autism and genetics

Posted on Autism

Study finds neglected mutations may play important role in the autism spectrum


UC San Diego and UCLA researchers find tandem repeats, which are also associated with Huntington’s disease, may contribute to autism.

Mutations that occur in certain DNA regions, called tandem repeats, may play a significant role in autism spectrum disorders, according to research led by Melissa Gymrek, assistant professor in the UC San Diego Department of Computer Science and Engineering and School of Medicine. The study, which was published in Nature on Jan. 14, was co-authored by UCLA professor of human genetics Kirk Lohmueller and highlights the contributions these understudied mutations can make to disease.

“Few researchers really study these repetitive regions because they’re generally non-coding–they do not make proteins; their function is unclear; and they can be difficult to analyze,” said Gymrek. “However, my lab has found these tandem repeats can influence gene expression, as well as the likelihood of developing certain conditions such as autism.”

In the paper, the lab studied around 1,600 “quad” families, which include mother, father, a neurotypical child and a child with
autism . Specifically, they were looking for de novo mutations, which appear in the children but not the parents. This analysis, led by UC San Diego graduate student and first author Ileena Mitra, identified an average of 50 de novo mutations at tandem repeats in each child, regardless of whether they were affected by autism.

On average, there were more mutations in autism children, and while the increase was statistically significant, it was also relatively modest. However, using a novel algorithmic tool developed by UC San Diego bioengineering undergraduate and second author Bonnie Huang, the researchers showed tandem repeat mutations predicted to be most evolutionarily deleterious were found at higher rates in autistic children.

“In our initial analysis, the ratio between the number of mutations in autistic children and neurotypical children was around 1.03, so barely above one,” said Gymrek. “However, after we applied Bonnie’s tool, we found relative risk increased about two-and-a-half fold. The kids with autism had more severe mutations compared to the controls.”

Finding so many previously undiscovered tandem repeat mutations is significant, as it matches the number of point mutations (single alterations in the A, C, G, T bases that make up DNA) typically found in each child.

The study also produced a wealth of information about the many factors that can influence these de novo mutations. For example, children with older fathers had more tandem repeat mutations, quite possibly because sperm continues to divide – and accumulate mutations – during a man’s lifetime. However, the changes in repeat length coming from mothers were often larger, though the reasons for this are unclear.

“The mutations from dad tended to be plus or minus one copy,” said Gymrek. “However, mutations from mom were usually plus or minus two or more copies, so we’d see more dramatic events when they came from the mother.”

This approach highlighted a number of genes that had already been linked to autism, as well as new candidates, which the lab is now exploring.

“We want to learn more about what these novel autismgenes are doing,” said Gymrek. “It’s exciting because repeats have so much more variation compared to point mutations. We can learn quite a bit from a single location on the genome.”


Posted on Autism

Advances in understanding autism, based on “mosaic” mutations

Mutations and chromosome deletions/duplications during embryonic development contribute to autism risk


Two studies in today’s Nature Neuroscience, led by researchers at Boston Children’s Hospital, Brigham and Women’s Hospital (BWH), and Harvard Medical School (HMS), implicate mosaic mutations arising during embryonic development as a cause of autism spectrum disorder (ASD). The findings open new areas for exploring the genetics of ASD and could eventually inform diagnostic testing.

Mosaic mutations affect only a portion of a person’s cells. Rather than being inherited, they arise as a “mistake” introduced when a stem cell divides. A mutation in a stem cell will only be passed to the cells that descend from it, producing the mosaic pattern. When mosaic mutations occur during embryonic development, they can appear in the brain and affect the function of neurons. The earlier in development a mutation happens, the more cells will carry it.

Characterizing mosaic mutations in the brain

The two studies were part of the Brain Somatic Mosaicism Network, funded by the National Institute of Mental Health. The first study used deep, ultra-high-resolution whole-genome sequencing to quantify and characterize mosaic mutations in the frontal cortex of people with and without ASD. It was led by Rachel Rodin, MD, PhD and Christopher Walsh, MD, PhD, of Boston Children’s, and Yanmei Dou, PhD and Peter Park, PhD, of HMS.

When the researchers examined samples of brain tissue from 59 deceased people with ASD and 15 controls — the largest cohort of brain samples ever studied — they found that most of the brains had mosaic “point” mutations (alterations in a single “letter” of genetic code). They calculated that embryos acquire several such mutations with each cell division, and estimate that about half of us carry potentially harmful mosaic mutations in at least 2 percent of our brain cells.

In the brains of people with ASD, however, mosaic mutations were more likely to affect parts of the genome that have a pivotal role in brain function. Specifically, they tended to land in “enhancers,” portions of DNA that do not code for genes but regulate whether a gene is turned on or off.

“In the brains of people with autism, mutations accumulate at the same rate as normal, but they are more likely to fall into an enhancer region,” says Rodin, first author on the paper. “We think this is because gene enhancers and promoters tend to be in DNA that’s unwound and more exposed, which probably makes them more susceptible to mutations during cell division.”

“Mutations in enhancers are a hidden kind of mutation that you don’t see in typical diagnostic exome sequencing, and it may help explain ASD in some people,” notes Walsh, chief of genetics and genomics at Boston Children’s and co-senior author on the paper with Park, who led the study’s computational analyses. “We also need to better understand the effects of these mutations on neurons.”

Mosaic deletions and duplications

The second study is the first large-scale investigation of copy number variants (CNVs) in people with ASD that occur in a mosaic pattern. As opposed to point mutations in a single gene, CNVs are deletions or duplications of whole segments of a chromosome, which may contain multiple genes.

A team led by Maxwell Sherman, MS of BWH, Po-Ru Loh, PhD of BWH, Park, and Walsh studied blood samples from about 12,000 people with autism and 5,500 unaffected siblings provided by the Simons Simplex Collection and the Simons Powering Autism Research for Knowledge (SPARK) datasets. They used blood as a proxy for brain tissue and applied novel computational techniques to sensitively detect mosaic mutations that likely arose during embryonic development.

“People have been interested in CNVs in autism for a long time, and would occasionally notice that some of them were mosaic, but no one had really looked at them in a large-scale study,” says Loh, co-senior author on the paper with Walsh and Park.

From these large samples, the team identified a total of 46 mosaic CNVs in the autism group and 19 in siblings. The CNVs affected 2.8 to 73.8 percent of blood cells sampled from each subject.

Size matters

Notably, the people with ASD were especially likely to have very large CNVs, with some involving 25 percent or more of a chromosome. The CNVs spanned a median of 7.8 million bases in the ASD group, versus 0.59 million bases in controls.

“This is one of the more interesting and surprising aspects of our study,” says Sherman, the paper’s first author and a PhD student at MIT. “The kids with ASD had very large CNVs that often hit dozens of genes, and likely included genes important for development. If the CNVs were in all their cells, rather than in a mosaic pattern, they would likely be lethal.”

The study also suggested that the larger the CNVs, the greater the severity of autism as assessed with a standard clinical measure. Another surprise was that smaller CNVs already known to be associated with ASD when found in all cells, such as deletions or duplications of 16p11.2 or 22q11.2, were not associated with autism when they occurred in a mosaic pattern.

“This suggests that in order to get autism, you have to mess up a large number of cells in the brain in a pretty substantial way,” says Walsh. “We’re fairly sure that these large CNVs change the behavior of the neurons that carry them.”

“We don’t really know what cell fraction is important, or what particular chromosomes are most susceptible,” notes Loh. “These events are still very rare, even in people with autism. As larger cohorts are assembled, we hope to get some finer-grained insights.”

The findings of these studies could eventually be incorporated into diagnostic testing in children with autism. Testing could incorporate the non-coding portions of the genome, such as gene enhancers and promoters, and include higher-resolution chromosomal analysis to identify large mosaic CNVs. For now, the findings add to the ever-evolving autism puzzle, deepening the mystery of why so many different genetic mechanisms can lead to the same presentation of autism.


Posted on Autism

Single mutation leads to big effects in autism-related gene

New findings suggest that a single mutation may contribute to increased prevalence of autism in boys than in girls. Image courtesy of Roche Lab/NINDS.

A new study in Neuron offers clues to why autism spectrum disorder (ASD) is more common in boys than in girls. National Institutes of Health scientists found that a single amino acid change in the NLGN4 gene, which has been linked to autism symptoms, may drive this difference in some cases. The study was conducted at NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

Researchers led by Katherine Roche, Ph.D., a neuroscientist at NINDS, compared two NLGN4 genes, (one on the X chromosome and one on the Y chromosome), which are important for establishing and maintaining synapses, the communication points between neurons.

Every cell in our body contains two sex chromosomes. Females have two X chromosomes; males have one X and one Y chromosome. Until now, it was assumed that the NLGN4X and NLGN4Y genes, which encode proteins that are 97% identical, functioned equally well in neurons.

But using a variety of advanced technology including biochemistry, molecular biology, and imaging tools, Dr. Roche and her colleagues discovered that the proteins encoded by these genes display different functions. The NLGN4Y protein is less able to move to the cell surface in brain cells and is therefore unable to assemble and maintain synapses, making it difficult for neurons to send signals to one another. When the researchers fixed the error in cells in a dish, they restored much of its correct function.

“We really need to look at NLGN4X and NLGN4Y more carefully,” said Thien A. Nguyen, Ph.D., first author of the study and former graduate student in Dr. Roche’s lab. “Mutations in NLGN4X can lead to widespread and potentially very severe effects in brain function, and the role of NLGNY is still unclear.”

Dr. Roche’s team found that the problems with NLGN4Y were due to a single amino acid. The researchers also discovered that the region surrounding that amino acid in NLGN4X is sensitive to mutations in the human population. There are a cluster of variants found in this region in people with ASD and intellectual disability and these mutations result in a deficit in function for NLGN4X that is indistinguishable from NLGN4Y.

In females, when one of the NLGN4X genes has a mutation, the other one can often compensate. However, in males, diseases can occur when there is a mutation in NLGN4X because there is no compensation from NLGN4Y.

The current study suggests that if there is a mutation in NLGN4X, NLGN4Y is not able to take over, because it is a functionally different protein. If the mutations occur in regions of NLGN4X that affect the protein levels, that may result in autism-related symptoms including intellectual deficits. The inability of NLGN4Y to compensate for mutations in NLGN4X may help explain why males, who only have one X chromosome, tend to have a greater incidence of NLGN4X-associated ASD than females.

“The knowledge about these proteins will help doctors treating patients with mutations in NLGN4X better understand their symptoms,” said Dr. Roche.

Posted on Autism

Study identifies 69 genes that increase the risk for autism

UCLA-led team compares DNA of children with the disorder to that of their siblings and parents

DNA and autism
DNA and autism

A UCLA-led research team has identified dozens of genes, including 16 new genes, that increase the risk of autism spectrum disorder. The findings, published in the journal Cell, were based on a study of families with at least two children with autism.

Researchers from UCLA, Stanford University and three other institutions used a technique called whole genome sequencing to map the DNA of 2,300 people from nearly 500 families. They found 69 genes that increase the risk for autism spectrum disorder; 16 of those genes were not previously suspected to be associated with a risk for autism.

Researchers also identified several hundred genes they suspect may increase the risk of autism based on their proximity to genes previously identified to carry an increased risk.  The study analyses further revealed several new biological pathways not previously identified in studies of autism.

The findings shed light on how genetic variants or mutations — the differences that make each person’s genome unique — are passed from parents to children affected with autism, said the study’s co-lead author Elizabeth Ruzzo, a UCLA postdoctoral scholar. Former UCLA postdoctoral scholar Laura Pérez-Cano is the study’s other co-lead author.

“When we look at parents of autistic children and compare them to individuals without autism, we find that those parents carry significantly more, rare and highly damaging gene variants,” Ruzzo said. “Interestingly, these variants are frequently passed from the parents to all of the affected children but none of the unaffected children, which tells us that they are significantly increasing the risk of autism.”

Of the children in the study, 960 have autism and 217 children do not. That enabled researchers to analyze the genetic differences between children with and without autism across different families.

“Studying families with multiple children affected with autism increased our ability to detect inherited mutations in autism spectrum disorder,” said Dr. Daniel Geschwind, senior, corresponding author of the study and the Gordon and Virginia MacDonald Distinguished Professor of Human Genetics, Neurology and Psychiatry at the David Geffen School of Medicine of UCLA.

“We show a substantial difference between the types of mutations that occur in different types of families, such as those that have more than one affected child versus those having only one child with ASD,” said Geschwind, who also was the study’s co-principal investigator and director of the UCLA Center for Autism Research and Treatment and director of the Institute of Precision Health at UCLA.

The research also found that the 16 genes newly determined to be associated with an increased risk for autism form a network with previously identified ASD risk genes. The way they interact with one another further heightens the risk, said the study’s co-senior author and co-principal investigator Dennis Wall, a Stanford University School of Medicine associate professor of pediatrics and of biomedical data science.

“They associate with each other more tightly than we’d expect by chance,” he said. “These genes are talking to each other, and those interactions appear to be an important link to autism spectrum disorder.”

The nearly 600 genes researchers suspect as carrying an increased risk of autism were identified through “guilt by association,” or through their interactions with other genes that already have been shown to carry an increased autism risk, Ruzzo said.

“And although not all of those genes will be found to increase the risk for autism, our analysis indicates that future studies will provide support for many of these genes,” she said.

The families studied are part of the Autism Genetic Resource Exchange (AGRE), which was originally developed nearly two decades ago by researchers and the National Institutes of Health in collaboration with Cure Autism Now, which is now a program of Autism Speaks.

Autism is a spectrum of neurological disorders characterized by difficulties with communication and social interaction. Geschwind has been working to identify the genetic causes and biological mechanisms of the disorder for more than a decade, and led the original development of the AGRE resource that was used in this study in the late 1990s. In 2018, he and colleagues at UCLA received their second, five-year grant from the NIH to expand autism research by studying genetic causes of autism in African American families.

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Posted on Autism

3q29 deletion survey: distinct social profile, high ASD risk Chromosomal deletion connected to both schizophrenia + autism

A survey of 93 people with 3q29 deletion syndrome reveals a distinct pattern of social disability and anxiety, even without a diagnosis of autism spectrum disorder.

The results were published online in Molecular Autism on July 16.

Geneticists at Emory University School of Medicine teamed up with clinicians at Children’s Healthcare of Atlanta’s Marcus Autism Center to evaluate the largest cohort of people with 3q29 deletion ever assembled. Because 3q29 deletion syndrome is relatively rare (1/30,000 people), most physicians who have seen a case have only seen one. Study participants were recruited through a registry website, and they or their parents completed questionnaires about social, communication and behavioral issues. The average age was 10, but adults up to age 41 were included.

In 3q29 deletion syndrome, a stretch of DNA containing several genes is missing from one of a child’s chromosomes. 3q29 deletion — usually spontaneous, not inherited — is one of the strongest genetic risk factors for schizophrenia, increasing the risk at least 20 fold. It also increases the likelihood of autism spectrum disorder at a similar level, the survey indicates: 24 fold for males and more than 40 fold for females.

Most people with 3q29 deletion did not have autism spectrum disorder (ASD) diagnoses (29 percent did), but overall they did have higher scores for social disability and anxiety. While not all participants were the same, their average profile was distinct from the general picture of autism spectrum disorder, in that people with 3q29 deletion tended to have high scores for restricted interests and repetitive behaviors, but only mild impairment in social motivation.

“The kids are motivated to have peer relationships, and desperately want them, yet aside from social motivation, they often lack other skills with which to form those relationships,” says senior author Jennifer Mulle, PhD, assistant professor of human genetics at Emory University School of Medicine.

“One of our recommendations is that all individuals with 3q29 deletion should receive a thorough ASD evaluation as standard of care, so that they can have access to social services and therapeutic programs.” Mulle says. “Because their intellectual disability is generally mild, cognitive behavioral therapy to teach social skills may be an effective intervention.”

Another distinctive aspect of 3q29 deletion syndrome is its relatively greater effects on ASD risk in females compared with males. In the general ASD population, males outnumber females 4 to 1; this ratio is reduced to 2 to 1 for ASD diagnoses in the 3q29 group.

The first author of the paper is Genetics and Molecular Biology graduate student Rebecca Pollak. She worked with associate scientist Melissa Murphy, PhD at Emory and Celine Saulnier, PhD and Cheryl Klaiman, PhD at Marcus Autism Center. Emory geneticists Michael Epstein, PhD and Michael Zwick, PhD also contributed to the paper.

Mulle sees investigating 3q29 deletion syndrome – and other genetic variations connected with schizophrenia and autism — as a way of unraveling the biological complexity of both conditions.

The Emory team is beginning to investigate individual genes found within the 3q29 deletion, aiming to understand molecular mechanisms. Working with cell biology chair Gary Bassell, scientists plan to create a human neuronal model of 3q29 deletion, using induced pluripotent stem cell lines. They are also investigating the patterns of gene activity in blood samples from 3q29 donors.

In April, Mulle and her colleagues from the Department of Human Genetics, including Tamara Caspary, PhD, David Weinshenker, PhD and Steve Warren, PhD published a mouse model of 3q29 deletion in Molecular Psychiatry. The mice display social and cognitive impairments that correspond to some symptoms of related neuropsychiatric disorders.