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Wednesday, April 4, 2012

De novo mutations in autism

A trio of papers in this week’s Nature identifies mutations causing autism in four new genes, demonstrate the importance of de novo mutations in the etiology of this disorder and suggest that there may be 1,000 or more genes in which high-risk, autism-causing mutations can occur.

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, 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 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).

There is already strong evidence that de novo mutations play an important role in the etiology of autism – first, de novo copy number variants (deletions or duplications of chunks of chromosomes) appear at a significantly higher rate in autism patients compared to controls (in 8% of patients compared to 2% of controls). Second, it has been known for a while that the risk of autism increases with paternal age – that is, older fathers are more likely to have a child with autism. (Initial studies suggested the risk was up to five-fold greater in fathers over forty – these figures have been revised downwards with increasing sample sizes, but the effect remains very significant, with risk increasing monotonically with paternal age). This is also true of schizophrenia and, in fact, of dominant Mendelian disorders in general (those caused by single mutations). The reason is that the germ cells generating sperm in men continue to divide throughout their lifetime, leading to an increased chance of a mutation having happened as time goes on.

The three studies in Nature were looking for a different class of mutation – point mutations or changes in single DNA bases. They each provide a list of genes with de novo mutations found in specific patients. Several of these showed a mutation in more than one (unrelated) patient, providing strong evidence that these mutations are likely to be causing autism in those patients. The genes with multiple hits include CHD8, SCN2A, KATNAL2 and NTNG1. Mutations in the last of these, NTNG1, were only found in two patients but have been previously implicated as a rare cause of Rett syndrome. This gene encodes the protein Netrin-G1, which is involved in the guidance of growing nerves and the specification of neuronal connections. CHD8 is a chromatin-remodeling factor and is involved in Wnt signaling, a major neurodevelopmental pathway, as well as interacting with p53, which controls cell growth and division. SCN2A encodes a sodium channel subunit; mutations in this gene are involved in a variety of epilepsies. Not much is known about KATNAL2, except by homology – it is related to proteins katanin and spastin, which sever microtubules – mutations in spastin are associated with hereditary spastic paraplegia. How the specific mutations observed in these genes cause the symptoms of autism in these patients (or contribute to them) is not clear – these discoveries are just a starting point, but they will greatly aid the quest to understand the biological basis of this disorder.

The fact that these studies only got a few repeat hits also means that there are probably many 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 around 30% 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. De novo mutations are likely to be the most severe class and thus most likely to cause disease with high penetrance themselves. But many inherited mutations may cause autism only in combination with one or a few other mutations.

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.

48 comments:

  1. Thank you for this post, which helped me understand this research, its findings, and their implications better. Our family participated in the Simons Simplex project, and it's nice to start seeing some meaningful results. And it's especially nice to have them explained in a way that I understand.

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  2. Studying the severe genetic syndromes associated with autism risk can shed light on the origins of ideopathic autism and the role and etiology of de novo sperm mutations and aging paternal effect. This has been discussed with full references in the comment section at the following website:

    http://sfari.org/news-and-opinion/news/2012/effect-of-paternal-age-seen-in-girls-with-autism

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  3. This comment has been removed by the author.

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  4. The researchers specifically went looking for de novo mutations in cases of autism that were highly likely, (pretty much certain?), to be caused by de novo mutations, and they found de novo mutations. I do not find this surprising or amazing or terribly enlightening. Is it still the case that most cases of autism are not caused by ne novo mutations, and a large proportion of cases appear to run in families and have a broader autistic phenotype assocated with them?

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    1. Rate of de novo cases estimated as high as 50%, but difficult to be precise - sporadic cases with no family history predominate - perhaps 90% according to NIH. More severe cases have higher probability of being de novo (mutation more likely to be selected against). Literature on broader autism phenotype is very sketchy, in my view. The consensus from people I've spoken to who have studied is that it is definitely a real phenomenon, but may apply to only a fraction of families (around 20% in one study). Could be due to incomplete penetrance of mutation or effects of multiple segregating mutations.

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  5. Good post. I'm reading these papers now.

    Isn't there a problem with defining "sporadic" ASD as "ASD without a family history" though?

    We know that rates of ASD diagnosis have skyrocketed recently. Almost certainly because of changes in how it's diagnosed.

    So if you take a kid diagnosed with ASD in 2010, say, the fact that he has "no family history of ASD" might just mean that all his relatives with ASD were born back when it was rarely diagnosed.

    That kid's father might well have been diagnosed with ASD if he'd been born today!

    So it seems that although you'd expect de novo mutations in "sporadic" ASD, I'm not convinced we can be sure that "sporadic" really is sporadic, at the moment; 10 years ago it would have been more straightforward but we are in the middle of the Age of Autism Diagnosis right now.

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    1. It is true that defining sporadic as no family history has problems based on changing recognition of condition (also on reproductive stopping - tendency not to have more children after having an autistic child - don't know if other siblings would have been affected). But there isn't any other way to define it. It's a bit semantic, perhaps - some sporadic cases will be due to de novo mutations and some to inherited mutations. Works better the other way - in families with multiple affected individuals you can be pretty sure it's inherited. (Though even there it can be due to de novo mutation in parental germline and germline mosaicism, generating multiple gametes with same, new mutation).

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    2. Oh yeah, I agree; my comment came across a bit too strong. I just mean I think we are probably overestimating how much ASD is sporadic, today, and we should bear that in mind. As you say, there's not much we can do differently!

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  6. More suport for rare mutations as cause of autism and other neurodevelopmental disorders from new paper in Cell by Talkowski et al (http://www.cell.com/abstract/S0092-8674(12)00411-4). They were looking at people with "balanced translocations" - where two chromosomes swap ends. No DNA is deleted or duplicated but sometimes one or other of the breakpoints is in the middle of a gene. Using a new sequencing approach, the authors identified the genes disrupted in a set of 33 autism patients. They find mutations in CHD8, supporting the findings referred to above and in many other interesting loci (FOXP1, CDKl5, MBD5, KIRREL3, EHMT1...) - some new, some with evidence from previous studies.

    Brief footnote: they find enrichment for this set of genes among those giving a GWAS signal for schizophrenia or bipolar disorder. They conclude this means that common polymorphisms in these same genes also contribute to risk. Could be, or could be that GWAS can pick up SNPs tagging rare mutations.

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  7. Neuroskeptic made a very good point:

    "So if you take a kid diagnosed with ASD in 2010, say, the fact that he has "no family history of ASD" might just mean that all his relatives with ASD were born back when it was rarely diagnosed."

    Yes, it might mean that his relatives were young adults in the age when autism was rarely diagnosed and autistic adults were routinely misdiagnosed as schizophrenics. There is loads of evidence of different types that this was a common practice throughout the 20th century in Anglophone countries, and it's anyone's guess whether this still happens on the continent, considering that autism is still given the Freudian treatment in France, and disciples of Freud love to throw around terms like "psychotic" with a carefree abandon.

    Autism and "childhood schizophrenia" were considered to be the similar or the same thing only three decades ago. There was a legitimate medical journal titled "Journal of Autism and Childhood Schizophrenia" which I believe changed it's title in 1979 and is now a leading autism journal. Autistics used to be diagnosed as schizophrenics. This fact makes a mockery of the idea that a family history of autism can be simply and accurately identified from this point in time.

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  8. Nearly forgot to make my other point. It is very clear that there are cases diagnosed as autism that are also diagnosed or undiagnosed cases of recognized genetic syndromes. I suspect that the label of autism or AS would probably be regarded as redundant, inexact or incorrect once a diagnosis of a genetic syndrome is made in many cases. I suspect that the characteristics of the entire population of people given a diagnosis of autism would vary according to the quality and scope of the diagnostic process that is practiced in various regions, and there is every reason to suspect that this might influence the proportion of cases of autism in which de novo mutations are judged to be the cause of the autism.

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  9. Thanks Lili, you make some excellent points regarding the vagaries of diagnostic categories over time and in different countries. When you say that a label of autism would probably be regarded as redundant one a diagnosis of a particular genetic syndrome is found, I think you are at least partly right. So, people with Fragile X syndrome are considered as Fragile X patients first and foremost (whether they are autistic or not).

    From a research point of view, such patients, with defined genetic syndromes, have been considered as separate from "real" autism (i.e., idiopathic autism that is not syndromic - associated with non-brain-related symptoms). What I think will happen more and more is that that idiopathic group will continue to shrink as we identify more and more discrete conditions (this is already happening, in fact). Eventually, we may realise there is no big, single category of autism left to explain.

    (The same may go for many psychiatric disorders, such as schizophrenia too. It has been the tradition that if an "organic" cause of psychosis was known, that the label schizophrenia was not used - a legacy of dualism). "Real" schizophrenia was the group that could not be explained by some obvious brain insult or genetic lesion - that category is also likely to continue to shrink (and maybe even eventually become obsolete).

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  19. I suspect that the characteristics of the entire population of people given a diagnosis of autism would vary according to the quality and scope of the diagnostic process that is practiced in various regions, and there is every reason to suspect that this might influence the proportion of cases of autism in which de novo mutations are judged to be the cause of the autism.
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