The recent issue of Neuron has a series of articles providing more information about the genetics of autism spectrum disorder (ASD). ASD is characterized by decreased social ability as a core feature, with other clinical features being variable. It is also not a single disease or disorder, and not just because of the spectrum of clinical features. Like many clinical entities, there can be many underlying causes that result is similar-looking clinical effects.

While debate rages as to possible environmental triggers or even causes of ASD, researchers have been slowly building a picture of ASD as a complex genetic syndrome. Literally hundreds of genes have been potentially implicated. Many of the genes linked to ASD are involved with brain proteins or brain organization.

The recent studies in Neuron look specifically at families with a single child with ASD. In families with multiple children, or with a parent and child on the spectrum, the disorder is likely inherited. But what of families with only one child with ASD, and at least one child without, with no affected parent? Such a pattern can also be consistent with an inherited disorder, if it is recessive or X-linked. In a recessive disorder both parents can be unaffected carriers, and 25% of children will be affected – so having a single affected child is not unusual. However, ASD genes tend to be dominant, which means at least one parent should be affected along with at least 50% of children.

Another way for single individuals to appear with genetic disorders is called variable penetrance. The same genes do not always translate into identical clinical manifestations. One family member can have a very subtle manifestation of an inherited disorder, while another (the one who gets identified and diagnosed) can have a more severe presentation.

There is also the phenomenon known as amplification. Some genetic disorders are caused by trinucleotide repeats – repeated three letter segments of DNA. The greater the number of repeats, the more severe the clinical syndrome. Repeat numbers tend to increase with each affected generation, and so a very mild manifestation in a parent can amplify to a severe presentation in a child. Such disorders, however, also tend to be dominant.

Yet another way for a genetic (but not inherited) disorder to appear in a single individual in a family is for that individual to have a spontaneous mutation – a mutation unique to them, and not inherited from a parent. This is the specific hypothesis being tested in the current study.

Sanders et al studied 1124 families with one affected child with ASD and one unaffected child, with unaffected parents. They found that 6-8% of them could be explained by changes in copy number variants – how many copies of specific genes were present. Most intriguing, they found:

We find significant association of ASD with de novo duplications of 7q11.23, where the reciprocal deletion causes Williams-Beuren syndrome, characterized by a highly social personality.

In other words – at one gene location where a deletion causes a syndrome characterized by a highly social personality, they found duplications associated with a decrease in sociability. This strongly suggests that the gene in question has a strong influence on sociability, and can be either turned up or down depending on the genetic change.

In another study in the same issue researchers find that large networks of genes are responsible for the ASD phenotype. Further they provide evidence that could explain the fact that males are at higher risk of ASD than females. They find that a much greater perterbation in the gene network is required for ASD to manifest in girls than in boys.

Conclusion

ASD is a complex disorder but researcher are slowly unraveling the changes in the brain that correlate with and cause the features of ASD. Further, research into the genetics of ASD is progressing rapidly and producing highly significant results.

We are still far from fulling explaining the genetic or neuroanatomy and physiology of ASD – but the utility of a scientific theory is better understood by how well the research is progressing, rather than how far we have already come. The fact that the genetic theory of autism is producing such useful results speaks to the power of this theory. This, of course, does not rule out environmental effects playing a role. Genes evolve to respond to the environment, and increasingly scientists are identifying important epigenetic factors in disease. But the research to date suggests a highly dominant role for genetics in autism, and this recent research adds to the growing body of research supporting this.