Autism genetics unravelled – experts respond

New research published in the leading journal Nature has started the difficult process picking apart the underlying genetic factors that contribute to Autism and Autism Spectrum Disorder (ASD).

Although it is well accepted that genetics make a strong contribution to ASD, most of the underlying causes remain unknown. In addition, despite the identification of specific DNA sequence variations associated with ASD, their exact contribution to disease has yet to be clarified.

Now, three new studies, have used increasingly accessible genome sequencing technology to compare the genetic differences between children with ASD and their parents and unaffected siblings. All three papers pointed towards mutations that were not necessarily passed on by the parents but may have arisen spontaneously. These changes, called de novo mutations, occur in many places throughout the genome, but researchers have identified several particular areas of the genetic code where mutations may have an impact on social development.

Together, the studies suggest that ASD may be caused by variation in multiple unrelated locations within the genome. Despite revealing unprecedented genetic complexity the studies provide a basis for future gene discovery, diagnostics and therapeutics.

Our colleagues at the UK SMC collected the following expert commentary. Feel free to use these quotes in your reporting. If you would like to contact a New Zealand expert, please contact the SMC (04 499 5476;

Dr Rosa Hoekstra, Lecturer in Psychology & Genetics, Open University, said:

“We already knew that there isn’t a ‘single gene for autism’, but these new research publications suggest that the underlying genetic mechanisms may be even more complex than previously thought.

“These studies show that de novo point mutations -small gene changes that are not inherited from either parent- in the protein coding part of our DNA are common, and that some of these new genetic changes may be implicated in the risk for developing autism.

“What makes it tricky is that these changes are fairly common in people without autism too. This means that not all de novo mutations result in an increased risk for autism, and a single genetic change is unlikely to be the sole cause of autism in any given individual. It is more likely that autism is caused by a combination of different gene variants.

“A striking result from these studies is the association between new genetic changes and paternal age: de novo mutations seem to be more common in children of older dads; and if a child with autism has such a new genetic mutation, it seems to be much more often of paternal than maternal origin. These findings are in line with earlier reports that older dads have a slightly increased risk of having a child with autism.”

Kevin Mitchell, Associate Professor, Smurfit Institute of Genetics, Trinity College Dublin, said:

“These studies provide an explanation for what seems like a paradox: on the one hand, twin studies show that autism is very strongly genetic (identical twins are much more likely to share a diagnosis than fraternal twins) – on the other, many cases are sporadic, with no one else in the family affected.  How can the condition be “genetic” but not always run in the family?  The explanation is that many cases are caused by new mutations – ones that arise in the germline of the parents (this is similar to conditions like Down syndrome).  The studies reported in Nature are trying to find those mutations and see which genes are affected.

“They are only possible because of the tremendous advances in our ability to sequence DNA.  The first genome cost three billion dollars to sequence and took ten years – we can do one now for a couple thousand dollars in a few days.  That means you can scan through the entire genome in any affected individual for mutated genes.  The problem is we each carry hundreds of such mutations, most of which don’t have a major effect, making it difficult to recognise the ones that are really causing disease.

“The solution is to sequence the DNA of large numbers of people with the same condition and see if the same genes pop up multiple times.  That is what these studies aimed to do, with samples of a couple of hundred patients each.  They also concentrated on families where autism was present in only one child and looked specifically for mutations in that child that were not carried by either parent – so-called de novo mutations, that arise in the generation of sperm or eggs.  These are the easiest to detect because they are likely to be the most severe.  (Mutations with very severe effects are unlikely to be passed on because the people who carry them are far less likely to have children).

“The three studies each provide a list of genes with de novo mutations found in specific patients.  Only a few of these showed a mutation in more than one patient.  This means that those specific mutations are quite likely to be causing autism in those patients.  They occur in genes involved in particular neurodevelopmental pathways.  These specific discoveries will thus greatly aid the quest to understand the biological basis of this disorder.

“The fact that they only got a few repeat hits also means that there are probably hundreds or even thousands of genes that can cause autism when mutated (if there were only a small number, we would see more repeat hits).  Some of these will be among the other genes on the lists provided by these studies and will no doubt be recognisable as more patients are sequenced.  Interestingly, many of the genes on the lists are involved in aspects of nervous system development or function and encode proteins that interact closely with each other – this makes it more likely that they are really involved.

“These studies reinforce the fact that autism is not one disorder – not clinically and not genetically either.  Like intellectual disability or epilepsy or many other conditions, it can be caused by mutations in any of a very large number of genes.  The ones we know about so far make up maybe 20-25% of cases – these new studies add to that list and also show how far we have to go to complete it.

“We should recognise too that the picture will also get more complex – in many cases there may be more than one mutation involved in causing the disease.   These complexities will emerge over time, but for now we can aim to recognise the simpler cases where a mutation in a particular gene is clearly implicated.  Each new gene discovered means that the fraction of cases we can assign to a specific cause increases.  As we learn more about the biology of each case, those genetic diagnoses will have important implications for prognosis, treatment and reproductive decisions.  We can aim to diagnose and treat the underlying cause in each patient and not just the symptoms.”

Jeremy Turk, Professor of Developmental Psychiatry, Institute of Psychiatry & St. George’s, University of London, said:

“Autism Spectrum Conditions are known to have a strongly genetic basis. Of that there is no doubt. There is a wealth of evidence from twin, family and adoption population studies, as well as laboratory genetic research, to support this.

“There are also a number of genetic conditions that predispose to autism spectrum disorders as part of their associated clinical presentations – so-called “behavioural phenotypes”.  This new research suggests paternal inheritance is important, and increasingly so with increasing paternal age.

“The race is now on to determine which genes are of particular relevance, what they do, and hence how individuals with autism spectrum conditions can be assisted better.

“Progress is being made, but clinical features that distinguish autism spectrum disorders from intellectual disabilities and developmental delays more broadly need substantially greater refinement.”

Patterns and rates of exonic de novo mutations in autism spectrum disorders‘ by Neale, B. et al, ‘Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations‘ by O’Roak, B. et al, and ‘De novo mutations revealed by whole-exome sequencing are strongly associated with autism‘ by Sanders, S. et al. are published in Nature