Gene mutations could cause up to half of autism cases

A study claims that nearly half of autism cases are caused by a combination of gene mutations.-
Im not surprised. We find our patients with new mutations every day. JR

A team led by researchers at Cold Spring Harbor Laboratory (CSHL) this week publishes in PNAS a new analysis of data on the genetics of autism spectrum disorder (ASD). One commonly held theory is that autism results from the chance combinations of commonly occurring gene mutations, which are otherwise harmless. But the authors' work provides support for a different theory.

They find, instead, further evidence to suggest that devastating "ultra-rare" mutations of genes that they classify as "vulnerable" play a causal role in roughly half of all ASD cases. The vulnerable genes to which they refer harbor what they call an LGD, or likely gene-disruption. These LGD mutations can occur "spontaneously" between generations, and when that happens they are found in the affected child but not found in either parent.

Although LGDs can impair the function of key genes, and in this way have a deleterious impact on health, this is not always the case. The study, whose first author is the quantitative biologist Ivan Iossifov, a CSHL assistant professor and on faculty at the New York Genome Center, finds that "autism genes" - i.e., those that, when mutated, may contribute to an ASD diagnosis - tend to have fewer mutations than most genes in the human gene pool.'

This seems paradoxical, but only on the surface. Iossifov explains that genes with devastating de novo LGD mutations, when they occur in a child and give rise to autism, usually don't remain in the gene pool for more than one generation before they are, in evolutionary terms, purged. This is because those born with severe autism rarely reproduce.

The team's data helps the research community prioritize which genes with LGDs are most likely to play a causal role in ASD. The team pares down a list of about 500 likely causal genes to slightly more than 200 best "candidate" autism genes.

The current study also sheds new light on the transmission to children of LGDs that are carried by parents who harbor them but whose health is nevertheless not severely affected. Such transmission events were observed and documented in the families used in the study, comprising the Simons Simplex Collection (SSC). When parents carry potentially devastating LGD mutations, these are more frequently found in the ASD-affected children than in their unaffected children, and most often come from the mother.

This result supports a theory first published in 2007 by senior author Michael Wigler, a CSHL professor, and Dr. Kenny Ye, a statistician at Albert Einstein College of Medicine. They predicted that unaffected mothers are "carriers" of devastating mutations that are preferentially transmitted to children affected with severe ASD. Females have an as yet unexplained factor that protects them from mutations which, when they occur in males, will be significantly more likely to cause ASD. It is well known that at least four times as many males as females have ASD.

Wigler's 2007 "unified theory" of sporadic autism causation predicted precisely this effect. "Devastating de novo mutations in autism genes should be under strong negative selection pressure," he explains. "And that is among the findings of the paper we're publishing today. Our analysis also revealed that a surprising proportion of rare devastating mutations transmitted by parents occurs in genes expressed in the embryonic brain." This finding tends to support theories suggesting that at least some of the gene mutations with the power to cause ASD occur in genes that are indispensable for normal brain development.

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Study: People with autism may be more susceptible to genetic sleep issues

A study indicates that people with autism might be more susceptible to carrying genetic mutations that changes their circadian clock.

People with autism are twice as likely to carry alterations in genes that regulate the circadian clock, or the body’s sleep-wake cycle, as those without the disorder. The findings, published 6 May in Brain and Development, may help to explain why most children with autism have troubled sleep¹.

Insufficient sleep is known to exacerbate the core symptoms of autism, such as social deficits and repetitive behaviors. The new findings suggest that the relationship between sleep and autism may have genetic roots.

“Sleep disturbance seems to be a main feature of autism,” says lead researcher Takanori Yamagata, professor of pediatric developmental medicine at Jichi Medical University in Shimotsuke, Japan. “My hypothesis is that some circadian genes may be related to some of the genetics of autism.”

To investigate this potential link, Yamagata and his team sequenced 18 genes known to govern the body’s day-night rhythms in 28 children and adults with autism, half of whom have sleep disorders, as well as 23 controls.

They identified a total of 68 mutations in 15 of these genes. About half of the mutations are ‘silent,’ which means they have no effect on the proteins the genes encode. But the other half are ‘missense’ mutations that disrupt the corresponding protein sequence. Nine of the mutations had never been reported before, Yamagata says.

People in the autism group have about twice as many mutations in circadian genes as do members of the control group, regardless of whether they have a sleep disorder.

Within the autism group, the researchers found seven missense mutations among individuals who have sleep disorders and the same number in those who sleep normally. By contrast, just one person in the control group carries a missense mutation in a circadian rhythm gene.

“We detected many mutations only in patients with autism, but almost nothing in the control group,” Yamagata says. “So I think these genes relate to some pathophysiology of autism.”

The researchers then used three types of computer algorithms to predict the impact of the missense mutations on the gene’s function. They found that 25 of the 33 missense mutations are likely to be benign, but 8 appear to be damaging.

One of the analyses found more damaging mutations in the individuals with autism who have sleep disorders than in those who sleep normally.

But the algorithms did not agree on which mutations are likely to be harmful. “Some of these virtual programs may reflect real damage, but they are not perfect,” Yamagata says.

The researchers are investigating whether these eight mutations in circadian genes interfere with brain development in mice. They’re starting with a mutation in a gene called TIMELESS that they found in a 9-year-old boy with autism who sleeps all day and stays awake all night. The boy’s mother, who also struggles with sleep but does not have autism, has the same mutation.

The results of these mouse studies may help elucidate the genetic relationship between sleep and autism.

“It is not yet clear exactly what the basis of this interaction is,” says Mustafa Sahin, associate professor of neurology at Harvard Medical School, who was not involved in the study. “It will be very interesting to further investigate the effects of these sequence variations.”

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Study: Mutations causing autism are linked to brain development

A study shows that specific mutations that cause autism are linked to how the child's brain develops.

Scientists at the University of California, San Diego School of Medicine have found that mutations that cause autism in children are connected to a pathway that regulates brain development. The research, led by Lilia Iakoucheva, PhD, assistant professor in the Department of Psychiatry, is published in the February 18 issue of Neuron.

The researchers studied a set of well-known autism mutations called copy number variants or CNVs. They investigated when and where the genes were expressed during brain development. "One surprising thing that we immediately observed was that different CNVs seemed to be turned on in different developmental periods," said Iakoucheva.

Specifically, the scientists noted that one CNV located in a region of the genome known as 16p11.2, contained genes active during the late mid-fetal period. Ultimately, they identified a network of genes that showed a similar pattern of activation including KCTD13 within 16p11.2 and CUL3, a gene from a different chromosome that is also mutated in children with autism.

"The most exciting moment for us was when we realized that the proteins encoded by these genes form a complex that regulates the levels of a third protein, RhoA," said Iakoucheva. Rho proteins play critical roles in neuronal migration and brain morphogenesis at early stages of brain development. "Suddenly, everything came together and made sense."

Further experiments confirmed that CUL3 mutations disrupt interaction with KCTD13, suggesting that 16p11.2 CNV and CUL3 may act via the same RhoA pathway. RhoA levels influence head and body size in zebrafish, a model organism used by geneticists to investigate gene functions. Children with 16p11.2 CNV also have enlarged or decreased head sizes and suffer from obesity or are underweight. "Our model fits perfectly with what we observe in the patients," said Guan Ning Lin, PhD, a fellow in Iakoucheva's laboratory and co-first author with Roser Corominas, PhD.

Interestingly, the RhoA pathway has recently been implicated in a rare form of autism called Timothy syndrome, which is caused by the mutation in a completely different gene. "The fact that three different types of mutations may act via the same pathway is remarkable," said Iakoucheva. "My hope is that we would be able to target it therapeutically."

Iakoucheva and colleagues are planning to test RhoA pathway inhibitors using a stem cell model of autism. "If we can discover the precise mechanism and develop targeted treatments for a handful of children, or even for a single child with autism, I would be happy," she said.

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Brain development in people with autism

This article discusses how brains develop in people with autism.

Geneticists at Heidelberg University Hospital's Department of Molecular Human Genetics have used a new mouse model to demonstrate the way a certain genetic mutation is linked to a type of autism in humans and affects brain development and behavior. In the brain of genetically altered mice, the protein FOXP1 is not synthesized, which is also the case for individuals with a certain form of autism. Consequently, after birth the brain structures degenerate that play a key role in perception. The mice also exhibited abnormal behavior that is typical of autism. The new mouse model now allows the molecular mechanisms in which FOXP1 plays a role to be explained and the associated changes in the brain to be better understood.

"While these kinds of results from basic research cannot be directly translated into treatment, they are still quite valuable for the affected individuals or in this case, for their parents and family. For many of them, it is important to be able to specifically put a name to the disorder and understand it. It can make dealing with it easier," said Professor Gudrun Rappold, Head of the Department of Molecular Human Genetics at Heidelberg University Hospital and senior author of the article. The results have now been published in a preliminary online version in the journal Molecular Psychiatry in cooperation with Miriam Schneider, Institute of Psychopharmacology at the Central Institute of Mental Health in Mannheim, and Dr. Corentin Le Magueresse, German Cancer Research Center (DKFZ) and Professor Hannah Monyer, Department of Clinical Neurobiology, Heidelberg University Hospital and DKFZ in Heidelberg.

Autism is a congenital perception and information-processing disorder in the brain that is frequently accompanied by intellectual disability and in rare cases, superior intelligence and special gifts such as photographic memory. The disorder is characterized by limited social interaction, repetitive behavior and language impairment. Furthermore, a wide range of other disturbances can occur. "Today, in addition to the defect in the FOXP1 gene, we are familiar with other genetic mutations that cause autism or increase the risk of this kind of disorder. However, we are only able to understand how they affect the molecular processes in the neurons, brain development and behavior for a few of these mutations," Rappold said.

This is also the case for FOXP1. Back in 2010, clear signs that structural flaws in this protein play a role in autism and mental disability had been discovered. But what role does it play in the healthy brain? What signal pathways is it involved in? Which other proteins does it interact with and exactly what damage is caused by its absence? The new mouse model has helped to shed light on these questions. The researchers discovered that the mice were born with a normally developed brain for the most part. During the course of the first weeks of life, the striatum, which is important for perception and behavior, degenerates. In a centrally located brain structure as well -- the hippocampus -- which is indispensable for developing long-term memory and recall, microscopically visible changes occur that can also impact signal processing. It could be proven, for example, that in the affected neurons the impulse conduction is changed through which signals are transmitted between neurons.

In addition to the striatum, the ventricles of the brain are degenerated; these are adjacent structures in the murine brain. "Enlarged ventricles were also detected in humans with a FOXP1 mutation," explained Dr. Claire Bacon, who works in the Molecular Human Genetics Department and is first author of the publication. The changes also trigger abnormal behavior that is comparable to the symptoms of autistic patients. The mice barely noticed their fellow mice and did not attempt to make contact to them. Further symptoms include stereotypical compulsive repetitive behaviors, hyperactivity and disturbed nestbuilding behavior.

The researchers now intend to study to what extent the communication of noise by FOXP1 mice (mice communicate via noises in the ultrasonic range) is impaired and whether there are also parallels to the disturbances in patients with FOXP1 mutation in this area as well. In addition, they plan to characterize the newly identified genes impacted by the FOXP1 in the brain and find out which signaling cascades and response paths are disrupted. In this way, they hope to find starting points for a specific treatment. "However, we first have to understand exactly how these changes occur before we can develop treatment concepts," Rappold stressed.

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Many genes are involved in autism

Two large-scale genetic studies show that many genes are involved in autism.

Two major genetic studies of autism, led in part by UC San Francisco scientists and involving more than 50 laboratories worldwide, have newly implicated dozens of genes in the disorder. The research shows that rare mutations in these genes affect communication networks in the brain and compromise fundamental biological mechanisms that govern whether, when, and how genes are activated overall.

The two new studies, published in the advance online edition of Nature on October 29, 2014, tied mutations in more than 100 genes to autism. Sixty of these genes met a “high-confidence” threshold indicating that there is a greater than 90 percent chance that mutations in those genes contribute to autism risk.

The majority of the mutations identified in the new studies are de novo (Latin for “afresh”) mutations, meaning they are not present in unaffected parents’ genomes but arise spontaneously in a single sperm or egg cell just prior to conception of a child.

The genes implicated in the new studies fall into three broad classes: they are involved in the formation and function of synapses, which are sites of nerve-cell communication in the brain; they regulate, via a process called transcription, how the instructions in other genes are relayed to the protein-making machinery in cells; and they affect how DNA is wound up and packed into cells in a structure known as chromatin. Because modifications of chromatin structure are known to lead to changes in how genes are expressed, mutations that alter chromatin, like those that affect transcription, would be expected to affect the activity of many genes.

One of the new Nature studies made use of data from the Simons Simplex Collection (SSC), a permanent repository of DNA samples from nearly 3,000 families created by the Simons Foundation Autism Research Initiative. Each SSC family has one child affected with autism, parents unaffected by the disorder and, in a large proportion, unaffected siblings. The second study was conducted under the auspices of the Autism Sequencing Consortium (ASC), an initiative supported by the National Institute of Mental Health that allows scientists from around the world to collaborate on large genomic studies that couldn’t be done by individual labs.

“Before these studies, only 11 autism genes had been identified with high confidence, and we have now more than quadrupled that number,” said Stephan Sanders, PhD, assistant professor of psychiatry at UCSF, co-first author on the SSC study, and co-author on the ASC study. Based on recent trends, Sanders estimates that gene discovery will continue at a quickening pace, with as many as 1,000 genes ultimately associated with autism risk.

“There has been a lot of concern that 1,000 genes means 1,000 different treatments, but I think the news is much brighter than that,” said Matthew W. State, MD, PhD, chair and Oberndorf Family Distinguished Professor in Psychiatry at UCSF. State was co-leader of the Nature study focusing on the SSC and a senior participant in the study organized by the ASC, of which he is a co-founder. ”There is already strong evidence that these mutations converge on a much smaller number key biological functions. We now need to focus on these points of convergence to begin to develop novel treatments.”

Autism, which is marked by deficits in social interaction and language development, as well as by repetitive behaviors and restricted interests, is known to have a strong genetic component. But until a few years ago, genomic research had failed to decisively associate individual genes with the disorder.

The two new studies highlight the factors that have radically changed that picture, State said. One is the advent of next-generation sequencing (NGS), which allows researchers to read each of the “letters” in the DNA code at unprecedented speed. Another is the establishment of the SSC; a 2007 study had suggested that de novo mutations would play a significant role in autism risk, and the SSC was specifically designed to help test that idea by allowing for close comparisons between children with autism and their unaffected parents and siblings. Lastly, collaborative initiatives such as the ASC are enabling teams of researchers around the world to work closely together, pooling their resources to create large datasets with sufficient statistical power to draw valid conclusions.

The large research teams behind each of the two new studies used a form of NGS known as “whole-exome” sequencing, a letter-by-letter analysis of just the portion of the genome that encodes proteins.

In November 2013, a study led by A. Jeremy Willsey, a graduate student in State’s lab, showed that the functional roles of the nine high-confidence autism risk genes that had then been discovered all converged on a single cell type in a particular place in the brain at a particular time during fetal development. Willsey is a co-author on both of the new Nature studies, which State believes will further accelerate our understanding of how the myriad of genes involved in autism affect basic biological pathways in the brain.

“These genes carry really large effects,” State said. “That we now have a bounty of dozens of genes, and a clear path forward to find perhaps hundreds more, provides an incredible foundation for understanding the biology of autism and finding new treatments.”

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Mutations and severe childhood epilepsies

An international study pinpoints a specific gene mutation that causes severe types of childhood epilepsies.

An international research team has identified gene mutations causing severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve cells communicate with one another.

“This research represents a paradigm shift in epilepsy research, giving us a new target on which to focus treatment strategies,” said pediatric neurologist Dennis Dlugos, M.D., director of the Pediatric Regional Epilepsy Program at The Children’s Hospital of Philadelphia, and a study co-author. “There is tremendous potential for new drug development and personalized treatment strategies, which is our task for the years to come.”

Multiple researchers from the U.S. and Europe performed the research, the largest collaborative study to date focused on the genetic roots of severe epilepsies. The scientists reported their results online today in the American Journal of Human Genetics (epub ahead of print).

Two international research consortia collaborated on the study—the Epi4K/EPGP Consortium, funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the European EuroEPINOMICS consortium. The genetic analysis was performed at the NINDS-funded Epi4K Sequencing, Biostatistics, and Bioinformatics Core at Duke University, led by Drs. David Goldstein, Erin Heinzen and Andrew Allen.

The current study added to the list of gene mutations previously reported to be associated with these severe epilepsy syndromes, called epileptic encephalopathies. The researchers sequenced the exomes (those portions of DNA that code for proteins) of 356 patients with severe childhood epilepsies, as well as their parents. The scientists looked for “de novo” mutations—those that arose in affected children, but not in their parents. In all, they identified 429 such de novo mutations.

In 12 percent of the children, these mutations were considered to unequivocally cause the child’s epilepsy. In addition to several known genes for childhood epilepsies, the study team found strong evidence for additional novel genes, many of which are involved in the function of the synapse.

Epilepsies are amongst the most common disorders of the central nervous system, affecting up to 3 million patients in the U.S. Up to one third of all epilepsies are resistant to treatment with antiepileptic medication and may be associated with other disabilities such as intellectual impairment and autism. Severe epilepsies are particularly devastating in children. In many patients with severe epilepsies, no cause for the seizures can be identified, but there is increasing evidence that genetic factors may play a causal role.

The research teams used a method called family-based exome sequencing, which looks at the part of the human genome that carries the blueprints for proteins. When comparing the sequence information in children with epilepsy with that of their parents, the researchers were able to identify the de novo changes that arose in the genomes of the affected children. While de novo changes are increasingly recognized as the genetic cause for severe seizure disorders, not all de novo changes are necessarily disease-causing.

“Everybody has one or two de novo mutations and it is our task to find those changes that cause disease,” said co-author Ingo Helbig, M.D., now at The Children’s Hospital of Philadelphia. “We pulled out those genes that have more mutations in patients with epilepsy than you would expect by chance. These genes will hopefully tell us a bit more about the underlying disease mechanisms and how we can address them with new treatments.” As a member of the European EuroEPINOMICS consortium, Helbig was a co-initiator of the transatlantic collaboration that conducted the study. Helbig is also a member of the Genetics Commission of the International League Against Epilepsy (ILAE).

The most surprising finding in the study by the international research group is a gene called DNM1, which was found to be mutated in five patients. The gene carries the code for dynamin-1, a structural protein that plays a role in shuttling small vesicles between the body of the neuron and the synapse. These vesicles are structures that contain neurotransmitters, chemical signals crucial to communication between nerve cells. When the researchers looked on a network level, they found that many of the genes that were found to be mutated in patients had a clear connection with the function of the synapse.

This research finding, says Dlugos, provides important information about the functional roles of the genes that were identified. “We knew that synaptic genes were important but not to this extent,” he added.

A spokesperson for Citizens United for Research in Epilepsy (CURE), a non-profit organization dedicated to finding a cure for epilepsy and increasing awareness of the disease, applauded this study. Dr. Tracy Dixon-Salazar, Associate Research Director at CURE and mother of a child with severe genetic epilepsy, added, “It is exciting to see the big consortia put the genomic data of almost 400 patients together. This clearly highlights that by working together we can find new genes faster, helping us to explain what causes this often devastating disease in children.”

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No link between sleep apnea and cancer

A study shows there is no link between sleep apnea and cancer.

Canadian researchers have found no apparent connection between sleep apnea and cancer in a new study of more than 10,000 people with this common sleep disorder.

People with sleep apnea experience repeated periods of disrupted breathing during sleep. Studies suggesting a link between the condition and cancer risk theorized that low oxygen levels might trigger cell mutations connected with cancer.

"We were not able to confirm previous hypotheses that obstructive sleep apnea is a cause of overall cancer development through intermittent lack of oxygen," said lead author Dr. Tetyana Kendzerska, from the Institute for Clinical Evaluative Sciences and Women's College Hospital at the University of Toronto.

The report, published Aug. 5 in the Canadian Medical Association Journal, is unlikely to put the question to rest, however.

"Additional studies are needed to find out whether there is an independent effect of sleep apnea on specific types of cancer," Kendzerska said.

Dr. Leonard Lichtenfeld, deputy chief medical officer of the American Cancer Society, said the findings suggest that sleep apnea by itself is not related to an increased risk of cancer. "However, for some people the factors that cause sleep apnea are related to an increased risk of cancer," he said.

Risk factors for sleep apnea include smoking, chronic lung disease, obesity and diabetes, Lichtenfeld said. "It is these conditions that are more likely to cause the increased cancer risk seen in other studies, not the sleep apnea itself," he said.

This study isn't the "final answer," he said. "More research will have to be done."

For the study, Kendzerska and colleagues studied about 10,150 patients suffering from sleep apnea who took part in a sleep study between 1994 and 2010. They linked this data to health databases from 1991 to 2013.

At the start of the study, about 5 percent of the patients had cancer. Over an average of nearly eight years of follow-up, an additional 6.5 percent of the participants developed cancer. Most common were prostate, breast, colorectal and lung cancers, the researchers said.

Although no link was seen for cancer in general, the researchers did find that low oxygen levels related to sleep apnea were associated with smoking-related cancers, such as lung cancer.

Dr. Yosef Krespi, director of the Center for Sleep Disorders at Lenox Hill Hospital in New York City, cautioned that while sleep apnea may not cause cancer, it is a serious condition that needs to be treated.

"One should not ignore sleep apnea," Krespi said. "Sleep apnea is a chronic progressive disorder that if left untreated can result in serious heart problems."

More than 18 million American adults have sleep apnea, according to the National Sleep Foundation. Some experts say the condition is increasing because of the obesity epidemic.

Sleep apnea can make a cancer patient's life more difficult, Krespi said.

"The quality of life of sleep apnea patients with cancer and their ability to tolerate treatments such as chemotherapy and radiation can be very different than those without the condition," he said.

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Genetics may determine how much sleep a person needs

A study shows that genetics may play a role in how much sleep a person needs each night.

The news: Ever wondered why some people can get a whole lot less sleep than others and still function? Their secret isn't just coffee — it might also be their DNA.

Published in the journal Sleep, researchers largely from the University of Pennsylvania and the Philadelphia area claim that a genetic mutation may partly explain why a certain few can get by on six hours of sleep a night rather than the standard seven to nine.

The study: The team discovered the mutation while conducting a sleep study with 100 pairs of healthy, same-sex twins who were monitored while sleeping at home and were then subjected to a battery of cognitive tests during a 38-hour awake session.

The participants who performed relatively well despite the forced sleep deprivation — and who slept noticeably less — tended to have a mutation in the BHLHE41 gene, called p. Tyr362HIS. The researchers concluded that this and similar "mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss." What's more, the same group also recovered faster from the effects of the 38-hour sleep deprivation session.

"This work provides an important second gene variant associated with sleep deprivation and for the first time shows the role of BHLHE41 in resistance to sleep deprivation in humans," American Academy of Sleep Medicine President Dr. Timothy Morgenthaler told TechTimes.

Though the study doesn't prove that people who can sleep less have a genetic mutation, it does provide solid experimental evidence that the reason some people can sleep less is partly genetic.

What it means for you: Your optimal sleep schedule may be less a matter of personal preference and more a function of biological need. Sadly, you're also probably overestimating your ability to get by on insufficient sleep. Previous research has indicated that the number of people who are mostly unaffected by just five or six hours of sleep per night is as low as 5% of those making the claim — the rest are likely chronically sleep-deprived and don't realize it.

Experts have debated how much sleep is actually necessary for most people, but generally settle at around seven to eight hours a day. Leading sleep researcher Hans Van Dongen tells Vox that, "If you sleep much less than you need, we have good reason to believe that will impair your health."

Sleeping less is probably not in most peoples' genetic cards. But if it is, you've got mom and dad to thank. 

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The CHD8 mutation was found to be a genetic link to Autism

A study found that the CHD8 mutation is a genetic link to autism.

In a collaboration involving 13 institutions around the world, researchers have broken new ground in understanding what causes autism. The results are being published in Cell magazine July 3, 2014: "Disruptive CHD8 Mutations Define a Subtype of Autism in Early Development."

"We finally got a clear cut case of an autism specific gene," said Raphael Bernier, the lead author, and UW associate professor in the Department of Psychiatry and Behavioral Sciences and the clinical director of the Autism Center at Seattle Children's.

Bernier said people with a mutation in the CHD8 gene have a very "strong likelihood" that they will have autism marked by gastrointestinal disorders, a larger head and wide set eyes.

In their study of 6,176 children with autism spectrum disorder, researchers found 15 had a CHD8 mutation and all these cases had similar characteristics in appearance and issues with sleep disturbance and gastrointestinal problems.

Bernier and his team interviewed all 15 cases with CHD8 mutations.

To confirm the findings, researchers worked with scientists at Duke University who do zebra fish modeling. The researchers disrupted the CHD8 gene in the fish and the fish developed large heads and wide set eyes. They then fed the fish fluorescent pellets and found that the fish had problems discarding food waste and were constipated.

Bernier said this is the first time researchers have shown a definitive cause of autism to a genetic mutation. Previously identified genetic events like Fragile X, which account for a greater number of autism cases, are associated with other impairments, such as intellectual disability, more than autism. Although less than half a percent of all kids will have this kind of autism related to the CHD8 mutation, Bernier said there are lots of implications from this study.

"This will be a game changer in the way scientists are researching autism," he said.

The results could lead the way to a "genetics-first approach" that could uncover hundreds more genetic mutations and lead to genetic testing. Genetic testing could be offered to families as a way of guiding them on what to expect and how to care for their child. Currently, autism is diagnosed based on behavior, said Bernier.

In the short term, Bernier said, clinicians can pay attention to the small population with this CHD8 mutation and provide targeted treatment.

Researchers say autism has currently been linked to different types of genetic events. The most commonly researched genetic events associated with autism are chromosomal re-arrangements, called "copy number variations," in which a chunk of chromosome is copied or deleted. But no one rearrangement affects more than 1 percent of all autism cases. While these copy number events are associated with autism, they do not have a definitive link, or as they say among researchers, a "strong penetrance."

Then there are genetic mutations in which a gene has been disrupted and is not creating the kind of protein it should create. The CHD8 gene mutation is the first gene mutation to show a very strong penetrance linked to a certain subtype of autism.

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New brain disorder discovered caused by genetic mutation

A new genetic brain disorder was found by two independent research teams. This disorder is characterized by sensory and motor defects, as well as reduced brain size.

A newly identified genetic disorder associated with degeneration of the central and peripheral nervous systems in humans, along with the genetic cause, is reported in the April 24, 2014 issue ofCell.

The findings were generated by two independent but collaborative scientific teams, one based primarily at Baylor College of Medicine and the Austrian Academy of Sciences, the other at the University of California, San Diego School of Medicine, the Academic Medical Center (AMC) in the Netherlands and the Yale University School of Medicine.

By performing DNA sequencing of more than 4,000 families affected by neurological problems, the two research teams independently discovered that a disease marked by reduced brain size and sensory and motor defects is caused by a mutation in a gene called CLP1, which is known to regulate tRNA metabolism in cells. Insights into this rare disorder, the researchers said, may have important implications for the future treatment of more common neurological conditions.

"What we found particularly striking, when considering the two studies together, is that this is not a condition that we would have been able to separate from other similar disorders based purely on patient symptoms or clinical features," said Joseph G. Gleeson, MD, Howard Hughes Medical Institute investigator, professor in the UC San Diego departments of Neurosciences and Pediatrics and at Rady Children's Hospital-San Diego, a research affiliate of UC San Diego. "Once we had the gene spotted in these total of seven families, then we could see the common features. It is the opposite way that doctors have defined diseases, but represents a transformation in the way that medicine is practiced."

Each child tested was affected by undiagnosed neurological problems. All of the children were discovered to carry a mutation in the CLP1 gene and displayed the same symptoms, such as brain malformations, intellectual disabilities, seizures and sensory and motor defects. A similar pattern emerged in both studies, one led by Gleeson, with Murat Gunel, MD, of the Yale University School of Medicine and Frank Baas, PhD, of the Academic Medical Center in the Netherlands, and the other by Josef Penninger and Javier Martinez of the Austrian Academy of Sciences, teamed with James R. Lupski, MD, PhD, of the Baylor College of Medicine.

"Knowing fundamental pathways that regulate the degeneration of neurons should allow us to define new pathways that, when modulated, might help us to protect motor neurons from dying, such as in Lou Gehrig's disease," said Penninger, scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences.

The CLP1 protein plays an important role in generating mature, functional molecules called transfer RNAs (tRNAs), which shuttle amino acids to cellular subunits called ribosomes for assembly into proteins. Mutations affecting molecules involved in producing tRNAs have been implicated in human neurological disorders, such as pontocerebellar hypoplasia (PCH), a currently incurable neurodegenerative disease affecting children. Although CLP1 mutations have been linked to neuronal death and motor defects in mice, the role of CLP1 in human disease was not known until now.

These scientists performed DNA sequencing on children with neurological problems. Seven out of the more than 4,000 families studied shared an identical CLP1 mutation, which was associated with motor defects, speech impairments, seizures, brain atrophy and neuronal death.

Bass at the AMC said the neurological condition represents a new form of PCH. "Identification of yet another genetic cause for this neurodegenerative disorder will allow for better genetic testing and counseling to families with an affected child," he said.

In a published paper last year, Gleeson and colleagues identified a different gene mutation for a particularly severe form of PCH, and reported early evidence that a nutritional supplement might one day be able to prevent or reverse the condition.

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Girls naturally more protected from autism development

This article explains why boys are four times more likely to develop autism and explains why girls may be naturally more protected from developing autism.

It takes more mutations to trigger autism in women than in men, which may explain why men are four times more likely to have the disorder, according to a study published 26 February in the American Journal of Human Genetics.

The study found that women with autism or developmental delay tend to have more large disruptions in their genomes than do men with the disorder. Inherited mutations are also more likely to be passed down from unaffected mothers than from fathers.

Together, the results suggest that women are resistant to mutations that contribute to autism.

"This strongly argues that females are protected from autism and developmental delay and require more mutational load, or more mutational hits that are severe, in order to push them over the threshold," says lead researcher Evan Eichler, professor of genome sciences at the University of Washington in Seattle. "Males on the other hand are kind of the canary in the mineshaft, so to speak, and they are much less robust."

The findings bolster those from previous studies, but don't explain what confers protection against autism in women. The fact that autism is difficult to diagnose in girls may mean that studies enroll only those girls who are severely affected and who may therefore have the most mutations, researchers note.

"The authors are geneticists, and the genetics is terrific," says David Skuse, professor of behavioral and brain sciences at University College London, who was not involved in the study. "But the questions about ascertainment are not addressed adequately."

Genetic burden:

The new study draws from the Simons Simplex Collection (SSC), a database of families that have one child with autism and unaffected parents and siblings. (This project is funded by the Simons Foundation, SFARI.org's parent organization.) In a 2011 study, researchers found that girls with autism in the SSC tend to have more large duplications or deletions of regions of the genome, called copy number variants (CNVs), than do boys with the disorder, although this disparity does not reach statistical significance2.

For the new study, Eichler and his colleagues cataloged the number of CNVs in 109 girls and 653 boys with autism from the SSC. They found that females are twice as likely as males to carry CNVs that are at least 400 kilobases long. (The larger the CNV, the more likely it is to disrupt important genes.)

When the researchers analyzed only CNVs that encompass risk genes for neurodevelopmental disorders, they found that females with autism are three times as likely as males with the disorder to carry CNVs that encompass these genes.

Females with autism also carry slightly more rare mutations that change a single DNA nucleotide than the men do. These are the "nastiest of nasty mutations," says Eichler, because they interfere with the protein's function.

The researchers saw a similar but smaller effect for CNVs in a larger group of 9,206 males and 6,379 females referred for genetic testing: 75 percent of this group turned out to have developmental delay, intellectual disability or autism.

Women in this group are 1.28 times more likely than men to carry large CNVs that include risk factors for these disorders.

Many autism-linked mutations arise spontaneously, or de novo, and about 80 percent of these come from the father.

Eichler and his colleagues found that women are far more likely than men to transmit the inherited mutations that confer autism risk.

Of the 27 large CNVs the researchers identified in the SSC group, 70 percent, or 19, were inherited from the mother. Mothers had similarly passed down about 57 percent of the 3,561 CNVs detected in the neurodevelopmental group.

Eichler intends to extend this work in a bigger study to assess whether certain mutations are more likely than others to be inherited.

"I think it's really critical to identify these inherited components," he says. "We know they're there, but we need to really focus on identifying the specific genes so we can advise [parents] a little more about recurrence."

However, it's unclear whether this gender bias is the result of genetics or reflects differences in diagnosis or the way females manifest symptoms of the disorder. Girls with autism tend to actively compensate for their symptoms in ways that boys don't, which may account for the discrepancy, says Skuse.

As a result, the females enrolled in studies may tend to be severely affected and carry multiple mutations. "There is some suggestion that higher-functioning females are out there in the general population, but they're not being referred," he says.

The study also does not address why women with autism transmit more mutations, or how they are protected from autism.

"We need to ask what it is about brain development that makes it such that females are protected -- because ultimately that is what we want know," says Aravinda Chakravarti, director of the Center for Complex Disease Genomics at the Johns Hopkins University School of Medicine in Baltimore. "We need to re-create that developmental environment."

The most obvious explanation for autism's gender bias is that because men have only one X chromosome, they are hypersensitive to mutations in this chromosome. In line with this theory, several autism-linked genes are located on the X chromosome. However, most of the mutations that show a gender bias in the new study are not on the X chromosome, suggesting that other factors must be involved.

This article has been modified from the original. An earlier version incorrectly stated that 80 percent of the genetic risk factors for autism arise spontaneously. The exact contribution of spontaneous genetic variants to autism is not known.

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Same mutations seen in epilepsy and autism

The same mutations are seen in children with epilepsy and autism indicating that the disorders may be linked.

Mutations in GABRB3, a brain receptor linked to autism, are prevalent in severe childhood epilepsy, according to a study published 12 September inNature¹.

The study also found that many of the spontaneous, or de novo, mutations found in children with epilepsy overlap with those linked to autism and fragile X syndrome.

About one-third of people with autism suffer from epilepsy. This overlap suggests that the two disorders may have a common origin — a theory borne out by examples of shared genetics.

Studies suggest that, biologically, autism is the result of an imbalance between excitatory and inhibitory brain signals, which may also underlie epilepsy.

In the new study, researchers sequenced the protein-coding DNA, or exomes, of 264 children who suffer from either infantile spasms or Lennox-Gastaut syndrome, and their parents. Both disorders are characterized by multiple seizures during sleep, which may lead to cognitive problems.

The researchers found multiple mutations in nine genes in the children with epilepsy that are not present in their parents. In particular, four children have a mutation in GABRB3, a receptor that transmits calming signals to neurons. None of 610 controls or their parents have a mutation in this gene.

A 2009 study found a rare variant of GABRB3 that affects neuronal signaling in 17 of 1,152 families with autism and 1 of 292 controls². 

Overall, the researchers found 277 mutations in the exomes of children with epilepsy that are not present in their parents. Of these, 41 are also seen in children with autism and 64 may be regulated by FMRP, the protein missing in fragile X syndrome.

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Australian vitamin treatment can significantly reduce migraine severity and frequency

A treatment developed in Australia claims to significantly reduce migraine severity and frequency by using vitamins that work with gene mutations.

AUSTRALIAN migraine sufferers won't have to live in the dark much longer.

Queensland-led genetics researchers have just launched a final, phase three clinical trial for a treatment that could drastically reduce symptoms in 20% of sufferers.

The trial is headed by Professor Lyn Griffiths, the new Executive Director of QUT's Institute for Health and Biomedical Innovation.

She and her world-leading team have identified several genes implicated in migraine and are translating that genetic information into new diagnostics and treatments.

Professor Griffiths said one of those genes causes a mutation in a particular enzyme, which stops the enzyme from working properly.

"We're trialling a specific combination of vitamins that can make that enzyme work better and make the gene then function properly," she said.

"Results so far have shown that, taken preventatively, the treatment has a very big impact on migraine - significantly reducing how severe they are, how frequent they are and the pain associated with any migraines.

"That can be very beneficial to sufferers with that gene mutation.

"This last phase in the trial is focused on dosage levels and, if it proves successful, we expect to have a tablet on the market in just over a year."

This week is Headache and Migraine Week, an initiative of the Brain Foundation.

Roughly 12 per cent of Australians suffer from migraine. It affects around 18 per cent of woman, six per cent of men and four per cent of children.

And there is a strong genetic link - about 90 per cent of people who experience migraines are not the only one in their family.

Professor Griffiths was one of the first scientists in the world to study the DNA links for migraine.

"I suffered from migraine as a teenager, my mum suffered from migraine, but as a geneticist looking at genes for various disorders I didn't even think about migraine until my son at about the age of four started suffering from migraine, including visual disturbances.

"So when you have someone close in your family who you really care about, you realize just how debilitating, how severe, it is; and I thought something needed to be done.

"We haven't identified all the genes yet. There's still a lot more research needed to identify all of them."

Professor Griffiths is urging people who suffer from migraine to join the Headache Register atheadacheaustralia.org.au.

There, sufferers can access the latest in migraine news and research, learn about current and upcoming treatment trials and download a Headache Diary to help them manage their disorder.

Professor Griffiths is confident researchers will find more targeted treatments in the future.

"You can't do this sort of research unless you have people in the public helping you," she said.

"I don't think people realise just how common migraine really is - it's a really common disorder, extremely debilitating and there's a real need to develop new treatments for it.

"We believe there are a number of different gene mutations that play a role in migraine and those different gene mutations need different treatments."

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