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.
Highlights
Evidence from recent human studies and animal models suggest that syndromic forms of Autism Spectrum Disorder (ASD) have behavioral overlap with idiopathic ASD but that there are identifiable behavioral signatures in each disorder[23]
Children with ASD and mGluR CNVs were more likely to have syndromic features than children with ASD without mGluR CNVs (74% of mGluR + classified as “Syndromic” vs. 16% of mGluR – ASD; p < 0.0001)
As mGluR network genes are present in the 22q11.2 region (RANBP1) and on chromosome 21 (APP GRIK1 MX1 PCBP3 SETD4), patients with ASD in the presence of 22q11.2DS, 22q11.2DupS or Trisomy 21 accounted for approximately one third of the patients with Syndromic ASD + mGluR network changes
Summary
Evidence from recent human studies and animal models suggest that syndromic forms of ASD have behavioral overlap with idiopathic ASD but that there are identifiable behavioral signatures in each disorder[23]. Other recent studies have proposed that phenotypic differences might be seen in children harboring mutations affecting genes associated with the mGluR gene network, including those with identifiable syndromes[23,25]. One limitation of these prior studies is that careful identification of children who may be more likely to have a syndromic form of ASD is limited. 20% of children with ASD are suspected to have an underlying genetic syndrome[2] For this reason, the American College of Medical Genetics recommends that all children with an ASD receive a genome-wide microarray and undergo an evaluation by a clinical geneticist.
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