen J.

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AU - Swedo, Susan E.

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