Autism spectrum disorders (ASDs), or pervasive developmental disorders (PDDs), are a category of complex developmental brain disorders that appear in early childhood, usually before the age of three. ASDs cause difficulties in social, communication and behavioural skills, but affected individuals can manifest a wide range of symptoms, from very mild to severe - hence the term "spectrum".
One in 110 children in the US has an ASD, with four times as many boys than girls being affected. In the last decade, diagnoses have increased tenfold.
ASDs are currently defined as five disorders:
Copy number variants (CNVs) – a form of structural variation - are deletions or duplications of genomic segments ranging from several thousand to a few million base pairs. A number of population-based studies have demonstrated that CNVs can affect as much as 12% of the human genome. Large scale studies have gone on to show the importance of CNVs in determining human phenotypic variation and disease susceptibility.
There is strong evidence that rare CNVs play a role in susceptibility to ASDs. A large study published in Nature by the Autism Genome Project (AGP), an international consortium of scientists from more than 60 institutions in 12 countries, compared the DNA of almost 1000 children with ASDs and healthy children, using 1 million single-nucleotide polymorphism (SNP) arrays. The study showed that rare CNVs, possibly acting in tandem, play a significant role in the genetic aetiology of this condition. The rare variants were identified in less than 1% of the normal population but strikingly, occurred almost 20% more frequently in ASD children.
Further recent research has focused on how CNVs mediate a phenotypic effect by altering gene expression levels, which is the focus of the study by Luo and colleagues published in the June 2012 edition of the American Journal of Human Genetics. A second paper from Holt and colleagues published in the May 2012 edition of the European Journal of Human Genetics investigates an alternative mechanism whereby CNVs combine the 5' and 3' ends of two genes, creating a novel 'fusion gene'.
This pair of papers sheds light on some of the genomic imbalances that could contribute to ASD pathogenesis. Bioline offers products ideal for use in genome-wide studies of structural variants and disease susceptibility.
Luo and colleagues used genome-wide transcriptome profiling to evaluate the functional consequences of rare structural CNVs in ASD. The UCLA team along with collaborators from Yale, Wellcome Trust Sanger Institute, Carnegie Mellon, and University of Pittsburgh identified a number of interesting candidate ASD loci at 12p11.22, 15q23, 1p34.3, 3q27, and 3p26.2. For example, the 3p26.2 loci, found deleted, harbours three genes: ITPR1, SETMAR and SUMF1, all of which are down-regulated. Although none of these genes has been previously associated with autism, they are all functionally linked to the nervous system.
This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level. The authors also demonstrate the usefulness of integrating gene expression and mutation data to prioritize candidate genes disrupted by potentially deleterious alterations.
Luo R., et al. Am. J. Hum. Gen. 91(1): 38–55 (2012) – Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders
Fusion-proteins play an important role in cancer genetics, as exemplified by BCR-ABL in leukemia and TMPRSS2-ERG in prostate cancers. A team from the Wellcome Trust Centre for Human Genetics, University of Oxford addressed the question of how common CNV-induced fusion transcripts are and whether they may play a role in ASD susceptibility. Firstly, using the published Illumina 1 million SNP array data from the AGP consortium, they performed bioinformatic analysis of existing CNV calls. They then validated CNVs using qPCR.
No evidence was found that fusion-gene generating CNVs led to ASD susceptibility. However, the discovery of a MAPKAPK5-ACAD10 transcript with an estimated frequency of ~1/200 suggests that gain-of-function mechanisms should be considered in future studies of genomic imbalance and disease susceptibility.
Holt, R., et al. Eur. J. Hum. Gen. doi: 10.1038/ejhg.2012.73 (2012) - CNVs Leading to Fusion Transcripts in Individuals with Autism Spectrum Disorder