Chromosome test reveals genetic causes of autism

[Atlantic Islander]

Screening the genome for small chromosomal abnormalities may identify potential genetic causes of autism or intellectual disability in 16 percent of children tested, according to a study published 24 May in the European Journal of Paediatric Neurology1.

The technique, called chromosome microarray analysis (CMA), should be the first step in any attempt to find the cause of a developmental disorder, the researchers say.

Duplications or deletions of chromosomal regions, called copy number variations (CNVs), are more common in people who have autism or other neurodevelopmental disorders than in controls. Clinicians have pushed for years for CNV identification with CMA to be standard practice in diagnosing autism, but because of cost considerations (in the U.S., the test is not usually covered by insurance) it is still not routine.

Other methods include looking at chromosomes under the microscope and probing specific genes known to lead to autism-like symptoms, such as the gene that underlies fragile X syndrome.

In the new study, researchers looked at 349 people who have autism, intellectual disability, developmental delay or unusual facial features. The standard screening tests described above had not flagged any genetic abnormalities in these individuals. CMA identified CNVs in 77 of the individuals.

Some CNVs are present among the general population and are not necessarily harmful. The researchers designated a CNV as ‘potentially causative’ if it was already known to be associated with a disorder, encompassed genes with a known neurological function, arose spontaneously in the affected individual or was inherited from affected parents.

They found potentially causative CNVs in 57 of the individuals tested. Of the 78 people with autism in the study, 18 have a CNV, 12 of which are potentially causative.

source (http://sfari.org/news-and-opinion/toolbox/2013/chromosome-test-reveals-genetic-causes-of-autism)

[Atlantic Islander]

June 9, 2010 -- Accumulation of rare DNA mutations in genes affecting brain function appears to be a major cause of autism, a large international study suggests.

"This will lead to a paradigm shift in understanding causes of autism," study researcher Stephen Scherer, PHD, of Toronto's Hospital for Sick Children, said at a news conference held to announce the findings.

Finding the cause of autism is like trying to put together a huge jigsaw puzzle with no idea of what the final picture should look like, says study researcher Anthony Monaco, MD, PhD, of the U.K.'s University of Oxford.

"What we have found are the edges of the puzzle. We now can say some of the pieces are the sky or the sand of the picture," Monaco said at the news conference. "We now see that some of the genetic changes in autism are related to connections in the brain."

The study used recently developed technology to look for unusual DNA deletions or duplications -- known as copy number variants or CNVs -- in 996 people with autism and 1,287 matched people without autism.

People with autism didn't have more CNVs than people without autism, and their CNVs weren't any bigger than usual. But in autism, CNVs are much more likely to occur in gene-containing regions of the genome.

And many of the genes in which these rare CNVs occur are linked to brain function -- especially the growth and maintenance of the synapses through which brain cells communicate with each other.

"This basically shows us that CNVs can account for a pretty appreciable percentage of autism spectrum disorder," study researcher John R. Gilbert, PhD, of the University of Miami's Institute for Human Genetics, tells WebMD.

The CNVs implicated in autism aren't all the same. In fact, the most common CNV identified in the study occurred in less than 1% of people with autism. Nearly every child studied has a unique CNV profile.

But in people with autism, CNVs cluster around networks of gene sets -- pathways -- that control brain-cell development and function. That's the paper's most important finding, says study researcher Louise Gallagher, MD, PhD, of Trinity College Dublin.

"So even if children have different genes that are influencing the development of their autism, we hope that if drug companies or biotech companies target these pathways, that the therapies might work for a broad number of the children who are affected," Gallagher said at a news conference. "Some of these therapies would still work because they act on pathways that are linked."
Autism Gene Studies: What's Next?

Studies under way are trying to link specific sets of CNVs to specific autism symptoms. Once this is done, genetic testing for CNVs could help parents identify children at high risk of autism, says study researcher Geri Dawson, PhD, of the advocacy group Autism Speaks.

"I can imagine a day when one can identify the specific genetic risk that led to an individual child's autism, and then using that genetic information to say what pathway has been affected and then choosing a medical intervention," Dawson said at the news conference.

There are no such medical treatments, although there are drugs that affect some of the pathways now linked to autism.

The new findings also shed light on the puzzling question of why children with severe autism may have brothers and sisters -- even identical twins sharing 100% of their genes -- who are unaffected.

Many of the CNVs identified in the study have what geneticists call "incomplete penetrance." This means that even if a person carries an autism-linked CNV in his or her genome, there's a chance it will have no effect.

This poses a problem for genetic testing, as children found to have autism-linked CNVs won't necessarily have autism. According to Scherer, the genes identified in the study would aid in early autism diagnosis in only about 10% of families.

Autism isn't the first disease to be linked to CNV's affecting brain function. CNV variants -- affecting some of the same pathways affected by autism-linked CNVs -- also play a role in intellectual disability (formerly called mental retardation) and schizophrenia.

Might CNVs be the long-sought factor that might make some children more susceptible to the risks posed by environmental toxins or even vaccinations?

"We do believe that environmental factors play a role in autism," Dawson said. "It is important as we continue with our science to learn how environmental factors interact with the genes we have identified here. But as of now, there is no evidence that vaccination is one of these factors."

The study findings appear in the June 9 online issue of the journal Nature.

source (http://www.webmd.com/brain/autism/news/20100609/genetic-mutations-may-be-key-cause-of-autism)

[Atlantic Islander]

http://imageshack.us/a/img703/7682/9j1f.jpg
Researchers are piecing together the many different genetic causes of
autism. Mutations in hundreds, possibly over a thousand, different genes
could potentially contribute to ASD.

Autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric conditions. Yet, most genetic links to ASD found in recent years have involved de novo mutations, which are not passed from parent to child, but instead arise spontaneously. While these mutations help explain how ASD develops in a fraction of cases, they don’t help us understand why autism so often runs in families.

Two new studies by Broad Institute researchers are among the first to account for some of autism’s heritability. Both studies, which were published January 23 in Neuron, investigate the role recessive genes play in ASD. These genes can be passed on through generations, but their effects are seen only if an individual inherits two identical copies of the gene – one from each parent.

One study, led by Mark Daly, a senior associate member of the Broad and co-director of its Medical and Population Genetics program, found that approximately 5% of autism cases could be linked to inherited, recessive mutations that completely disrupt gene function. A second study, led by Broad associate member Christopher A. Walsh, found that autism risk could also be attributed to inherited mutations that resulted in only a partial loss of gene function. Moreover, Walsh’s team found that many of these partially-disabling mutations occurred in genes in which a complete disruption of the gene has been known to cause more severe or even fatal inherited diseases. This suggests that milder forms of some severe, Mendelian diseases – diseases caused by a single gene – may present as autism spectrum disorders.

Both teams used whole-exome sequencing in their investigations, allowing them to focus on the exomes, or the roughly 1% of the human genome that codes proteins, of several individuals.

Daly’s team scanned the exomes of roughly 1,800 autism cases and controls, looking for instances in which children inherited two broken copies of the same gene from their parents. Such “double knockouts” are relatively rare and are often disease-causing, since non-functioning genes are incapable of producing proteins needed by the body. The researchers found that double knockouts occurred in twice as many cases as controls, and estimated that those mutations could account for approximately 3% of autism risk.

The team also looked at knockouts on the X-chromosome in males, who only inherit one copy of that chromosome. They found a 1.5-fold increase in knockouts on the X-chromosome in males with autism versus controls, which they estimate may account for an additional 2% of autism cases. This finding may help to explain why males are more likely to have ASD than females.

Daly, who is also an associate professor at Harvard Medical School and Massachusetts General Hospital, said that the work helps define a specific genetic mechanism that explains some of autism’s heritability.

Walsh’s team found a separate mechanism that further helps to explain the role recessive inheritance plays in ASD. His team looked at the whole-exome sequencing data for 200 families in which children with autism had parents who were first cousins – a group whose shared ancestry would make it easier to identify recessive gene patterns. By comparing the genetic data of individuals or siblings with ASD with that of their healthy siblings and parents, the researchers were able to spot mutations suspected to be at play in the disease.

Many of the mutations they found caused only a partial loss of gene function, as opposed to the complete knockouts that Daly’s team studied. Interestingly, many of these mutations occurred in genes previously linked to more severe, Mendelian diseases. While complete loss-of-function in those genes would have caused the more severe Mendelian disorder, the partial loss-of-function mutations observed by Walsh’s team instead gave rise to ASD. For instance, some of the team’s subjects carried mutations in the gene AMT. Complete loss-of-function in that gene is known to cause nonketotic hyperglycinemia (NKH), a severe neonatal syndrome that typically leads to death within the first year of life. The team’s subjects had some, but not all, of the symptoms of NKH, in addition to ASD symptoms.

A similar pattern was found with other mutations identified by Walsh’s team; they found mutations in PEX7 (previously linked to rhizomelic chondrodysplasia punctate, or RCDP), SYNE1 (cerebellar ataxia), and VPS13B/COH1 (Cohen syndrome).

“We’ve known for a long time that many Mendelian diseases had milder forms,” Walsh said. “What we didn’t realize is that if you took a cohort of patients diagnosed with ASD, that some of them would have these milder forms of Mendelian disease.”

Walsh, who is also a professor of pediatrics and neurology at Harvard Medical School and chief of the division of genetics at Boston Children's Hospital, noted that the number of different genetic mutations uncovered by both his and Daly’s team supports the long-held theory in ASD research that autism is a heterogeneous condition with many different genetic causes. Mutations in hundreds, possibly over a thousand, different genes could potentially contribute to ASD.

Given this heterogeneity, Timothy Yu, a Broad researcher and first author on Walsh’s study, emphasized that that the sliver of autism accounted for by the particular genes identified in their study is very small.

“The important message from our study is that we found this category of partial loss-of-function mutations that contribute to some cases of ASD,” Yu said. “Now that we know that they exist we can try to figure out ways to look for them – in lots of genes, not just in the few that we found.”

Daly echoed this message.

“The specific genes that are found to be knocked out in these cases can provide key clues about the underlying biology of autism, and may generate hypotheses about ways to treat it,” he explained.

The Walsh lab and the Daly lab are now joining forces and intend to collaborate with other centers around the country that are sequencing the genes of children with ASD. They plan to pool the data from a larger number of patients and further explore the role of recessive mutations in autism.

Dr. Daly’s research was supported by funding from NIH.

Other Broad researchers involved in the work include Elaine Lim, Soumya Raychaudhuri, Christine Stevens, Daniel MacArthur, Benjamin Neale, Andrew Kirby, Douglas Ruderfer, Menachem Fromer, Monkol Lek, Jason Flannick, Stephen Ripke, Stacey B. Gabriel, Mark dePristo, David M. Altshuler, and Shaun Purcell. Researchers from Massachusetts General Hospital, Brigham and Women’s Hospital, Yale University School of Medicine, Baylor College of Medicine, Carnegie Mellon University, University of Pennsylvania, NHLBI Exome Sequencing Project, University of Texas Health Science Center at Houston, Mount Sinai School of Medicine, and the University of Illinois at Chicago collaborated on this work.

Dr. Walsh’s research was supported by the NIMH, Simons Foundation, and the Howard Hughes Medical Institute.

Other Broad researchers involved in the study include Maria Chahrour, Christine Stephens, and Stacey B. Gabriel. The work was done in collaboration with researchers from Boston Children’s Hospital, The Autism Consortium, Harvard Medical School, Massachusetts General Hospital, McGill University, The University of Tokushima, University of Virginia, Yale University School of Medicine, Schulich School of Medicine and Dentistry, United Arab Emirates University, Istanbul University, Armed Forces Hospital at King Abdulaziz Naval Base (Saudi Arabia), King Faisal Specialist Hospital and Research Center, Brown University, University of Washington, Dr. Sami Ulus Childrens’ Hospital (Turkey), Kuwait Center for Autism, Kuwait Medical Genetics Center, Hamad Medical Corporation (Qatar), Weil-Cornell Medical College, and University of New South Wales.

source (http://www.broadinstitute.org/news/4624)

[Atlantic Islander]

http://www.aspergerssyndrome.org/HTM/Autism_Genetics.htm

[Sikeliot]

I'm not surprised it's genetic. Most of the men on my father's side of the family (including my father) are autistic.

[SilverKnight]

I still think that there is some correlation between many cases of autism and these damn vaccines.

[blogen]

I still think that there is some correlation between many cases of autism and these damn vaccines.

http://m.cdn.blog.hu/cr/criticalbiomass/image/post_img/2013/08/autism-organic_food.png

Correlations... ;)

[SilverKnight]

Correlations... ;)
Nice trolling dude

Maybe that's because smart people (like me) have woken up to not just evil vaccines but foods such as GMOS, pesticides and want to eat organic instead.

Hey buddy take your time to see this video:
http://www.youtube.com/watch?v=j3IMSUApeW4

These parents wouldn't think this is funny,whatsoever! :eek:


Watch it...

[Atlantic Islander]

Nice trolling dude

Maybe that's because smart people (like me) have woken up to not just evil vaccines but foods such as GMOS, pesticides and want to eat organic instead.

Hey buddy take your time to see this video:
http://www.youtube.com/watch?v=j3IMSUApeW4

These parents wouldn't think this is funny,whatsoever! :eek:


Watch it...

You are the one that's trolling, constantly posting about a hoax.

[Prisoner Of Ice]

The way genes work is they don't ever cause anything directly they just make things more likely. So what you could be seeing is a genetic inclination that makes you more susceptible to brain damage which could well come from things like aluminum and mercury that no sane people think should be injected into children.

There's no mental illness genes that cause it 100%, at most it is 50% usually correlations are more like 5-10%. That's why human genome is a bust for medical purposes and won't be leading to the cure of anything. And turns out the correlation between start of vaccination and rise of autism is stronger. WHOOPS!