Rare genetic variations play role 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 international study involving Oxford University researchers and published in the journal Nature.

The Oxford team now hope to carry out a pilot study to see whether tests that look for this type of genetic change can help in the diagnosis of new cases of autism. Similar tests are already in use to help diagnoses of learning disability (also called intellectual disability).

'Our research strongly suggests that this type of rare genetic variation is important and accounts for a significant portion of the genetic basis of autism,' says Professor Tony Monaco of the Wellcome Trust Centre for Human Genetics at the University of Oxford. 'By identifying the genetic causes of autism, we hope in the future to be able to improve the diagnosis and treatment of this condition which can affect children and their families so severely.'

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, of which Oxford was a leading member - set out to compare the incidence of rare copy number variants in 996 people with autism spectrum disorders and 1287 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.

'Disruption of genes through rare losses or duplications of whole stretches of DNA is more common among people with autism spectrum disorders, especially in regions of our genomes that we already know to be important in autism,' says Alistair Pagnamenta of Oxford University, one of the lead authors of the Nature study. 'This is good evidence that this type of genetic variation is important to understanding the causes of this condition.'

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.

Professor Monaco's team in Oxford in collaboration with Dr Jeremy Parr in Newcastle are now applying for funding to carry out a pilot study of a similar DNA microarray test for copy number variants, initially among 1000 cases where children have been newly diagnosed with autism.

'Just knowing about these genetic changes can help the families involved come to terms with why their child has autism, but it can also be important where there are siblings too in determining future risk,' says Professor Monaco.

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.