Researchers discover 102 genes associated with autism

In the largest genetic sequencing study of autism spectrum disorder (ASD) to date, researchers have identified 102 genes associated with risk for autism.

The discovery shows significant progress towards teasing apart the genes associated with autism from those associated with intellectual disability and developmental delay, conditions which often overlap.

According to the World Health Organisation (WHO), one in 160 children has an autism spectrum disorder (ASD).

ASDs begin in childhood and tend to persist into adolescence and adulthood. In most cases the conditions are apparent during the first five years of life.

"This is a landmark study, both for its size and for the large international collaborative effort it required.

"With these identified genes we can begin to understand what brain changes underlie ASD and begin to consider novel treatment approaches," said Joseph D Buxbaum, Director of the Seaver Autism Center for Research and Treatment at Icahn School of Medicine at Mount Sinai.

For the study published in the journal Cell, an international team of researchers from more than 50 sites collected and analyzed more than 35,000 participant samples, including nearly 12,000 with ASD, the largest autism sequencing cohort to date.

Using an enhanced analytic framework to integrate both rare, inherited genetic mutations and those occurring spontaneously when the egg or sperm are formed, researchers identified the 102 genes associated with ASD risk.

Of those genes, 49 were also associated with other developmental delays.

The larger sample size of this study enabled the research team to increase the number of genes associated with ASD from 65 in 2015 to 102 today.

In addition to identifying subsets of the 102 ASD-associated genes, the researchers showed that ASD genes impact brain development or function and that both types of disruptions can result in autism.

"Through our genetic analyses, we discovered that it's not just one major class of cells implicated in autism, but rather that many disruptions in brain development and in neuronal function can lead to autism," said Buxbaum.

It's critically important that families of children with and without autism participate in genetic studies because genetic discoveries are the primary means to understanding the molecular, cellular, and systems-level underpinnings of autism.

"We now have specific, powerful tools that help us understand those underpinnings, and new drugs will be developed based on our newfound understanding of the molecular bases of autism," the researchers noted.
 

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Scientists discover how gene mutation causes autism and intellectual disability

Scientists at Northwestern University near Chicago have made a significant stride in the quest to understand autism and other intellectual disabilities. Researchers at the school published a study in Neuron outlining why a specific gene mutation causes intellectual disability and autism spectrum disorder in children. 

The study identifies a gene called Usp9x. Individuals with mutations in this gene grow fewer synapses in the brain. When fully functional, the gene protects a protein called akyrin-G that is responsible for growing an stabilyzing synapses. These synapses help cells communicate, and are especially important in developing brains in order for children to learn.

When the Usp9x gene is mutated, it can't protect the akyrin-G protein, which degrades and destabilizes. Scientists found that individuals with this specific gene mutation showed "developmental delay, difficulty learning, increased anxiety and hyperactivity."

“We have solved an important piece of the puzzle in understanding how this mutation causes intellectual disabilities and mental illness,” Peter Penzes, lead author for the study and director of Northwestern's Center for Autism and Neurodevelopment said in a statement.

The Usp9x gene also protects several other proteins that may cause intellectual disability and autism when degraded. Less severe mutations of the ankyrin-G protein have also been linked to the development of schizophrenia and bipolar disease.

According to the Centers for Disease Control and Prevention, 1 in 59 children in the U.S. is diagnosed with autism spectrum disorder (ASD). Individuals with ASD may have problems with social, emotional, and communication skills. Boys are four times more likely to be diagnosed than girls, and the disorder occurs across racial, ethnic and socioeconomic groups.

The CDC also says more people than ever are being diagnosed with ASD.  It's unclear whether the increase is due to a broadening definition of the disorder, better efforts in diagnosis or a true increase in the number of people with ASD. The organization believes the increase in diagnosis is due to a combination of the three factors.

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Hope for brain related genetic disorders

Researchers have reversed a mutation in mice that leads to the genetic disorder WAGR syndrome — which causes intellectual disability and obesity in people — an advance that may lead to drugs for shaping the brain’s nerve connections.

The study noted that the gene editing technology they used was unique as it changed the epigenome — how the genes are regulated — without changing the actual genetic code of the mice.

The researchers found that a gene, C11orf46, was an important regulator during brain development.

They said, the gene turned on and off the direction-sensing proteins which helped guide the long fibres growing out of newly formed nerve cells, or neurons. 

According to the researchers, these neurons are responsible for sending electrical messages, helping them form into a bundle which connects the two hemispheres of the brain, known as the corpus
callosum. 

The scientists said, failure to properly form this bundled structure can lead to conditions such as intellectual disability, autism, or other brain developmental disorders.

“Although this work is early, these findings suggest that we may be able to develop future epigenome editing therapies that could help reshape the neural connections in the brain, and perhaps prevent developmental disorders of the brain from occurring,” said the study's co-author.

According to the study, WAGR syndrome — also known as chromosome 11p13 deletion syndrome — can result when some genes present along with C11orf46 are deleted by chance. 

As part of the study, the researchers used a genetic tool, called a short hairpin RNA, to cause less of the C11orf46 protein to be made in the brains of mice. 

They found that the neuron fibres in the mouse brains with less of the C11orf46 protein failed to properly form the corpus callosum — similar to what is seen in WAGR syndrome.

The researchers also found that a gene that makes another direction-sensing protein — Semaphorin 6a — was more actively produced in mice with lower C11orf46. 

Following this, the researchers used a modified form of the gene editing technology, CRISPR, and tweaked a portion of the gene which regulated Semaphorin production in cells. 

According to the study, this allowed C11orf46 to function normally in the brains of these mice, and restored the neuron fibre bundling, similar to how it is in normal brains. The researchers wrote in the study that there is therapeutic potential for shaping the brain’s nerve connections by targeting genes and proteins that activated and repressed the process. 

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Discovery of new De novo mutation may lead to better treatment

It has been found in a recent study that developmental disorders affect certain skills of humans like attention, memory, language, and social interaction.

Although many new developmental disorders have been identified in recent years, there are many more which are left undiscovered.

In this study, the researchers analyzed genomic data from over 31,000 parent-child trios obtained from the UK's Deciphering Developmental Disorders Project.

Analysis of these trios yielded more than 45,000 'de novo' mutation (DNMs). They developed an improved method to test for the enrichment (over-representation) of damaging DNMs in individual genes.
 
One of the researchers, said: "We found 307 significantly enriched genes, 49 of which are novel. With all of these genes, we were able to explain about 51 per cent of the DNM burden in our dataset. We then modeled different underlying genetic scenarios to get an idea of where the remaining de novo burden lies and how we can go about finding it."

About 40 per cent of developmental disorders is caused by DNMs, equivalent to about one birth in every 295 in the UK alone. The prevalence of the disease increases with the age of the parents.

The disorders usually become visible during childhood and include severe diseases such as autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), intellectual disability, and Rett syndrome.

A possible expectation is that the DNMs in the genes which are as yet undiscovered are less penetrant, i.e., they present symptoms in fewer people.

"We may need to adapt our system of gene discovery in order to capture these fewer penetrant genes," said a researcher.

The researchers also hope to increase their sample size in order to try to detect ever more genes associated with developmental disorders.

However, the identification of 40 new genes already provides valuable information to clinicians and to drug developers.

One of the lead researchers of the study, said: "Developmental delay is often caused by new mutations arising during the formation of sperm or eggs."

"By combining data on new mutations identified in the DNA of more than 30,000 patients, the scientists could implicate a role for 49 new genes in developmental delay."

"This study shows the power of large-scale international collaboration to advance our understanding of this disorder and improve diagnostics as well as patient management," added the Prof. 

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Intellectual disability among children linked to air pollution

A team of researchers has linked intellectual disabilities among children to rising air pollution, stressing that exposure outdoor may impede cognitive development. According to the study, British children with intellectual disabilities are more likely than their peers to live in areas with high outdoor air pollution.

The team reached the conclusion from an analysis of data extracted from a Cohort Study, a nationally representative sample of more than 18,000 UK children born in 2000 to 2002.

"We know that people with intellectual disabilities in the UK have poorer health and die earlier than they should.

"This research adds another piece to the jigsaw of understanding why that is the case and what needs to be done about it," said lead author. Averaging across ages, children with intellectual disabilities were 33 per cent more likely to live in areas with high levels of diesel particulate matter and 30 per cent more likely to live in areas with high levels of nitrogen dioxide.

"These children were 30 per cent more likely to live in areas with high levels of carbon monoxide and 17 per cent more likely to live in areas with high levels of sulphur dioxide," the findings showed.
The authors noted that intellectual disability is more common among children living in more socio-economically deprived areas, which tend to have higher levels of air pollution.

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Hope for parents whose child has rare but serious form of epilepsy

A recent study has offered new hope for parents who have a child with a rare but serious form of epilepsy, epileptic encephalopathy (EE). New ways of sequencing the human genome mean geneticists and genetic counselors have much more to say to parents who wonder if future children might carry the disease, said co-senior author.

These advances offer insights for all of us because they are part of the growing study of mosaicism – the fact that many of us do not in fact have just one genome in us. We are what scientists call mosaics – bunches of cells that may have different genotypes buried deep within us.

“A mosaic mutation happens some time after fertilization when cells are dividing, which requires copying the entire DNA. If one of those cells makes a copying error that introduces a mutation. All the cells that come from that cell will carry the same mutation. So you end up with a mosaic pattern where some cells have the mutation and some cells don’t. That’s the mosaic,” the author said.

The fact that, say, 10 percent of your cells scattered throughout your body might be different than other cells may be completely unimportant. But if 10 percent of your sperm or oocytes have the mutation, that could be a big problem if that mutation affects the brain development of the child.

A big question from any parent of a child with EE is what are the odds that our other children might have this condition? For decades, parents whose child had epilepsy were told there’s a 1 to 5 percent chance that other children might inherit the mutation. This was based on clinical evidence – the numbers of recurrences physicians saw in the clinic.

But armed with more precise testing, the geneticists found parental mosaicism that wasn’t easily detected before in about 10 percent of families, putting these families at higher risk of passing the mutation to another child. What this means in practical terms is that this small group probably accounts for most of the recurrences. For some parents, there’s good news: if this parental mosaicism was not detected, your odds of having another such child with epilepsy could be much less than 1 percent.

“We have the technology to pick out mosaic cells in a sea of otherwise normal cells. The percentage of families where we can identify mosaicism in the parent is higher than most of us thought it would be. While the overall recurrence risk (across all families) is about 1 percent, for those families where we can find the mosaic mutation in the parents, it’s not a 1 percent risk. It’s much higher than that. And we now have the tools to help give them that information, and help them with better family planning and decision-making down the road,” he said.

“Our study focused on patients with severe epilepsy. But the finding that 10 percent of the parents have mosaicism may actually apply to a broad range of other disorders, including autism and intellectual disability,” he added.

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Here`s how protein impacts intellectual disability

A new study has paved the way for the potential treatments of intellectual disability and other neurodevelopmental disorders.

Your brain needs just the right balance between excitatory "on" signals and inhibitory "calm down" signals. Now scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that a protein helps balance nerve cell communication.

"This paper adds a new dimension to our understanding of the molecular mechanisms that impact intellectual disability," said researcher Brock Grill. "Our study is the first to identify a defect in neuron communication caused by altering the activity of a gene called HUWE1, which causes intellectual disability, including Juberg-Marsidi-Brooks syndrome."

Studying neuronal communication is important because the brain needs to balance excitatory neurotransmitters (to increase signal transmission) and inhibitory neurotransmitters (to calm nerve cells down). An imbalance in the excitatory/inhibitory ratio is a central feature of many neurodevelopmental disorders--which occurs through gene overexpression or a loss of gene function.

For the study, Grill and his colleagues investigated neuronal communication balance using a simple model circuit in the nematode C. elegans, a small, transparent worm. Despite its small size, this worm shares half its genetic make-up with humans, which makes it an ideal model to study the genetics of neuron function.

The researchers took a close look at GABA, the principal inhibitory neurotransmitter in C. elegans and the human brain. In C. elegans, the protein responsible for regulating GABA transmission is called EEL-1; in humans, the equivalent protein is known as HUWE1.

The researchers studied the function of EEL-1/HUWE1 in the worm motor circuit and found that decreasing or increasing the protein alters GABA transmission, upending the excitatory/inhibitory balance, a shift that leads to impaired locomotion and increased sensitivity to electroshock-induced seizure.

"Using a simple model circuit, we've identified a key player required to achieve a balance of excitation and inhibition," Grill noted. "This opens up a new concept for why HUWE1 causes intellectual disability. HUWE1 affects only the release of the GABA neurotransmitter, not the levels or function of the GABA receptor, Grill noted. He said more research is needed into how this actually affects the brain.

"The paper is an important step in understanding how increased or decreased activity of HUWE1 can alter circuit function and lead to intellectual disability," said first author Karla Opperman.

The study represents important progress in understanding the molecular underpinnings of intellectual disability. In particular, results from the study show for the first time that mutations that cause Juberg-Marsidi-Brooks syndrome result in loss of HUWE1 function and can impair nerve cell function.The study is published online in the journal Cell Reports.

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