The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder

Tara L. Wenger, Charlly Kao, Donna M. McDonald-Mcginn, Elaine H. Zackai, Alice Bailey, Robert T. Schultz, Bernice E. Morrow, Beverly S. Emanuel, Hakon Hakonarson

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV's) were overrepresented in children with syndromic ASD and if mGluR â œ second hitâ confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV's are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV's vs. 3.2% in controls (p <0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p <0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for â œ second mGluR hitsâ 20% with 22q11.2DS + ASD ha second hitsâ in mGluR network genes vs 2% in 22q11.2DS-ASD (p <0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.

Original languageEnglish (US)
Article number19372
JournalScientific Reports
Volume6
DOIs
StatePublished - Jan 19 2016

Fingerprint

DiGeorge Syndrome
Gene Regulatory Networks
Autism Spectrum Disorder
Metabotropic Glutamate 5 Receptor
Fragile X Syndrome
Tuberous Sclerosis

ASJC Scopus subject areas

  • General

Cite this

Wenger, T. L., Kao, C., McDonald-Mcginn, D. M., Zackai, E. H., Bailey, A., Schultz, R. T., ... Hakonarson, H. (2016). The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder. Scientific Reports, 6, [19372]. https://doi.org/10.1038/srep19372

The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder. / Wenger, Tara L.; Kao, Charlly; McDonald-Mcginn, Donna M.; Zackai, Elaine H.; Bailey, Alice; Schultz, Robert T.; Morrow, Bernice E.; Emanuel, Beverly S.; Hakonarson, Hakon.

In: Scientific Reports, Vol. 6, 19372, 19.01.2016.

Research output: Contribution to journalArticle

Wenger, TL, Kao, C, McDonald-Mcginn, DM, Zackai, EH, Bailey, A, Schultz, RT, Morrow, BE, Emanuel, BS & Hakonarson, H 2016, 'The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder', Scientific Reports, vol. 6, 19372. https://doi.org/10.1038/srep19372
Wenger, Tara L. ; Kao, Charlly ; McDonald-Mcginn, Donna M. ; Zackai, Elaine H. ; Bailey, Alice ; Schultz, Robert T. ; Morrow, Bernice E. ; Emanuel, Beverly S. ; Hakonarson, Hakon. / The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder. In: Scientific Reports. 2016 ; Vol. 6.
@article{011ede11ff23425398a36cbf235c7019,
title = "The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder",
abstract = "While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV's) were overrepresented in children with syndromic ASD and if mGluR {\^a} œ second hit{\^a} confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV's are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5{\%} of ASD had mGluR CNV's vs. 3.2{\%} in controls (p <0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74{\%} vs 16{\%}, p <0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for {\^a} œ second mGluR hits{\^a} 20{\%} with 22q11.2DS + ASD ha second hits{\^a} in mGluR network genes vs 2{\%} in 22q11.2DS-ASD (p <0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.",
author = "Wenger, {Tara L.} and Charlly Kao and McDonald-Mcginn, {Donna M.} and Zackai, {Elaine H.} and Alice Bailey and Schultz, {Robert T.} and Morrow, {Bernice E.} and Emanuel, {Beverly S.} and Hakon Hakonarson",
year = "2016",
month = "1",
day = "19",
doi = "10.1038/srep19372",
language = "English (US)",
volume = "6",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - The Role of mGluR Copy Number Variation in Genetic and Environmental Forms of Syndromic Autism Spectrum Disorder

AU - Wenger, Tara L.

AU - Kao, Charlly

AU - McDonald-Mcginn, Donna M.

AU - Zackai, Elaine H.

AU - Bailey, Alice

AU - Schultz, Robert T.

AU - Morrow, Bernice E.

AU - Emanuel, Beverly S.

AU - Hakonarson, Hakon

PY - 2016/1/19

Y1 - 2016/1/19

N2 - While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV's) were overrepresented in children with syndromic ASD and if mGluR â œ second hitâ confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV's are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV's vs. 3.2% in controls (p <0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p <0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for â œ second mGluR hitsâ 20% with 22q11.2DS + ASD ha second hitsâ in mGluR network genes vs 2% in 22q11.2DS-ASD (p <0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.

AB - While abnormal signaling mediated through metabotropic glutamate receptor 5 (mGluR5) is involved in the pathophysiology of Autism Spectrum Disorder (ASD), Fragile X Syndrome and Tuberous Sclerosis, the role of other mGluRs and their associated signaling network genes in syndromic ASD is unknown. This study sought to determine whether mGluR Copy Number Variants (CNV's) were overrepresented in children with syndromic ASD and if mGluR â œ second hitâ confers additional risk for ASD in 22q11.2 Deletion Syndrome (22q11DS). To determine whether mGluR network CNV's are enriched in syndromic ASD, we examined microarrays from children with ASD (n = 539). Patient categorization (syndromic vs nonsyndromic) was done via blinded medical chart review in mGluR positive and randomly selected mGluR negative cases. 11.5% of ASD had mGluR CNV's vs. 3.2% in controls (p <0.001). Syndromic ASD was more prevalent in children with mGluR CNVs (74% vs 16%, p <0.001). A comparison cohort with 22q11DS (n = 25 with ASD, n = 50 without ASD), all haploinsufficient for mGluR network gene RANBP1, were evaluated for â œ second mGluR hitsâ 20% with 22q11.2DS + ASD ha second hitsâ in mGluR network genes vs 2% in 22q11.2DS-ASD (p <0.014). We propose that altered RANBP1 expression may provide a mechanistic link for several seemingly unrelated genetic and environmental forms of ASD.

UR - http://www.scopus.com/inward/record.url?scp=84955240372&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84955240372&partnerID=8YFLogxK

U2 - 10.1038/srep19372

DO - 10.1038/srep19372

M3 - Article

VL - 6

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 19372

ER -