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

Joan C. 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 W. Tsao; Susan E. Swedo

doi:10.1016/j.cortex.2013.02.009

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

Joan C. 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 W. Tsao, Susan E. Swedo

Research output: Contribution to journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	2700-2710
Number of pages	11
Journal	Cortex
Volume	49
Issue number	10
DOIs	https://doi.org/10.1016/j.cortex.2013.02.009
State	Published - Nov 2013
Externally published	Yes

Keywords

11p Deletion
Autism
Brain-derived neurotrophic factor
IQ
WAGR syndrome

ASJC Scopus subject areas

Neuropsychology and Physiological Psychology
Experimental and Cognitive Psychology
Cognitive Neuroscience

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10.1016/j.cortex.2013.02.009

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Han, J. C., Thurm, A., Golden Williams, C., Joseph, L. A., Zein, W. M., Brooks, B. P., Butman, J. A., Brady, S. M., Fuhr, S. R., Hicks, M. D., Huey, A. E., Hanish, A. E., Danley, K. M., Raygada, M. J., Rennert, O. M., Martinowich, K., Sharp, S. J., Tsao, J. W., & Swedo, S. E. (2013). Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome. Cortex, 49(10), 2700-2710. https://doi.org/10.1016/j.cortex.2013.02.009

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 & 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

@article{b56aece59d654d80825be8705cd46044,

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.",

keywords = "11p Deletion, Autism, Brain-derived neurotrophic factor, IQ, WAGR syndrome",

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

note = "Funding Information: This study was funded by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( ZIAHD008898 and Z1AHD00641 ) and the National Institute of Mental Health ( ZIAMH002868 ) of the National Institutes of Health (NIH), and by the NIH Bench-to-Bedside Program. We thank the members of International WAGR Syndrome Association for assistance in identifying families who were willing to participate in this study. We thank Jack Yanovski and Daniel Weinberger for helpful discussions. We thank Margaret Pekar, Miriya Tune, Mark Lee, Matthew Tsang, Tanvee Singh, Emily Yin, Jamila Crossman, and Rachel Kim for assistance with psychological testing and administrative support. Disclaimer: the opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy or the Department of Defense. ",

year = "2013",

month = nov,

doi = "10.1016/j.cortex.2013.02.009",

language = "English (US)",

volume = "49",

pages = "2700--2710",

journal = "Cortex",

issn = "0010-9452",

publisher = "Masson SpA",

number = "10",

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T1 - Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome

AU - Han, Joan C.

AU - Thurm, Audrey

AU - Golden Williams, Christine

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.

AU - Tsao, Jack W.

AU - Swedo, Susan E.

N1 - Funding Information: This study was funded by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development ( ZIAHD008898 and Z1AHD00641 ) and the National Institute of Mental Health ( ZIAMH002868 ) of the National Institutes of Health (NIH), and by the NIH Bench-to-Bedside Program. We thank the members of International WAGR Syndrome Association for assistance in identifying families who were willing to participate in this study. We thank Jack Yanovski and Daniel Weinberger for helpful discussions. We thank Margaret Pekar, Miriya Tune, Mark Lee, Matthew Tsang, Tanvee Singh, Emily Yin, Jamila Crossman, and Rachel Kim for assistance with psychological testing and administrative support. Disclaimer: the opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy or the Department of Defense.

PY - 2013/11

Y1 - 2013/11

N2 - 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.

AB - 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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KW - Autism

KW - Brain-derived neurotrophic factor

KW - IQ

KW - WAGR syndrome

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

Abstract

Keywords

ASJC Scopus subject areas

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