Research results in a number of childhood and adult disorders, including autism, are challenging psychiatric diagnostic classifications of diseases. A normal distribution of autism traits exists across the population (see my recent post “Autism or Autism Trait in the Normal Population? The Crisis of Defining Normal“). Current research points to the existence of gene variants (technically alleles) that must reach some sort of critical combination in individuals to be diagnosed as autism or autism spectrum disorders.

A new review paper “The Genetics of Child Psychiatric Disorders: Focus on Autism and Tourette Syndrome” published October 21, 2010 in Neuron gives a rigorous account of the studies and research techniques used, their promise and limitations, and where the state of the art is likely to go from here.

The paper focuses on child psychiatric genetics and associated biological mechanisms underlying autism and Tourette syndrome. Here I’ll focus on what he says about autism and only mention Tourette syndrome as it may relate to autism.

The author points out that research has shifted its focus from common alleles that are found in at least 5% of the population to rare alleles. It seems that common alleles carry moderate effects and are neither necessary nor sufficient to cause the full set of traits that result in the diagnosis of autism spectrum disorders. A combination of common and rare risk alleles seems necessary for the emergence of pathological traits falling at the extremes of a population distribution.

It’s clear now that the human genome tolerates a tremendous amount of what would have previously been presumed to be deleterious variation. This means that humans can carry a large number of both common and rare gene variants without obvious negative effects. Family members of children diagnosed with autism or autism spectrum disorders tend to demonstrate subclinical manifestations of autism traits due to the presence of some, but not all, risk alleles.

How do we figure out the contribution of a particular allele to autism? The accurate interpretation of the impact of particular alleles will be dependent on specific knowledge of how the relevant genes and proteins function in the body. Current evidence already points to some convergence in the molecular mechanisms associated with alleles implicated in autism. (More on this in a moment.)

It has become apparent from recent observations that a wide range of neuropsychiatric manifestations emerge from identical rare gene variants. Functionally identical mutations may lead to autism spectrum disorders, intellectual disability, seizure disorder, schizophrenia, attention deficit hyperactivity disorder, Tourette syndrome, obsessive-compulsive disorder, or some combination of the above.

Here are a few of the examples given in the review paper:

• Specific genes modifications (22q11.2 deletions) have long been implicated in the risk for psychosis in addition to autism spectrum disorders. Data pointing to overlapping risks for schizophrenia and autism spectrum disorders at the 16p11.2 locus is particularly compelling.
• Mutations in the SHANK3 gene have been identified in individuals with schizophrenia as well as those with autism spectrum disorders.
• Structural variations at CNTNAP2 have been reported not only in autism spectrum disorders and schizophrenia but Tourette syndrome as well and this overlap has also been observed with regard to NLGN4X.

Recent findings on how mutations of individual genes affect fundamental neurobiological processes are consistent with the findings that single genes influence multiple traits. The genes NLGN4X and SHANK3 mentioned above along with other genes implicated in autism spectrum disorders influence connections (synapses) important for communication between brain cells (neurons). These finding have lead to specific ideas on how cognitive and social traits may be mediated through various molecular mechanisms at the synapse. Clinical trials are in progress for individuals with fragile X as well as with autism spectrum disorders.


Other related blog posts:

Autism and the Brain: Recent Results from Brain Imaging Studies

Reduced Direct Eye Contact and Autism Spectrum Disorders: Reduced Orientation or Active Avoidance?

Abnormal Brain Growth in Toddlers Diagnosed with Autism

Autism or Autism Trait in the Normal Population? The Crisis of Defining Normal