Where are the genes that control sex differences in autism?

…they aren’t where you would think.  ASF fellow Dr. Donna Werling from UCSF explains.


Dr. Donna Werling studies sex differences in autism at UCSF

Males are approximately 4 times more likely to be diagnosed with autism spectrum disorder (ASD) than girls and women1,2, and for the most part, scientists don’t know why. To figure out how sex differences in human biology might contribute to ASD risk, we compared patterns of gene expression from males and females in the developing and adult human brain. We found that genes that show higher expression levels in males relative to females include many of the same genes that are expressed at higher levels in the brains of individuals with autism relative to controls3. What these male-elevated and ASD-elevated genes do in the brain may be a clue to the sex difference in ASD prevalence.

A closer look at these genes showed that they are known to be involved in the functions of microglia and astrocytes. Microglia are a type of cell involved in the immune system of the brain, and astrocytes are different type of cell that provides support to neurons that communicate across regions of the brain. Our findings suggest that these non-neuronal cell types may play a role in the biology behind the male-biased risk for ASD and may provide insight on why more males are diagnosed compared to females.

How did we do this? It involved lots of time and access to valuable resources.

In order to understand the role of different cell types in the brain, we needed to study actual brain tissue from people. In order to do this, we turned to a project called BrainSpan4, a publicly available data set generated from post-mortem human samples from the brains of males and females. Brain tissue is an incredibly rare resource and this dataset is invaluable in our research. Using these data from BrainSpan, we generated a list of genes that have different expression levels in males and females in the adult cerebral cortex and we used this list to look at two questions relating to autism:

Our first question was “Do genes that are directly associated with autism risk differ between males and females?” For example, the genes CHD8 and TSC1 which are both known to contribute to the cause of ASD5,6. If these genes show up differently in males and females, then mutations in these genes would affect male and female brains differently, which might lead to the sex differences we see in ASD diagnoses. In fact, we found this was not the case: genes directly associated with autism risk do not show up differently in males and females.

Our second question was “Do genes that are indirectly associated with autism differ between the sexes?” For our study, we considered genes that show changes in expression level in the ASD brain to be indirectly associated with autism7,8. This includes genes that show low expression in the ASD brain; these genes may be affected by directly associated ASD risk genes from our first question. This also includes genes that show high expression in the ASD brain; these genes are related to the brain’s immune system. If these indirectly associated genes with altered expression in the ASD brain are expressed differently in males and females, this would suggest that autism and sex-differential biology affect some of the same molecular or cellular pathways in the brain. These shared pathways may modulate the impact of risk factors such that males are more strongly affected. In contrast to our first question, we found that several of the indirectly ASD associated gene sets did overlap significantly with sex-differentially expressed genes. Specifically, gene sets with coordinated, elevated expression in the ASD brain overlap with genes with higher expression in males, and these overlapping genes are associated with microglia and astrocytes.

These results suggest that, instead of directly affecting ASD risk genes, sex-differential biology interacts with ASD risk biology downstream from these ASD risk genes, and that this interaction may involve the functions of microglia and/or astrocytes.

We repeated our experiment and replicated our results in two additional data sets, including one data set from prenatal brain samples. This is especially important because midfetal development is a key time for the expression, and presumably function, of directly associated ASD risk genes10,11. Therefore, the patterns that we see demonstrate that not only do microglial and astrocyte genes differ by sex in the adult brain, but they also differ in the same region and time window of development when ASD risk genes are robustly expressed..

That microglia and astrocytes may be involved in sex differences in ASD is intriguing, since these types of cells are becoming more and more recognized for their roles in neural circuitry development by supporting the formation, maintenance, and/or pruning of synapses12,13. Therefore, sex differences in the functions of these cell types could lead to differences in neuroanatomy and function between males and females. Supporting this idea, studies in rodent models show that the numbers of microglia that take up residence in the brain during early development differ between males and females14, and also that astrocytes in the hypothalamus express estrogen receptors and change morphology in response to estradiol exposure15. However, it is not currently known whether these phenomena also occur in humans.

Since microglial and astrocyte genes and cells function downstream from currently known ASD risk genes, treatments that mimic these specific processes could potentially help large numbers of patients with diverse genetic backgrounds. However, several key questions remain. First, our results must be replicated in larger data sets, preferably including comparable numbers of typically developing and autistic males and females. This will be necessary to corroborate the patterns we see and to more directly investigate the interacting effects of sex and ASD on gene expression. The only way we can do this is with more brain tissue from people with autism, which is why the Autism BrainNet is so important for the community. Further research will also be required to determine why microglial and astrocyte genes differ in males and females, and to clarify exactly how sexually dimorphic microglia and/or astrocytes function in the brain to influence neurodevelopment and ASD risk.

Eventually, a major goal will be to translate these findings into tangible benefits for individuals with ASD and their families, perhaps by developing therapeutics that target functional pathways at the intersection between sexually dimorphic and autistic biology. By implicating ASD-upregulated microglial and astrocyte genes at this intersection, our study has uncovered an intriguing new avenue to pursue in our endeavor to fully understand ASD and the striking sex difference in its prevalence.

We gratefully acknowledge the data resources of the BrainSpan consortium, as well as the generous donations from individuals and families that make such invaluable data sets possible. I also acknowledge my co-authors on this study, Dr. Daniel Geschwind and Dr. Neelroop Parikshak, our funding from the US National Institute of Mental Health (5R37MH060233 and 5R01MH094714 to DHG; Autism Center for Excellence network grant 9R01MH100027; F30MH099886 and T32MH073526 to NNP; F31MH093086 to DMW), and Dr. Stephan Sanders and Dr. Alycia Halladay for their input on this post. Finally, I would like to thank the Autism Science Foundation for the opportunity to share this work with the community.



  1. Wingate, M. et al. Prevalence of autism spectrum disorder among children aged 8 years – Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2010. Morbidity and Mortality Weekly Report Surveillance Summaries 63, (2014).
  2. Fombonne, E. Epidemiology of pervasive developmental disorders. Pediatr. Res. 65, 591–598 (2009).
  3. Werling, D. M., Parikshak, N. N. & Geschwind, D. H. Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat. Commun. 7, 10717 (2016).
  4. BrainSpan: Atlas of the Developing Human Brain. (2013). at <http://www.brainspan.org&gt;
  5. Basu, S. N., Kollu, R. & Banerjee-Basu, S. AutDB: a gene reference resource for autism research. Nucleic Acids Res. 37, D832–6 (2009).
  6. Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515, 216–221 (2014).
  7. Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).
  8. Gupta, S. et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5, 5748 (2014).
  9. Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).
  10. Willsey, A. J. et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155, 997–1007 (2013).
  11. Parikshak, N. N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008–1021 (2013).
  12. Stevens, B. Neuron-astrocyte signaling in the development and plasticity of neural circuits. Neurosignals 16, 278–288 (2008).
  13. Schafer, D. P. et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74, 691–705 (2012).
  14. Schwarz, J. M., Sholar, P. W. & Bilbo, S. D. Sex differences in microglial colonization of the developing rat brain. J Neurochem 120, 948–963 (2012).
  15. McCarthy, M. M., Todd, B. J. & Amateau, S. K. Estradiol modulation of astrocytes and the establishment of sex differences in the brain. Ann. N. Y. Acad. Sci. 1007, 283–297 (2003).


Using the human brain to understand “omics” in autism

by Shannon Ellis, Ph.D. at Johns Hopkins University


Shannon Ellis, PhD

Autism is a complex neurodevelopmental disorder with a definitively established genetic basis1. However, complete understanding of the genetic etiology remains elusive. While the role for certain CNVs in autism has been definitively established2,3 and exome sequencing studies have begun to uncover rare de novo mutations that play a role in the disorder4–9, we are far from identifying the names of the hundreds of genes likely contributing to the disorder.

While naming the genes that play a role in autism is critical, it has become increasingly clear that changes in the DNA sequence are only a first step toward complete understanding. Additionally, scientists acknowledge that they must know what the genes do, not only what they are. Therefore, our lab has begun to get a handle on what is altered at the level of gene expression and DNA methylation within the primary affected tissue in autism – the brain. This is part of a larger field called “omics”: meaning “genomics” (the study of DNA sequence), “transcriptomics” (the study of gene expression), “epigenomics” (the study of how genes are expressed, “proteomics” (how proteins are regulated by DNA expression) and “metabolomics” (the chemical processes of making and breaking down compounds). Our study focused on transcriptomics and epigenomics.

To understand the processes in the brains of people with autism, we had to study the brains of people with autism. Therefore, we worked with the Autism BrainNet (formerly the Autism Tissue Program) to obtain brain samples and extract RNA. We were interested in RNA because it is produced from DNA. Using DNA as a template, RNA is formed as the first step in creating proteins. The proteins are what carry out the function of the cell. The number of copies of RNA is a reflection of the gene expression of the cell: the more copies, the more gene expression. While differences in an individual’s DNA are undoubtedly of interest to the study of autism, it is also important to look for differences in gene expression and protein levels to fully understand the disorder. We used the RNA to look at the gene expression of about 14,000 genes. Additionally, in these same individuals, DNA samples were used to estimate methylation levels at cytosines across cytosine-rich regions of the genome.


How DNA is transcribed to RNA then translated to proteins

Last year, we published some results on the transcriptomic part. When we looked at the gene expression, we identified three groups of genes that showed different patterns of expression between autism cases and controls. The first two groups included genes that influence the way neurons work, how they interact with each other, and how they grow and communicate to form the human brain. Interestingly, the genes that showed differences in gene expression were different genes than those identified in previous studies that, rather than looking at gene expression differences, looked to identify DNA differences important to autism. This demonstrates that genes that have differences in their DNA are different from those genes showing downstream differences at the level of gene expression. The third group was made up primarily of M2-microglia genes, suggesting in increased immune response in the brains of autistic individuals. We want to stipulate that this does not mean that alterations in the immune system of the brain cause autism. It could be that abnormal gene expression in the brain triggers an M2 microglia response. Future work is required before we can determine if the increased immune response leads to or is a result of autism. Nevertheless, from a treatment standpoint, this work provides pathways that, despite variable genetic causes, can be targeted for treatment in affected individuals going forward.

We moved this further to compare the gene expression overlap in the brains of people with autism with other neuropsychiatric disorders. Previous studies have shown that there is an overlap in which genes have DNA differences across neuropsychiatric disorders. To establish if this overlap holds up at the level of the transcriptome, we compared gene expression differences across three disorders: autism, schizophrenia, and bipolar disorder.  While there was little overlap between autism and bipolar disorder, there was significant overlap between the expression patterns in genes in autism and schizophrenia brains11, with consistent decreased expression at neuronal and synaptic plasticity genes across these two disorders. This work extended the known genetic overlap between neuropsychiatric disorders by establishing a relationship between alterations in gene expression found in both autism and schizophrenia.

Finally, as gene expression is directly regulated by DNA methylation, we looked to determine if DNA methylation differences play a role in autism.  Methylation is a process where a methyl group attaches to a part of a DNA sequence and turns down the expression of that gene. To look at DNA methylation, we looked at cytosines. Cytosines are places in our genome where these methyl groups normally attach. Thus far, most work has studied CpG methylation. This refers to when a methyl group attaches to a cytosine (C) that is directly next to a guanine (G) nucleotide. This CpG context is where methylation most frequently occurs in the genome. However, methylation can occur at cytosines next to other DNA nucleotides (C, T, or A), and this is referred to as CpH methylation. As CpH methylation occurs at higher levels in the brain relative to other tissues, we did not want to limit our study to CpG sites alone, but rather wanted to look for differences in CpH methylation as well. We found increased levels of methylation at CpH, but not CpG, sites globally within the autistic brain. We are currently working on why there is this difference and why it is seen in autism, but as CpH methylation is largely specific to the human brain (as compared to blood or other cells), it is a particularly compelling finding.

While we acknowledge we have not answered all the questions, we now have a better understanding of what is going on in the brain of individuals with autism. In particular, in addition to further establishing a relationship between schizophrenia and autism, this work not only highlights a role for increased immune activation within affected individuals, providing a particular pathway to target when considering future therapies, but also, for the first time, suggests a role for increased methylation at cytosines within the CpH context in the brains of autistic individuals.



  1. Gaugler, T. et al. Most genetic risk for autism resides with common variation. Nat. Genet. 46, 881–885 (2014).
  2. Marshall, C. R. & Scherer, S. W. Detection and characterization of copy number variation in autism spectrum disorder. Methods Mol. Biol. Clifton NJ 838, 115–135 (2012).
  3. Sebat, J. et al. Strong Association of De Novo Copy Number Mutations with Autism. Science 316, 445–449 (2007).
  4. Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature (2012).
  5. Yu, T. W. et al. Using Whole-Exome Sequencing to Identify Inherited Causes of Autism. Neuron 77, 259–273 (2013).
  6. Iossifov, I. et al. De Novo Gene Disruptions in Children on the Autistic Spectrum. Neuron 74, 285–299 (2012).
  7. O’Roak, B. J. et al. Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat. Genet. 43, 585–589 (2011).
  8. Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature (2012).
  9. De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515, 209–215 (2014).
  10. Gupta, S. et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5, 5748 (2014).
  11. Ellis, S. E., Panitch, R., West, A. & Arking, D. E. Transcriptome Analysis of Cortical Tissue Reveals Shared Sets of Down-Regulated Genes in Autism and Schizophrenia. bioRxiv 29132 (2016).


Picture of me

Boaz Barak, ASF fellow, from MIT

This blog was written by Dr. Boaz Barak, an ASF fellow and an author on a recent publication  in Neuron that used animal models to show that different mutations of the same gene can lead to different psychiatric disorders.  The study was led by Dr. Yang Zhou in Prof. Guoping Feng’s lab at MIT.   In this case, one mutation has been associated with schizophrenia and the other with autism. Dr. Barak explains their findings below.

Autism is one of the most heritable neuropsychiatric disorders. Mutations in genes associated with autism will eventually lead to the expression of malfunctioning proteins. One such gene that is known to be mutated in Phelan-McDermid syndrome is Shank3, encoding the postsynaptic protein SHANK3.  People with Phelan-McDermid Syndrome, or PMS, often show symptoms of autism.

To study the role of genetic mutations in autism etiology, our lab engineered mouse models that express the mutated gene in their brains, allowing the researchers to study the behavioral, physiological and biochemical consequences of these gene mutations.

We induced two different mutations but in the same gene, Shank3, based on human mutations found in patients. By doing so, we showed evidences how different mutations in the same gene can lead to two different disorders, autism and schizophrenia.

Interestingly, we found that mice with the autism-related mutation (InsG3680), demonstrate impairments earlier in life than those with the schizophrenia-related  mutation (R1117X), coinciding with the early onset of autism spectrum disorders symptoms. Specifically, starting from very early age, impaired electrical activity of neurons was measured in the striatum, a brain region important for integration and coordination of multiple neurological processes necessary for normal behavior. Along with the abnormal neuronal activity of cells, we found impaired social behavior in the mice with the mutation, together with extensive repetitive behavior. Looking for biological findings that might explain these abnormalities, we found molecular changes in the composition of proteins in the synapse and the transcripts (mRNA) responsible for the expression of those synaptic proteins.

Overall this study shed new light on the pathophysiology of autism and schizophrenia, and enables the research community to study the consequences of two different human-based mutations in novel mouse models.

Why is this important for people with autism?  Hopefully, the data published will help in developing drugs targeted to fix the physiological and the behavioral abnormalities of the Shank3 mutation. Improved understanding of such syndromic cases will lead to better basic understanding of also other types of neurodevelopmental disorders, and ultimately, the discussed mouse models will assist the research community in validating potential drugs before testing them on people with autism.

Late last year, a study from tissue researchers at NYU showed angiogenesis in brains of people with autism spectrum disorder (ASD).   Angiogenesis is the creation of new blood vessels in the brain which normally stops around age 2.  Because of the study of post-mortem brain tissue, researchers were able to find evidence that in people with ASD, the development of blood vessels in the brain is in flux and changing across the lifespan.  Dr. Ephraim Azmitia, the lead author of the study that was able to complete this investigation because of the Autism BrainNet, explains the research here.


Dr. Ephrain Azmitia from NYU

Q:  Dr. Azmitia, please explain what you found.

A:  In 2014 we first discovered that brain blood vessels in the brains of people with ASD, but not those not diagnosed with ASD, showed continuous angiogenesis. We have spent all our time focused on this observation and have now published a full-length paper in Journal of Autism and Development Disorders entitled Persistent Angiogenesis in the Autism Brain. We found that splitting angiogenesis (not sprouting angiogenesis) is found in every area of the brain from ASD donors  that we examined; cortex from auditory and face recognition areas, general temporal association cortical areas, midbrain, pons and cerebellum. The angiogenesis continued even in brains from donors over the age of 28 while it was only lightly seen in very young brains (< 2 years) of typically developing donors.

Q: Why is this important?  

A:  First, our findings demonstrated that autism affects the whole brain, not just one localized region. While certain brain regions have been targeted based on behavioral studies, the whole brain should be considered.

Second, it appears blood vessels in the brain are involved in ASD. Splitting angiogenesis occurs when blood vessels are reorganizing, usually to supply more active neurons and glial cells with additional oxygen and nutrients. This implies that brains cells of autistic patients may be more active and dynamic than those without autism. It is possible splitting angiogenesis keeps cells richly supplied with blood so they retain their highly interactive condition, and fail to form more stable connections needed for mature complex functions such as language and social behaviors.

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Marker of angiogenesis is elevated in brains of people with autism, but not after 2 years of age in people not diagnosed with ASD.

Q:  Will this lead to new interventions?

A:  Therapies and drugs are widely available to control dividing vascular cells, such as seen in tumor growth. Unfortunately, most of these drugs are targeted for spouting angiogenesis, which is the form of vascular growth seen in tumor formation. Future research on regulating this type of angiogenesis is needed which then needs to be studied to determine if it helps ease symptoms.

Q:  How can I contribute to this type of research?

A:  Scientific research like this is not possible without the ability to study the brains of people with autism.  To register, go to www.takesbrains.org.

By Alycia Halladay, PhD, Chief Science Officer
and the Scientific Advisory Board of the Autism Science Foundation

2015 was an unprecedented year for autism research with many significant advances that will improve the lives of people with autism. Just last week, for example, the CDC reported a 5-month decrease in the age that children are first being evaluated for autism, which means families are learning the signs, acting earlier, and, hopefully, starting early intervention services earlier. In 2015, we changed the way we think about females with autism, gained a better understanding of the underlying genetic causes of autism, and made important progress in both behavioral and medical interventions.  Here’s a summary of some of the year’s most significant findings.

Researchers are expanding their attention beyond boys with autism, to the girls and women.

More males are diagnosed with autism than females. This means fewer girls and women participate in research, some scientific conclusions only apply to males, and, in some cases, females are not even studied because of the assumption it is a “male” disorder. This has disadvantaged understanding of females with autism. Luckily, 2015 was a year that science challenged the assumptions that autism is a male disorder.

The journals and news outlets are catching on to the special need to look at females with autism. A special issue of Molecular Autism was published that included many groundbreaking studies on females with autism, including studies involved in early behavior, genetics, and brain structure. A special issue in the journal Autism invited submissions this year, to be published in 2016 or 2017. Also, Spectrum News compiled a summary of what is known about females with autism, from basic science to specific challenges seen in girls and women with ASD. It includes science reports and essays written by women on the spectrum.

So, what did scientific research reveal in 2015? First, the brains of girls with autism are different than boys with autism, specifically regions relating to language function and the way that different regions of the brain connect to each other1,2. Differences in the size of the corpus callosum are seen even before a diagnosis3, and researchers believe they may help explain why symptoms are different in boys and girls.

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Differences in size of different regions of the brain in boys and girls with and without autism.

The corpus callosum consists of neural fibers that connect the left and right sides of the brain. Very early signs of autism may also be different in boys and girls4, but they are subtle and young boys and girls with autism may be more similar than different.5,6 Findings from the study of the molecular signatures in the brains of males and females with autism are hard to interpret because of the number of female brains with autism to study.7 The sex bias in autism diagnosis is also reflected in a scarcity of biological samples, including brain tissue, from females with ASD. If you are a woman with autism, or the parent of a girl with autism, please consider registering for the Autism BrainNet. It’s easy, and registrants receive regular updates on why this resource is so important.

But it’s not only the girls with autism bringing attention to research in sex differences, it’s the whole family. For example, families in which there is more than one person diagnosed or a female diagnosed tend to show higher levels of autism symptoms both in the affected person and in siblings8,9 and girls with autism show more genetic mutations10. These findings together suggest a protective factor in females which protects against the same symptom presentation as boys.

IMG_1876 (3)

Undiagnosed sisters play an important role in understanding autism.

Therefore, researchers have started expanding the scope of research from just the individual affected with autism to all family members, so that susceptibility and protective mechanisms from certain symptoms may be uncovered.10,11Earlier this year, the Autism Science Foundation launched a new initiative based on the study of unaffected females called the Autism Sisters Project. You can learn more at www.autismsciencefoundation.org.

It’s not just about an autism diagnosis

One of the questions that has plagued clinicians who make an autism diagnosis is the degree to which the symptoms may change over time, both in the short term and the long term. Two separate studies followed infants with a high probability of a later diagnosis and showed that if a diagnosis was given to a toddler at 18 months, that diagnosis stuck later on in life.12,13 However, that doesn’t mean that the threshold for a diagnosis is always met this early, as a proportion of children were diagnosed at 3 years but not earlier.12,13   Those that received a diagnosis later still showed some of the core features of ASD, but tended to have higher language ability and lower severity of autism symptoms before age 3.   There were also distinct patterns across time in each of the groups, reinforcing the variability in presentation of symptoms as well as providing data on how symptoms develop over time in each subset. These findings have enormous clinical importance, as primary care doctors need to continue to monitor children who show early signs and symptoms but do not meet all the criteria of a diagnosis.13,14

Dr. Peter Szatmari

Peter Szatmari, MD, led a study following children with autism  from ages 2 through 6.

However, while a diagnosis is stable, this does not necessarily mean that delays or impairments stay the same forever. Canadian researchers followed children with autism from age 2 to age 6 and tracked their cognitive ability and their ability to function in daily life (called adaptive behavior). They found that how children started didn’t necessarily predict how they fared later on, as most children with intellectual disability at age 2 didn’t have the same cognitive impairments at age 6.15 While adaptive behavior was more stable, 20% showed improvements in the years after the initial diagnosis.15 These findings show that autism changes and sometimes improves. Further these results underscore that in addition to monitoring autism symptomatology, there is a need to address how children with autism function overall.

Due to lack of funding, researchers studying infants who have a high likelihood of an autism diagnosis tend to stop their studies when the participants are 3 years old. However, a few projects were able to follow families through school age, and the findings may likely alter the way people think about autism. For example, in one long-term study at University of California, Davis, children with and without an autism diagnosis by age 3 were evaluated until they turned 11. The researchers looked beyond ASD and found a higher rate of ADHD symptoms, especially in the girls.16 ADHD and autism often occur together, so while they are different disorders, they may be two diverging roads from the same highway.

Better understanding of underlying genetic causes, and new information on epigenetic mechanisms

In 2015, rapid progress in the genetics of ASD continued. As has been the case in recent years, the lion’s share of progress in identifying specific genes has come through the study of so called germ-line de novo mutations. These are newly occurring changes in DNA that are only in the parent’s sperm or egg cell, are passed on and present in every cell in the child’s body, but are not detectable in the parent’s blood. A new study this year of germ-line de novo mutation bringing together new and previously published data from over 5500 families identified a total 65 genes with strong evidence for a role in ASD risk.10 This study replicated findings girls carry a greater genetic burden than boys, confirming prior findings17 that de novo mutations play an important role even in children with high IQ, and once again highlighted the importance of synaptic function and chromatin modification (discussed later) for the biology of ASD that was reported last year.18 These investigators also found, interestingly, that large copy number variations (CNVs), such as 16p11.2, are very likely to carry many risk genes each with modest risk, rather than one single “smoking gun”.

These findings contribute to the global picture of the genetic underpinnings of autism, which have become much more clear in the past few years. Several papers have shown that variations that are common in the population play an important role in ASD,19,20 in fact carrying most of the risk. This is called “common variation”. Common variation accounts for most of the genetic risk for autism in the entire human population, however, the vast majority of individuals do not have symptoms.  It is thought that most people with autism have multiple common variations which increase risk for autism. On the other hand, rare de novo mutations that can affect just one nucleotide of a key autism gene can also play major contributory role.21 In addition to germ line de novo mutations and common risk alleles which are heritable, a recent study from Boston22 highlighted the contribution to ASD of an additional type of mutation, called somatic mosaicism. These are new mutations that occur in the affected individual but sometime after fertilization of the egg. This is most commonly seen in cancer. In order to see the mutation, scientists need to study the organ of interest, in this case, the brain. This was the first time somatic mutations were identified in brain tissue of individuals with


Difference between somatic and germline mutations

autism. There may be even more of these somatic mutations in the brain, and knowing about them may not just inform geneticists about the underlying neurobiology, but shed light on what factors might increase the risk for such mutations to occur. 22 These findings highlight the importance of brain tissue in studying risk factors for ASD.

But the genetic influence of ASD is not just limited to the sequence of the A’s and C’s and G’s in the code of the DNA or the structure of chromosomes. A growing body of literature is demonstrating that the epigenetic code, or the code that influences how genes are turned on and off, may be just as important. As environmental factors target epigenetic markers in the DNA, this is part of the missing link in understanding gene/environment interactions in ASD.


As important as DNA sequence, epigenetic markers affect ASD risk.

One of the reasons geneticists don’t understand epigenetics is that there was no “Human Epigenome Project” to mirror the 2003 Human Genome Project. This is surprising considering doctors are sure that the epigenome contributes to different disorders and diseases, such as diabetes, cancer, and syndromes with a high prevalence of autism like Angelman’s Syndrome and Prader-Willi.23 This year was important for epigenetics research, because a group of researchers published a map of 111 epigenetic markers on the genome from over 183 types of cells, all data has been made publically available for other researchers to study.24 This advance will definitely increase the pace and productivity of science around the role of epigenetics and autism.

In 2012, a gene called CHD8 was reported to increase autism risk.25,26 CHD8 affects chromatin remodeling, or how the DNA is kept tightly wound, which in turn has a major effect on when and where genes are expressed (turned on and off). If CHD8 is disrupted, then DNA does not express itself properly. This year, geneticists looked at what this gene did, and found that it regulated the expression of many other known autism risk genes during fetal development.27. This information makes CHD8 a more interesting gene to understand the bigger picture of brain development in autism. Scientists agree that in the next phase of genetic research, discovery of new genes is going to be matched with figuring out what they do, and how they work together.


CHD8, involved in chromatin remodeling, is a genetic point of convergence for ASD risk

Another mechanism involved in epigenetics is methylation. This is the attachment of methyl groups to different parts of the DNA sequence that turns off gene expression. In a high-risk siblings study, fathers of a child with ASD showed methylation patterns in sperm that were similar to that seen in the cerebellum of people with autism.28 This suggests that this altered methylation may contribute to autism risk.

Other evidence of gene/environment interactions comes from studies on copy number variations, which are the duplication of or the deletion of parts of a chromosome that can result in the disruption of a gene or genes. Copy number variations contribute to ASD risk, but why they are more often seen in people with autism is still understudied. By looking at environmental factors, researchers have discovered that maternal infection, a risk factor for autism, interacts with the occurrence of these copy number variations to increase ASD symptoms. 29 This finding is a direct demonstration of how environmental factors can increase risk through genetic mechanisms.

Single genes, multiple solutions.

In addition to the more recent discoveries of de novo mutations identified in “typical” autism cases described above, there is a long history of studies of so-called syndromic forms of autism. As more data is accumulated, the distinctions between these groups is becoming less clear, but in general, those genes associated with ASD as well as other characteristic physical features have been considered syndromic, including the Fragile X protein causing Fragile X, or Shank gene causing Phelan-McDermid Syndrome. These are also sometimes described as “single gene” causes of ASD because it appears that a damaging mutation in one of these is sufficient on its own to lead to ASD. As research identifies more of the rare mutations discussed earlier21 the number of these syndromic forms will increase. In the big picture, syndromic/single gene forms of autism account for a relatively small proportion of all ASD cases, however, what they tell us about these syndromic forms can lead to discoveries that impact all forms of autism.

Charles Bluebonnets 2008 (2)

People with Phelan-McDermid Syndrome are often also diagnosed with autism.

In fact, a recent analysis of the shank gene, known to cause Phelan- McDermid Syndrome, shows that mutations of different types of the shank gene are seen across the spectrum of individuals with autism: both those with high IQ and lower IQ and everything in between.30 In other words, this gene doesn’t just show up in those with a certain phenotype, and in fact, one type of mutation shows up in about 2% of individuals with ASD.30 So therapies that were developed for Phelan- McDermid Syndrome may be helpful in treating different types of autism.

Understanding the role of these genes in pathology also helps in understanding the course and symptoms of the disorder. For example, using brain tissue of people with autism, with or without a specific mutation in chromosome 15, neuropathologists showed that there were fewer and smaller neurons in the auditory brainstem–the part of the brain crucial for hearing and distinguishing sounds.31 These cellular deficits are more severe in those with mutation, but the fact that they are present in both groups suggests that there is a common mechanism between auditory problems, pointing to common solutions. In other areas of the brain, scientists see specific persistent and profound decreases in cell size in areas of the amygdala and hippocampus, both involved in emotion, in those with the mutation. 32 These neurobiological differences contribute the phenotype of people with this genetic marker, like lower IQ and high rates of epilepsy. These findings were made possible through postmortem brain tissue donated to the Autism BrainNet.


To register with the Autism BrainNet, go to http://www.takesbrains.org

Postmortem brain tissue is also leading to new targets of treatment. Last year a study reinforced the importance of a type of immune cell in the brain, called microglia, in autism neurobiology.33 This year, a study found that a regulator of microglia activity, the mGLUr5 receptor, less active in brain tissue of people with autism.34 This receptor is also known to be a key target in Fragile X syndrome, and together, this data advances the idea that microglia may help control the shape the shape and size of neurons.   When microglia are overactive, this process goes awry and leads to disorders of synaptic plasticity, like autism. This discovery has already led to more research on the role of the microglia in cellular processes with hopes that it will be a feasible treatment target.

New genes that significantly contribute to autism are being discovered. Families are using the power of social media like Facebook to
find each other, and what was once an interesting finding on a gene array is turning into a syndrome. For example, earlier this year mc1407fe29c9610756a92704a12efe6deutations in a gene called DYRK1a, a gene where too many copies is associated with Down Syndrome, showed that not enough of this gene is associated with a very specific form of autism: those with low intellectual functioning, early seizures, and stereotyped behavior.35 A number of research and advocacy groups have now banded together to improve research in autism where there is a known genetic cause: http://www.gdaac.org.

The big question is whether genetic forms of autism have a hope of being treated. A few years ago, a completely revolutionary study showed that replacing the deficient gene involved in Rett Syndrome reversed the symptoms in a mouse model. 36 This year, the disorder that is produced by too much of this gene, MeCP2, was reversed using targeted gene technologies. 37  Similar modifications of activity of UBE3A, in the area of chromosome 15 associated with autism, have been shown in animal models.38 While it is way too early for clinical trials in humans, the reversal of the behavioral and cellular phenotype in individuals with Rett Syndrome and Dup15 opens the door to targeted gene interventions being available for multiple causes of ASD, even long after the behavioral features present.

New discoveries in treatment: it’s about what you should be doing, and what you shouldn’t be doing.

Many years ago, the first randomized clinical trials on early interventions were conducted. The results of those projects on some early markers of behavior at or around age of diagnosis were published. They were mostly positive, but none of these interventions were shown to improve the core symptoms of autism. Earlier this year, researchers at the University of Washington reported that by 6 years of age, children who had participated in an intervention called the Early Start Denver Model (ESDM) not only maintained the gains attained through this intervention, but continued to improvements in the core symptoms of autism39.   So in terms of what families should be doing, early interventions continue to be filed in the “do” category.

There were some interesting findings relating to pharmacological interventions for autism. The hormone oxytocin, otherwise known as the “love hormone,” had previously been shown to benefit individuals with ASD when administered in clinical settings via an intravenous (IV) drip. An IV drip is not really feasible in most real world settings, so researchers studied whether or not a nasal spray of oxytocin would work as well. As it turns out, it did. There were some improvements in some of the social behaviors of autism, but the effects were mild.40 Even so, this therapy is worth following up in additional studies where other interventions are controlled for as well.

Just as important to finding things that help is scientific data on things that don’t. For example, many parents of children with autism turn to dietary interventions like the gluten free casein free (GFCF) diet. Some children with (and without) autism have gluten sensitivities and in these cases, the diet is a good idea. But other parents just don’t know where else to turn and this diet has received enough anecdotal acclaim that they are willing to give it a try. But in many cases there is a large placebo effect, meaning, parents expect or want an effect so much that they unknowingly exaggerate improvement. Very few rigorous research studies have investigated the effects on autism behavior controlling for this placebo effect, until this year. Using a study design that allowed for children to eat either gluten and casein containing or free foods without either them or their caregivers knowing what was in them, the clinicians didn’t see any improvement in autism behaviors41. This casts doubt on the utility of the GFCF diet for treatment of autism symptoms, although, if monitored by a dietician, the diet does not seem to be harmful.

The world of behavioral interventions was turned on its ear earlier this year with a study challenging one of the most common procedures of applied behavioral analysis: repetition. In repetition, a stimulus is presented over and over again to facilitate learning. However, researchers studying repetition in autism found that too much repetition may actually impair the ability of people with high functioning autism to be flexible.42 The implications are clear: when it comes to repetition in some people with autism: maximize with moderation.

Bridging the gap from people in the clinic to people in the community.

Understanding of the early signs and symptoms of autism in the clinic has significantly advanced practice in the pediatrician’s office.43 This year, the same group of researchers that provided the data to enforce early screening for all children with autism challenged primary care providers to look even more closely and take even more action for those with a suspected diagnosis.44 In addition, in the face of the U.S. Preventive Services Task Force (USPSTF) ambiguity on the importance of universal screening for autism, this group continued to urge autism-specific tools to identify autism at 18 and 24 months.44 Finally, they urged culturally- appropriate interventions that involve all family members.


Amanda Gulsrud, PhD, from UCLA, works with a child with autism

As mentioned earlier, a number of rigorous studies examining the effectiveness of parent – mediated early interventions have reinforced the benefits of interventions targeting social, emotional, behavioral domains for the potential prevention of ASD symptoms. While improvements in overall behavior in children and parenting are seen, the effect on specific autism symptoms is unclear.45 On the other hand, reducing behavioral problems in those with autism is a huge concern of parents, and the largest randomized behavioral intervention study on behavioral issues in autism to date  compared  parent-training to parent education was published in 2015. There were improvements in these behavioral problems in both groups, but parent training was clearly superior.   After 6 months of treatment, children in the parent-training group showed a 48 percent improvement on parent ratings of disruptive behavior compared to a 32 percent decline for parent education, and 70% of those in the parent-training group saw an overall positive response by a clinician. 46  The data is encouraging, but data on standardized, objective measures of outcome showed modest improvements in behavior. This study reinforces the value of parent-training models to improve outcomes, and other research in the past year has focused on the right ways to train parents. This means making sure parents are getting the support and feedback they need and delivering the interventions the way they were designed. 47 This is clearly important, as the ultimate goal of developing a behavioral intervention is to make sure that it can be shared with children in a variety of settings under a variety of circumstances, not just those in a university clinic. Also important is the level that these parent-driven interventions produce improvements that make a difference clinically, not just in a statistical analysis.

Another important component of understanding what interventions will work for individuals with autism is knowledge about some of the behavioral characteristics that match well with different types of interventions. These are called moderators of outcome. In addition to IQ at start of intervention, now clinicians know that vocabulary and ability to intentionally communicate during toddler years can predict later outcome. 48 These moderators should now be incorporated into personalized decisions made about what type of interventions will lead to the best chance of improvements in different people, and will better inform treatment decisions. Teaching children with autism as a way to exchange knowledge may not always be effective, those children with autism without cognitive impairment still don’t always grasp the intentions of teaching.49   This calls for alternative methods of learning and teaching in those with autism.

mandatesAll the science is great, but what about getting the services paid for? As it turns out, getting insurance mandates in place doesn’t solve all of the challenges around making sure families receive appropriate care. As researchers at the University of Pennsylvania revealed, forcing insurance companies to pay for services increases the demand, and supply was already at capacity before, creating new problems. The efforts of insurance mandates is an important and crucial first step to providing much needed services for families, but should be followed up by incentives to increase the workforce and infrastructure.50

This is a just a sampling of some of the 2015 research that has made an impact on the science of autism. Science can be incremental, it can be slow, but each year there is progress–studies that changes the way scientists think or how the community manages autism. headshotPlease add your thoughts by commenting below or sending an email to ahalladay@autismsciencefoundation.org. See you in 2016!



  1. Nordahl CW, Iosif AM, Young GS, et al. Sex differences in the corpus callosum in preschool-aged children with autism spectrum disorder. Molecular autism. 2015;6:26.
  2. Schaer M, Kochalka J, Padmanabhan A, Supekar K, Menon V. Sex differences in cortical volume and gyrification in autism. Molecular autism. 2015;6:42.
  3. Wolff JJ, Gerig G, Lewis JD, et al. Altered corpus callosum morphology associated with autism over the first 2 years of life. Brain : a journal of neurology. 2015;138(Pt 7):2046-2058.
  4. Hiller RM, Young RL, Weber N. Sex differences in pre-diagnosis concerns for children later diagnosed with autism spectrum disorder. Autism : the international journal of research and practice. 2015.
  5. Messinger DS, Young GS, Webb SJ, et al. Early sex differences are not autism-specific: A Baby Siblings Research Consortium (BSRC) study. Molecular autism. 2015;6:32.
  6. Harrop C, Gulsrud A, Kasari C. Does Gender Moderate Core Deficits in ASD? An Investigation into Restricted and Repetitive Behaviors in Girls and Boys with ASD. Journal of autism and developmental disorders. 2015;45(11):3644-3655.
  7. Hu VW, Sarachana T, Sherrard RM, Kocher KM. Investigation of sex differences in the expression of RORA and its transcriptional targets in the brain as a potential contributor to the sex bias in autism. Molecular autism. 2015;6:7.
  8. Turner TN, Sharma K, Oh EC, et al. Loss of delta-catenin function in severe autism. Nature. 2015;520(7545):51-56.
  9. Frazier TW, Youngstrom EA, Hardan AY, Georgiades S, Constantino JN, Eng C. Quantitative autism symptom patterns recapitulate differential mechanisms of genetic transmission in single and multiple incidence families. Molecular autism. 2015;6:58.
  10. Sanders SJ, He X, Willsey AJ, et al. Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Neuron. 2015;87(6):1215-1233.
  11. Gockley J, Willsey AJ, Dong S, Dougherty JD, Constantino JN, Sanders SJ. The female protective effect in autism spectrum disorder is not mediated by a single genetic locus. Molecular autism. 2015;6:25.
  12. Ozonoff S, Young GS, Landa RJ, et al. Diagnostic stability in young children at risk for autism spectrum disorder: a baby siblings research consortium study. Journal of child psychology and psychiatry, and allied disciplines. 2015;56(9):988-998.
  13. Zwaigenbaum L, Bryson SE, Brian J, et al. Stability of diagnostic assessment for autism spectrum disorder between 18 and 36 months in a high-risk cohort. Autism research : official journal of the International Society for Autism Research. 2015.
  14. Zwaigenbaum L, Bauman ML, Fein D, et al. Early Screening of Autism Spectrum Disorder: Recommendations for Practice and Research. Pediatrics. 2015;136 Suppl 1:S41-59.
  15. Flanagan HE, Smith IM, Vaillancourt T, et al. Stability and Change in the Cognitive and Adaptive Behaviour Scores of Preschoolers with Autism Spectrum Disorder. Journal of autism and developmental disorders. 2015;45(9):2691-2703.
  16. Miller M, Iosif AM, Young GS, et al. School-age outcomes of infants at risk for autism spectrum disorder. Autism research : official journal of the International Society for Autism Research. 2015.
  17. Sanders SJ, Ercan-Sencicek AG, Hus V, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70(5):863-885.
  18. De Rubeis S, He X, Goldberg AP, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209-215.
  19. Gaugler T, Klei L, Sanders SJ, et al. Most genetic risk for autism resides with common variation. Nature genetics. 2014;46(8):881-885.
  20. Klei L, Sanders SJ, Murtha MT, et al. Common genetic variants, acting additively, are a major source of risk for autism. Molecular autism. 2012;3(1):9.
  21. Krumm N, Turner TN, Baker C, et al. Excess of rare, inherited truncating mutations in autism. Nature genetics. 2015;47(6):582-588.
  22. D’Gama Alissa M, Pochareddy S, Li M, et al. Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. Neuron.88(5):910-917.
  23. Simmons D. Epigenetic influence and disease. Nature Education. 2008;1(1).
  24. Roadmap Epigenomics C, Kundaje A, Meuleman W, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015;518(7539):317-330.
  25. O’Roak BJ, Vives L, Fu W, et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science. 2012;338(6114):1619-1622.
  26. Neale BM, Kou Y, Liu L, et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012;485(7397):242-245.
  27. Cotney J, Muhle RA, Sanders SJ, et al. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nature communications. 2015;6:6404.
  28. Feinberg JI, Bakulski KM, Jaffe AE, et al. Paternal sperm DNA methylation associated with early signs of autism risk in an autism-enriched cohort. International journal of epidemiology. 2015;44(4):1199-1210.
  29. Mazina V, Gerdts J, Trinh S, et al. Epigenetics of autism-related impairment: copy number variation and maternal infection. Journal of developmental and behavioral pediatrics : JDBP. 2015;36(2):61-67.
  30. Leblond CS, Nava C, Polge A, et al. Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments. PLoS genetics. 2014;10(9):e1004580.
  31. Lukose R, Beebe K, Kulesza RJ, Jr. Organization of the human superior olivary complex in 15q duplication syndromes and autism spectrum disorders. Neuroscience. 2015;286:216-230.
  32. Wegiel J, Flory M, Schanen NC, et al. Significant neuronal soma volume deficit in the limbic system in subjects with 15q11.2-q13 duplications. Acta neuropathologica communications. 2015;3(1):63.
  33. Gupta S, Ellis SE, Ashar FN, et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nature communications. 2014;5:5748.
  34. Chana G, Laskaris L, Pantelis C, et al. Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications. Brain, behavior, and immunity. 2015;49:197-205.
  35. van Bon BW, Coe BP, Bernier R, et al. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Molecular psychiatry. 2015.
  36. Tropea D, Giacometti E, Wilson NR, et al. Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proceedings of the National Academy of Sciences of the United States of America. 2009;106(6):2029-2034.
  37. Sztainberg Y, Chen HM, Swann JW, et al. Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides. Nature. 2015.
  38. Yi JJ, Berrios J, Newbern JM, et al. An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A. Cell. 2015;162(4):795-807.
  39. Estes A, Munson J, Rogers SJ, Greenson J, Winter J, Dawson G. Long-Term Outcomes of Early Intervention in 6-Year-Old Children With Autism Spectrum Disorder. Journal of the American Academy of Child and Adolescent Psychiatry. 2015;54(7):580-587.
  40. Yatawara CJ, Einfeld SL, Hickie IB, Davenport TA, Guastella AJ. The effect of oxytocin nasal spray on social interaction deficits observed in young children with autism: a randomized clinical crossover trial. Molecular psychiatry. 2015.
  41. Hyman SL, Stewart PA, Foley J, et al. The Gluten-Free/Casein-Free Diet: A Double-Blind Challenge Trial in Children with Autism. Journal of autism and developmental disorders. 2015.
  42. Harris H, Israeli D, Minshew N, et al. Perceptual learning in autism: over-specificity and possible remedies. Nature neuroscience. 2015;18(11):1574-1576.
  43. Johnson CP, Myers SM, American Academy of Pediatrics Council on Children With D. Identification and evaluation of children with autism spectrum disorders. Pediatrics. 2007;120(5):1183-1215.
  44. Zwaigenbaum L, Bauman ML, Choueiri R, et al. Early Identification and Interventions for Autism Spectrum Disorder: Executive Summary. Pediatrics. 2015;136 Suppl 1:S1-9.
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  48. Yoder P, Watson LR, Lambert W. Value-added predictors of expressive and receptive language growth in initially nonverbal preschoolers with autism spectrum disorders. Journal of autism and developmental disorders. 2015;45(5):1254-1270.
  49. Knutsen J, Mandell DS, Frye D. Children with autism are impaired in the understanding of teaching. Developmental science. 2015.
  50. Baller JB, Barry CL, Shea K, Walker MM, Ouellette R, Mandell DS. Assessing early implementation of state autism insurance mandates. Autism : the international journal of research and practice. 2015.


NEW YORK, NY (December 10, 2015) – The Autism Science Foundation today hailed new Centers for Disease Control and Prevention (CDC) findings of an improvement in the age of initial diagnosis of autism. Citing new data from its pilot Early Autism and Developmental Disabilities Monitoring Network (ADDM) study, the CDC reported a five-month decrease in the age of first comprehensive developmental evaluation for autism in a cohort of 4 year-old preschool children with autism. On average, these children born in 2006 had an average age of diagnosis of 2 years, 3 months, compared to children born in 2002 who had an average age of diagnosis of 2 years 8 months.

“The decrease in age of first evaluation for concerns is an important improvement because we know that the earlier children are identified and the sooner they begin early intervention services, the better their long term outcome,” said Dr. Alycia Halladay, chief science officer of the Autism Science Foundation.  “By continuing to study children’s development between age 4 and 8, we can gain actionable information that can inform how school districts and other service-providers can best help children during this critical developmental period.”

The prevalence of 4 year-olds was 30% less than seen in 8 year-olds, which is not an entirely new finding. Earlier this year, the High Risk Baby Siblings Research Consortium reported that while a diagnosis at 18 months is stable, some children do not meet criteria for a diagnosis until 3 years.  Children with a lower IQ were more likely to receive an early diagnosis, confirming earlier findings that children with more behavioral symptoms are more likely to be picked up earlier.

Screen Shot 2015-12-10 at 11.46.09 AMSaid Autism Science Foundation President Alison Singer, who participated in a CDC teleconference about
the new findings: “What’s five months in the scheme of things? It’s huge. That’s five months a mother or father doesn’t have to spend questioning their toddler’s development and behavior — or questioning whether they should be doing more to help him. That’s five fewer months of painful uncertainty. For a parent, five months can be an eternity.”

Added Singer, “We’ve gained five months, which is wonderful news. Now let’s be greedy and try to gain 12 months, 18 months, for all children. We need to keep chipping away at the delay and disparity in diagnosis. We’re making important and measurable progress, but, working together, we can do even more.”

Halladay noted:  “While this is great news, there is still progress to be made with regards to racial and ethnic variation in age of diagnosis.   At 4 years of age, there was no difference in diagnosis rates between African American and Caucasian children.  However, African American children still experience a delay in the age of first developmental evaluation.”

The overall prevalence of autism in the cohort of 4 years-olds was reported to be 13.4 per 1000 (1 in 75). This is the first time prevalence numbers have been reported for 4 year-old children. For the past 15 years, the ADDM network has reported autism prevalence in 8 year-old children. The new CDC data are not the widely cited “1 in x” prevalence data; those data, which measure the change in prevalence among 8 year-old children, are reported every two years and are next expected in the spring of 2016.

The same methodology was used to measure prevalence in 4 year-old children and in 8 year-old children: examination of school and health records. Preschool records were examined in 5 sites, a subset of the 12 ADDM sites.

Today’s report was published in the Journal of Developmental and Behavioral Pediatrics.

About The Autism Science Foundation

The Autism Science Foundation (ASF) is a 501(c)(3) public charity. Its mission is to support autism research by providing funding to scientists and organizations conducting autism research. ASF also provides information about autism to the general public and serves to increase awareness of autism spectrum disorders and the needs of individuals and families affected by autism. To learn more about the Autism Science Foundation or to make a donation, visit www.autismsciencefoundation.org.


Contact:                Rubenstein Communications, Inc.

Adam Pockriss – apockriss@rubenstein.com/212.843.8286

A study published today in Neuron  examines brain tissue of people diagnosed with autism to better understand the symptoms of autism, and when mutations in the DNA occurred. In other words, did the genetic mutation originate from the parents DNA, or did it happen sometime after the egg and the sperm formed an embryo?   Knowing when they occurred helps in understanding how autism can be passed on, how standard blood tests for autism should be used, and how often genetic mutations occur in brain tissue.


Alissa D’Gama, from Boston Children’s Hospital and Harvard University, was first author on the study

To illustrate the importance of different mutations, here is a primer.   Most human genetic diseases are the result of inherited DNA mutations, in other words, those that are present in one of the parents. There is one big exception to this: cancer. But other genetic diseases, like sickle cell disease and cystic fibrosis, result from inherited DNA. Maybe the parent doesn’t have the same exact mutation, but a geneticist can trace the mutation to one of the parents. Because the mutation came from the parent, the mutation is present when the sperm and egg join and the embryo is formed. These mutations end up in all the tissues of the affected individual: blood, saliva, organs. So you can look at any of these tissues and still see the mutation. A doctor doesn’t need the organ of interest to study them.  They are inherited.

In contrast to an “inherited” mutation, is a “heritable” mutation. For example, there is more evidence to show that de novo mutations are important in autism diagnosis. You’ve heard word de novo or “of new”, meaning, they end up in the offspring but can’t be seen in either parent.  These mutations may be in the sperm and the egg or the cells that come before the sperm and egg, called the germline, but they aren’t in the blood or spit or cells of the parents. In other words, to a geneticist without sperm or eggs to study, they are de novo. These sorts of heritable mutations are in all cells, including blood, saliva, skin cells, and organs.   More and more, scientists are showing that in autism, these de novo mutations result in psychiatric issues like autism spectrum disorders.   Scientists know more about these mutations in the last 5 years than they ever did, and how they cause problems in the genetic code.  These are germline mutations.

But what scientists don’t know a lot about is the role of somatic mutations in neurodevelopmental disorders. These are mutations that happen AFTER the embryo started forming, and they affect a certain organ of interest. Because they are not in every cell in the body,  they are called somatic mutations. Only a subset of cells, or a specific organ, shows the mutation. This is the sort of mutation you see in cancer., and a biopsy is needed to see them.  A doctor would need the specific organ to find it.  This is the sort of mutation that occurs as cells constantly divide through your lifetime. If you think about how many times your cells turn over, it’s inevitable that a mutation is going to happen somewhere at sometime. They can be common and not harmful. However, sometimes, for example in cancer, they are harmful.


Adapted from the National Cancer Institute and the American Society of Clinical Oncology

If you are lost right now, you are not alone.  This is pretty advanced genetics to most people.  See the image to the right to graphically explain the difference between somatic and germline

Scientists have the resources to study germline mutations and de novo mutations in blood or saliva. But until recently, it has not been possible to study somatic mutations. How would you know if autism is the result of a somatic mutation? You’d have to study the brains of people with ASD. And that’s what a group at Boston Children’s Hospital did recently and just published their findings. While somatic mutations in autism are rare, they do exist.  Alissa D’Gama, the first author, explains why the project is important:

“Identifying a few cases with somatic mutations shows us that such mutations can occur in ASD and that somatic mutations may be another genetic mechanism that contributes to ASD risk. Understanding that some mutations can occur late in development and only be present in the brain has important implications for clinical genetic testing, as studying the blood will miss the somatic mutations present only in brain.”

So how does this impact people with autism? 1. Scientists now know that there are genetic mutations in the brain that are specific to tITBhe brain, and not found in other tissues; and 2.   These somatic mutations may be responsible for the neuropathology of autism spectrum disorders.   The word “may” is used because there is still so much researchers do not know, but could know, if there were more brains of people with autism to study.   This type of analysis was only possible through the accrued collection of dozens of brains of people with autism. Please consider registering for the Autism BrainNet at www.takesbrains.org. It is not binding like a consent, and when you register, you will continue to receive important updates like this.

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