De novo mutations in autism

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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.


  1. Research that looks for correlations between heredity and illness becomes less impressive by the day.

    However the recent discovery that hypoxia might underlie congenital birth defects is earth shaking.
    Nature and Nurture: World‐first Discovery Sheds New Light On Congenital Birth Defects

    Dunwoodie’s group then went on to test the genetic risk factor in a mouse model combined with an environmental insult in the form of hypoxia. Surprisingly, they found a marked increase in spinal abnormalities in the offspring, when the mothers were exposed to only 8 hours of low oxygen during an entire 21‐day pregnancy.

    “We found that the combination of the genetic risk as well as exposure to low oxygen, resulted in our subjects being up to 10 times more likely to develop congenital scoliosis, than those that only had the genetic risk factor,” says Dunwoodie.

    “What this brief period of low oxygen essentially did was disrupt the pathway responsible for development of the spine, and we know that the same pathway is used in the development of limbs and many organs, including the heart, kidneys, brain and cranio‐facial region,” adds Dunwoodie.

    Bob Graham, a professor and executive director of the cardiac research institute, says around 25 percent of patients with congenital scoliosis also have some form of congenital heart defect, indicating that a single environmental ‘insult’ such as hypoxia, can potentially affect the development of more than one organ in the body.

  2. I have an idea I’ve been working on for several years regarding autism and ADHD, involving “Lamarckian Inheritance” which points the finger at neonatal accelerated growth, induced by uncoupling of normal growth and development laws responsible for maintenance of scaling genes, which may include CHD8, SCN2A, KATNAL2 and NTNG1. I’m wondering whether the lack of infectious disease experience (of the mother and father), throughout a modern human’s growth and development period, due to the use of vaccination and antibiotics, has unlocked scaling laws within the foetus, associated at a genetic level, with ecological constraints, enforced within a species, as a means of ensuring the best survivorship of the individual and a population (such as a tribe), without outgrowing the perceived resource value of the dominant homeland (environment) economy. Is it possible that the many gene variants, associated with Autism and ADHD, perceived as mutation, within the brain, are really genes which have been unlocked from a strict algorithm responsible for ensuring healthy scaling laws, which dictate the spatial body plan and cell mass within all modular components, including the brain and somatic organs (arms, legs, fingers, toes…………… and skull). Is it possible, that by unlocking the genomes scaling laws, the organism is now experimenting with changes to the hominid formula, which in the neonate, includes phenotypes with experimental brain designs; basically unscaled development of the cerebral cortex, which in autism means, in some cases (as an example) a frontal cortex with 65% more neurons etc.

    So, could increased body size, of modern neonates, and the accelerated growth seen in a high majority of today’s children, be a result of similar adventures by the human genome, trying top capitalise on novel scaling rules which dictate that it may be possible to reallocate resources through the growth and development phase of human development, because of the reduced perception of danger, regarding the threat of infectious disease, which no longer exists (at least, at a genetic level).

  3. DE novo mutations, yes ,but there is always the posibility that during the maturation of egg or sperm that there will be epigenetic factors involved , maybe this is another aproach towards these pychic diseases.

    Dr.J.A;E; Gilles

  4. Uh oh, maternal obesity increases the risk of Autism by about 2/3rds. Obesity is associated with chronic inflammation and inflammation is associated with almost every disease process mankind has ever studied.
    Maternal Obesity, Diabetes Associated With Autism, Other Developmental Disorders

    “…mothers who were obese were 67 percent more likely to have a child with ASD than normal-weight mothers without diabetes or hypertension, and were more than twice as likely to have a child with another developmental disorder.”

    “The authors note that obesity is a significant risk factor for diabetes and hypertension, and is characterized by increased insulin resistance and CHRONIC INFLAMMATION, as are diabetes and hypertension. In diabetic, and possibility pre-diabetic pregnancies, poorly regulated maternal glucose can result in prolonged fetal exposure to elevated maternal glucose levels, which raises fetal insulin production, resulting in chronic fetal exposure to high levels of insulin.”

  5. With regard to maternal obesity and autism, I would say, that part of the present obesity problem, world-wide, is also associated with “Lamarckian Inheritance” in the form of epigenetics, whereby a child’s genome (and phenotype) capitalizes on stored fat via a misunderstanding of the life history experience of both parents, where, uncoupling of scaling genes, and lengthening of the limbs (through reduced harris lines caused by reduced experience with infectious disease, due to antibiotic and vaccination use), increases heat loss from the limbs at a faster rate than what would happen in a normal environment, causing the hunger center with the brain to continually fire up the need to eat. Basically, in a natural environment (if humans were living as feral animals), through infectious disease, an ecosystem can restrain the growth and development (and population size) of a species so as not to bankrupt the economy of the ecological system, through excessive harvesting of primary resources. Also, longer limbs change the physics of movement whereby longer steps decrease energy consumption. As such, once more the brain suffers from confusion, whereby, the experience of the parents, when it comes to energy consumption and energy expenditure, is decoupled from the historical knowledge of the organism, and what is stored as survival knowledge, within the genome. The result, is confusion of fetal growth and development genes, as the organism is set free to explore alternative growth and development trajectories.

  6. Mark Houston

    I’m sure if you asked the studies authors they would tell you that the connection between obesity and Autism is in some way related to harmful inflammation or a secondary consequence of harmful inflammation.

    The next time you read that a disease is associated with obesity think associated with inflammation. The two are connected like pepperoni and cheese.

  7. DR01D: “Research that looks for correlations between heredity and illness becomes less impressive by the day”??? How a report on the discovery of four new genes in which mutations cause autism leads you to that conclusion is baffling.

  8. kjmtchl

    “We identified POTENTIALLY causative de novo events in 4 out of 20 probands, particularly among more severely affected individuals, in FOXP1, GRIN2B, SCN1A and LAMC3.”

    You wrote that these 4 mutations cause Autism and yet the study abstract says that they are “potentially causitive”.

    Over the last 20 years the only common denominator I’ve seen in the field of genetics is oversold findings.

    While it’s certainly possible that these 4 genes trigger Autism I wouldn’t bet on it. If history is any guide future research will suggest that they are merely associated with an increased risk of disease or the original discovery was a false positive.

  9. Well, you’re right, I overstated the case with respect to these specific discoveries, though the fact that NTNG1 mutations have previously been found (multiple independent times) in Rett syndrome makes that finding pretty strong. The others look strong from these three papers but time will tell. More generally, we already know of over a hundred separate genetic conditions caused by mutations in either single genes or by copy number variants that can cause autism (see, for example: Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Betancur C. Brain Res. 2011 Mar 22;1380:42-77). They do not always result in the symptoms of autism (as in Fragile X syndrome for example, where autistic symptoms are common but not universal), but, in the cases where the individual does have autism, the evidence that the specific mutation is causing those symptoms is extremely strong (i.e., the most reasonable and probable inference is that if they did not have the mutation they would not have autism).

    In contrast, previous associations with common SNPs, which supposedly contribute only a tiny increase in risk alone but a large effect in aggregate, have not held up over time. In my opinion, that is because that model of the genetic architecture of illness is not correct – that does not imply (at all) that the illness is not primarily genetic.

  10. kjmtchl

    Maybe that didn’t come out quite right. I didn’t mean that you were overselling a particular finding. I mean that EVERYONE oversells these findings. If tomorrow scientists discover that a gene raises the risk of Disease X by 10% the headline the next day will be “Scientists Find Gene That Causes Disease X”. It’s easy to become cynical.

  11. I also don’t find associations with increased risk in the range of 10% very convincing (e.g., expressed as natural frequencies, from an average population risk of say 1% to an increased risk of 1.1%). Many GWAS results are actually less than that, which is why it is very hard to interpret what they mean in an individual. In contrast, the risks associated with mutations in genes like FMR1, MeCP2, PTEN and many many others now identified are huge – ten, twenty, thirty-fold. Any of these mutations is thankfully rare, but that does not bear on the magnitude of the effect in the individuals who carry them. It just means we have a long way still to go to account for all or even a majority of cases.

  12. @ Mark Houston:
    I think you are seeking a different kind of “why” than the majority of the people who do these genetic studies.

    If there are cases where a rare mutation in a gene occurs along with a phenotype of autism (or schizophrenia, or ADHD) multiple times, then it doesn’t seem that far off to conjecture that this mutation was necessary for the phenotype, in those individuals. Whether it’s sufficient is up for debate–that may be where environmental effects come in.

    This is all a very phenomenological type of “why”–when piece X breaks, phenotype Y can result. This single-gene causality sheds little light, however, on why it makes sense that the system breaks in certain characteristic ways rather than others. This is even more true when it is seen that the same mutations can show up in multiple different disorders. While it may be a small step to suggest that had gene X not mutated, uncommon phenotype Y would probably be absent, a model that can robustly predict whether phenotype Y or Z occurs based solely on knowledge of a few mutations X1, X2, etc. is much more difficult. Even more so, if you try to predict the manifestation of a spectrum disorder, i.e. whether the autism will involve speech difficulty or hyperlexia, for instance–and these are the things that really have meaning for what special accommodations or interventions are necessary.

    Things like growth patterns and resource trade-offs are much more likely to capture the failure modes as a whole. Biological systems clearly seem to malfunction in a very different way from human machines. If a brake fluid line is ruptured in a car, it will not cause the steering to become more accurate. The most adaptive we can get with designs is to incorporate redundancy, which delays the consequences of progressive malfunction. Probably the most fascinating characteristic of biological systems, in my opinion, is their ability to “get by with what they have”. Yes, there are things like congenital blindness and deafness where there is simple absence of a trait, but more often there are both extreme losses of function and gains of function in the same disorder.

    It is probably more apt to think of an organism like an ecosystem where loss of one species causes die-offs of some species and overgrowths of others. True understanding of biological phenotypes will only come about by understanding the interconnectedness of this “ecosystem”, which is much farther off than “lacking X correlates with end result Y”.

  13. Rosko, you hit on a really interesting and, I think, crucial question. If mutations in so many different genes can result in autism (or schizophrenia or epilepsy), then the question shifts to why those particular phenotypes emerge. This is not just down to a general degradation of brain systems nor to the specific primary effects of each mutation on any particular brain system. It is a property of the system itself, that when disturbed in various ways, it tends to gravitate towards particular pathophysiological states. What the chain of events is that leads from any specific mutation to the eventual phenotype is not clear (though it can be investigated directly in animal models). What is clear is that, for the vast majority of cases, we will not be able to predict the phenotype accurately even from full genome sequences, given that even monozygotic twins show a wide range of phenotypic expression. This is a neurodevelopmental question – you cannot relate genotype to phenotype directly. The genotype is expressed through the processes of development – these may channel the system into particular states (typically functioning in most cases, but specific pathologic states in others). And these processes are intrinsically noisy, contributing substantially to phenotypic variance.

  14. The most interesting aspect of this research to me as a practitioner, is that there is a general increase in genetic degradations that can not be attributed to hereditary, per se. From a historical perspective and from what I see in classroom and therapeutic settings, there a general decline in the neurological systems of the children that we are producing–leading to a broad spectrum of disorders that include learning disabilities, sensory-processing disorders, attention deficit disorders, autism, Asberger Syndrome and psychiatric disorders. Most have co-morbid symptoms or factors and can include deficits in the functions of organ systems throughout the body. De novo mutations are the most likely cause of this spectrum of neurological deficits. Rosko’s comment about regarding the organism as an ecosystem is on point.

  15. Couldn’t the correlation of autism with older fathers be a consequence of men with social deficits tending to marry late?

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