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 "second hit" 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 "second mGluR hits". 20% with 22q11.2DS + ASD had "second hits" 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.
authors.affiliation: Seattle Children's Hospital, Department of Pediatrics, Seattle, WA 98105 USA.|Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Wenger
authors.affiliation: Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.
authors.forename: Charlly
authors.initials: C
authors.lastname: Kao
authors.affiliation: Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.
authors.forename: Donna M
authors.initials: DM
authors.lastname: McDonald-McGinn
authors.affiliation: Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.affiliation: Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Bailey
authors.affiliation: Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Schultz
authors.affiliation: Albert Einstein College of Medicine, Department of Genetics, Bronx, NY 10461 USA.
authors.forename: Bernice E
authors.initials: BE
authors.lastname: Morrow
authors.affiliation: Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Emanuel
authors.affiliation: Children's Hospital of Philadelphia, Department of Pediatrics, Philadelphia, PA 19104 USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000209:etiology*; D002872:Chromosome Deletion; D002892:Chromosomes, Human, Pair 22; D056915:DNA Copy Number Variations; D018628:Gene Dosage; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D012306:Risk; D013577:Syndrome
chemical_list: D018094:Receptors, Metabotropic Glutamate