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Glycan susceptibility factors in autism spectrum disorders.

ABSTRACT: Idiopathic autism spectrum disorders (ASDs) are neurodevelopmental disorders with unknown etiology. An estimated 1:68 children in the U.S. are diagnosed with ASDs, making these disorders a substantial public health issue. Recent advances in genome sequencing have identified numerous genetic variants across the ASD patient population. Many genetic variants identified occur in genes that encode glycosylated extracellular proteins (proteoglycans or glycoproteins) or enzymes involved in glycosylation (glycosyltransferases and sulfotransferases). It remains unknown whether "glycogene" variants cause changes in glycosylation and whether they contribute to the etiology and pathogenesis of ASDs. Insights into glycan susceptibility factors are provided by studies in the normal brain and congenital disorders of glycosylation, which are often accompanied by ASD-like behaviors. The purpose of this review is to present evidence that supports a contribution of extracellular glycans and glycoconjugates to the etiology and pathogenesis of idiopathic ASDs and other types of pervasive neurodevelopmental disorders.

SUBMITTER: Dwyer CA

PROVIDER: S-EPMC5556687 | biostudies-other | 2016 Oct

REPOSITORIES: biostudies-other

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Project description:Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into 3 phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all 3 subgroups of ASD are 5 novel genes which appear to associate with androgen sensitivity, which may underlie the strong 4:1 bias towards affected males. Gene expression profiling of 116 LCL from autistic (87) and nonautistic (29) individuals were obtained using a custom-printed DNA microarray containing 39,936 elements (TIGR 40K Human array, GPL3427) and a reference design in which each sample was compared to the Stratagene Universal Human RNA standard. The 87 autistic samples were divided into phenotypic subgroups (language, mild, savant) on the basis of cluster analyses of scores from an autism diagnostic questionnaire, the Autism Diagnostic Interview-Revised instrument. Differentially expressed genes were determined for all autistic vs. control groups, as well as for each of 3 phenotypic ASD groups and controls.

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Glycan susceptibility factors in autism spectrum disorders.

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