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Hallmayer on the genetics of autism

Joachim Hallmayer

On Feb. 18, Nature Genetics published the largest-ever study on the genetics of autism. The research is the fruit of an international autism genetics consortium, called the Autism Genome Project. The consortium, which was funded by the nonprofit group Autism Speaks and by the National Institutes of Health, brings together more than 120 scientists from more than 50 institutions in 19 countries to share data and expertise to identify genes responsible for susceptibility to autism. Recently the School of Medicine and Lucile Packard Children's Hospital joined forces to form an autism working group—an interdisciplinary effort to identify the neurological basis of the disorder.

Joachim Hallmayer, MD, associate professor of psychiatry and a member of the autism working group, chaired the collaboration's executive committee. In addition, he recently co-authored a paper in Nature Reviews Neuroscience describing the disconnect in autism research between the focus of research conducted by scientists and the research topics considered newsworthy in the media. Here he discusses the research findings.

1. What are autism spectrum disorders? How many people are affected?

Hallmayer: Children with autism find it difficult to relate to others. They have problems with language and social interactions, and many exhibit significant mental impairment. Those with Asperger's disorder have similar social difficulties but they achieve normal language milestones. A third category, known as "pervasive developmental disorders-not otherwise specified," is used for children who don't have all the symptoms of autism or Asperger's, but who still struggle in these areas. On Feb. 9, the Centers for Disease Control released a 14-state study that suggested the incidence of autism spectrum disorders could be as high as one in 150 children.

2. Are autistic spectrum disorders genetic? If so, why do they vary in severity?

Hallmayer: Autism is strongly genetic. If one identical twin individual is affected the chance that the co-twin is also affected is between about 70 and 90 percent vs. about 3 to 5 percent in the case of a non-identical twin. However, this does not mean that environmental factors are unimportant.

For example, the specific symptoms experienced by affected individuals within a family or twin pair can vary widely. This leads us to believe that, while certain genes increase the risk that a child may develop some type of autism, the presence and severity of particular symptoms experienced by that child depend on other genetic and environmental factors.

Finally, about 10 percent of autism cases can be ascribed to single-gene disorders (such as fragile X syndrome, tuberous sclerosis complex and Rett syndrome), or to chromosomal abnormalities—all of which affect brain development. Abnormal brain development early in life is probably another risk factor for developing clinical symptoms seen in autism spectrum disorders.

3. This isn't the first time researchers have tried to identify genetic regions important in ASD. What's different about this research?

Hallmayer: This study is by far the largest study ever conducted, in terms of both researchers and research subjects. In it, we analyzed over 1,400 families with more than one affected family member. Furthermore, we combined two types of data to determine which chromosomal regions might be involved in the development of autism: linkage analysis, which tests whether specific genetic markers are located near a putative autism susceptibility gene; and chromosomal copy number variation, in which we track subtle chromosomal abnormalities among affected individuals.

Although substantial evidence suggests that about 7 to 8 percent of individuals with autism have chromosomal abnormalities, standard tests miss many subtle chromosomal aberrations. Detection of such changes not only helps to identify candidate genes, but also improves linkage analysis by allowing us to separate chromosome abnormality-bearing families from those with other types of mutations.

Finally, our large sample size allowed us to subdivide our families based on specific characteristics such as the gender of affected individuals.

4. What did the research find?

Hallmayer: Results from our linkage analyses implicate portions of chromosomes 11 and 15 as candidate autism susceptibility regions. We also found a family with a deletion in a gene called neurexin 1 that appeared to correlate with a diagnosis of autism in this family. Neurexin 1 is involved in neuronal contact and communication between a kind of nerve cell called a glutamate neuron. While promising, these results need to be followed up with more refined genetic maps to home in on other specific candidate genes. We also need to look more closely at chromosomal anomalies in large samples of children with autism.

5. What might this research mean for the parent of a child with autism?

Hallmayer: It can be very difficult to parent a child with autism. Our hope is that identifying candidate autism susceptibility genes will allow us to better understand how these genes interact with environmental factors to influence early brain development. It is likely that a number of autism genes will be identified in the next couple of years, so we are making slow but significant progress toward our goal of developing possible therapies for this condition.