Rare genetic variations of DNA implicated in autism

Losses and duplications of whole chunks of DNA at sites across our genomes are likely to play a role in autism spectrum disorders, suggests a new study published in the journal Nature.

The international research group, which includes members from The University of Manchester, say the findings could lead to the development of new treatments for autism.

“Our results suggest that this type of genetic variation is a significant risk factor in susceptibility to autism,” said Dr Janine Lamb, from the Centre for Integrated Genomic Medical Research at The University of Manchester.

“Identification of these genetic variants is beginning to highlight the biological pathways that are likely to be involved. We hope that this knowledge will lead to improved diagnosis, earlier intervention and better outcomes for individuals affected by autism and their families in the future.”

Autism spectrum disorders are known to have a predominantly genetic basis from twin and family studies, but the genetic changes responsible are varied and remain largely unknown.

Single gene mutations or large rearrangements in chromosomes are responsible for a minority of cases of autism. Some rare mutations in genes are known to be risk factors for the condition, and a range of commonly occurring changes in DNA sequence have been linked to autism but only account for a small proportion of its genetic basis.

Stretches of DNA – perhaps including one gene, perhaps 10–20 genes – are often lost or duplicated in our genomes. Sometimes these genetic variations, called copy number variants, are inherited from parents, while some appear for the first time in offspring. Scientists had wondered if some copy number variants that occur only rarely (in fewer than one in 100 people) might account for a significant proportion of autism’s missing genetic component.

The technology is now available to search for rare copy number variants across the whole human genome. So the Autism Genome Project Consortium – an international collaboration involving researchers from institutions across the USA, Canada and Europe, set out to compare the incidence of rare copy number variants in 996 people with autism spectrum disorders and 1,287 unaffected people, all with European ancestry.

They found that people with autism spectrum disorders had on average 19% more copy number variants that disrupted genes than in the control group.

Within the copy number variants that were found, the researchers were able to identify where they had been inherited and where they had newly emerged by looking at parent-child transmission.

Many of the lost or duplicated DNA chunks occurred in genetic regions already implicated in autism. But they were found in many new gene regions too, suggesting these genes offer new biological pathways that might be involved in autism spectrum disorders.

The scientists also looked at the functions of the genes interrupted by the copy number variants. The team found that genes involved in both neural cell development and signalling pathways were unusually common.

Many of these affected genes are also thought to play a role in other neurodevelopmental disorders and these results fit with what is being discovered in other conditions. Rare copy number variants have already been shown to play a role in learning disability, and there seems to be some overlap in the genes implicated in both autism and learning disability. There may even be some overlap with other conditions such as epilepsy and schizophrenia. It is becoming clear that affected genes and pathways can lead to very different outcomes in different people.

Tests for the presence of copy number variants are already available to help the diagnosis of learning disability. Where children are thought to have a learning disability, genetic tests may be done that first look under the microscope for abnormalities in chromosomes then DNA microarrays might be used to search for copy number variants. The tests can confirm a diagnosis and help guide the care and support that is then provided. Genetic counselling for the children and their families is always available.

The team in Manchester are now carrying out a pilot study to identify additional rare mutations outside of genes that also increase the risk of autism spectrum disorders.


Notes for editors

Autism spectrum disorders are a group of developmental disorders that emerge in early childhood. The disorders are characterised by difficulties in social interaction, communication, and understanding other people’s emotions and behaviour. The estimated number of children under 18 in the UK with an autism spectrum disorder is 133,500, according to the National Autistic Society.

The Autism Genome Project (AGP) is an international autism genetics research consortium, consisting of 120 scientists from more than 60 institutions and representing 11 countries. The AGP is co-funded by Autism Speaks, the Medical Research Council, Autistica, Canadian Institutes of Health Research, Health Research Board (Ireland), Genome Canada and the Hilibrand Foundation. For further details visit: http://www.autismgenome.org/

The paper ‘Functional impact of global rare copy number variation in autism spectrum disorder’ by Dalila Pinto and colleagues is published online in the journal Nature with an embargo of 18:00 UK time on Wednesday, 9 June, 2010.

For further information contact:

Aeron Haworth
Media Relations
Faculty of Medical and Human Sciences
The University of Manchester

Tel: 0161 275 8383
Mob: 07717 881563
Email: aeron.haworth@manchester.ac.uk