Neurology Center

An unusually gripping genetics paper from Biological Psychiatry: Pagnamenta et al.

The authors discuss a family where two out of the three children were diagnosed with autism. In 2009, they detected a previously unknown copy number variant mutation in the two affected brothers: a 594 kb deletion knocking out two genes, called DOCK4 and IMMP2L.

Yet this mutation was also carried by their non-autistic mother and sister, suggesting that it wasn't responsible for the autism. The mother's side of the family, however, have a history of dyslexia or undiagnosed "reading difficulties"; all of the 8 relatives with the mutation "performed poorly on reading assessment".

Further investigation revealed that the affected boys also carried a second, entirely separate, novel deletion, affecting the gene CNTNAP5. Their mother and sister did not. This mutation came from their father, who was not diagnosed with autism but apparently had "various autistic traits".

Perhaps it was the combination of the two mutations that caused autism in the two affected boys. The mother's family had a mutation that caused dyslexia; the father's side had one that caused some symptoms of autism but was not, by itself, enough to cause the disorder per se.

However, things aren't so clear. There were cases of diagnosed autism spectrum disorders in the father's family, although few details are given and DNA was only available from one of the father's relatives. So it may have been that the autism was all about the CNTNAP5, and this mutation just has a variable penetrance, causing "full-blown" autism in some people and merely traits in others (like the father).

In order to try to confirm whether these two mutations do indeed cause dyslexia and autism, they searched for them in several hundred unrelated autism and dyslexia patients as well as healthy controls. They detected the a DOCK4 deletion in 1 out of 600 dyslexics (and in his dyslexic father, but not his unaffected sister), but not in 2000 controls. 3 different CNTNAP5 mutations were found in the affected kids from 3 out of 143 autism families, although one of them was also found in over 1000 controls.

This is how psychiatric genetics is shaping up: someone finds a rare mutation in one family, they follow it up, and it's only carried by one out of several hundred other cases. So there are almost certainly hundreds of genes "for" disorders like autism, and it only takes a mutation in one (or two) to cause autism.

Here's another recent example: they found PTCHD1 variants in a full 1% of autism cases. It seems to me that autism, for example, is one of the things that happens when something goes wrong during brain development. Hundreds of genes act in synchrony to build a brain; it only takes one playing out of tune to mess things up, and autism is one common result.

Mental retardation and epilepsy are the other main ones, and we know that there are dozens or hundreds of different forms of these conditions each caused by a different gene or genes. The million dollar question is what it is that makes the autistic brain autistic, as opposed to, say, epileptic.

The "rare variants" model has some interesting implications. The father in the Pagnamenta et al. study had never been diagnosed with anything. He had what the authors call "autistic traits", but presumably he and everyone just thought of those as part of who he was - and they could have been anything from shyness, to preferring routine over novelty, to being good at crosswords.

Had he not carried the CNTNAP5 mutation, he'd have been a completely different person. He might well have been drawn to a very different career, he'd probably never have married the woman he did, etc.

Of course, that doesn't mean that it's "the gene for being him"; all of his other 23,000 genes, and his environment, came together to make him who he was. But the point is that these differences don't just pile up on top of each other; they interact. One little change can change everything.

Link: BishopBlog on why behavioural genetics is more complicated than some people want you to think.

Pagnamenta, A., Bacchelli, E., de Jonge, M., Mirza, G., Scerri, T., Minopoli, F., Chiocchetti, A., Ludwig, K., Hoffmann, P., & Paracchini, S. (2010). Characterization of a Family with Rare Deletions in CNTNAP5 and DOCK4 Suggests Novel Risk Loci for Autism and Dyslexia Biological Psychiatry, 68 (4), 320-328 DOI: 10.1016/j.biopsych.2010.02.002