The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13.

Department of Medical Microbiology and Immunology, University of California, Davis, CA 95616, USA.
Neurobiology of Disease (Impact Factor: 5.2). 10/2008; 38(2):181-91. DOI: 10.1016/j.nbd.2008.08.011
Source: PubMed

ABSTRACT A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: A variety of genetic disorders of known etiology present with behavioral profiles similar to that described in autism spectrum disorders (ASDs). Although some of these disorders are more likely to be associated with a comorbid ASD diagnosis, there exist cases in which there is a lack of empirical evidence to support a dual diagnosis. Two disorders, Williams syndrome (WS) and 15q13.3 deletion syndrome, have both been reported in the literature as examples of this phenotypic overlap. We present a case study of a young child with both WS and 15q13.3 deletion syndrome and significant ASD-related symptomatology. The results of a developmental evaluation, specifically the rationale for ruling out a comorbid ASD, are the focus of the present report. Implications for careful diagnostic consideration in cases of patients with known genetic conditions are also discussed.
    Journal of Developmental and Physical Disabilities 02/2015; 27(1). DOI:10.1007/s10882-014-9404-2 · 0.89 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: GABAA receptors (GABAARs) are Cl−-selective ligand-gated ion channels that mediate both fast synaptic inhibition and persistent tonic inhibition in the CNS. The receptor is composed of subunits that affect biophysical and pharmacological properties of the channel. A growing number of studies have examined copy number variations, mutations, and polymorphisms in genes encoding GABAAR subunits and found that changes in subunit function and expression are linked to a variety of neurological disorders. GABAARs are targets for a wide range of pharmaceutical agents including benzodiazepines, barbiturates, general anesthetics, and neurosteroids. It remains to be fully determined how genetic variations in GABAA subunits affect clinical pharmacology. Conversely, there is growing interest in the use of GABAergic drugs to treat disorders with an etiology arising from genetic variations in GABAA subunits.
    03/2014; 4(1):42-48. DOI:10.1007/s40140-013-0046-1
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome. We have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq. Analysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication. Chromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome.
    Molecular Autism 01/2014; 5(1):44. DOI:10.1186/2040-2392-5-44 · 5.49 Impact Factor

Full-text (2 Sources)

Available from
May 29, 2014