AUTISM PREVENTION FATHER BABIES 24-34 PATERNAL AGE IS KEY IN NON-FAMILIAL AUTISMVaccines: April 2012

Friday, April 13, 2012

Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD.

Nature. 2012 Apr 4. doi: 10.1038/nature10989. [Epub ahead of print]

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.

O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE.

Source

Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington 98195, USA.

Abstract

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

Thursday, April 05, 2012

TIME OLDER FATHERS RAISE RISK OF AUTISM

3D Clinic

Four new studies this week take on the genetics of autism, finding further evidence that older fathers are at increased risk of having an autistic child and suggesting that, overall, the genetic roots of the condition are incredibly complex.

Read more: http://healthland.time.com/2012/04/05/autism-studies-confirm-genetic-complexity-and-risk-for-older-fathers/#ixzz1rDAEdrZ2

Older fathers 'link' to austism

Thursday, April 05, 2012 - 01:27 PM

Defective sperm from older fathers may trigger “new” genetic mutations linked to autism, a study has shown.

Researchers found that “de novo”, or newly created, mutations played an important role in autistic spectrum disorders (ASDs).

These defects were “overwhelmingly paternal” in origin, said the scientists.

Fathers were four times more likely to generate the mutations than mothers. The gene defects were also “positively correlated” with paternal age.

The findings added to previous research showing that older fathers are slightly more at risk of having an autistic child.

Scientists analysed the DNA of 677 individuals from 209 families with a single child with autism, and 50 unaffected brothers and sisters.

They identified 248 “de novo” mutations, of which 120 were classified as “severe” and likely to produce shortened or malfunctioning proteins.

From this list the researchers focused on 60 mutations most likely to contribute to autism risk.

There was “strong direct evidence” of a “substantially” higher mutation rate in fathers which rose with increasing age.

The US scientists, led by Dr Evan Eichler, from the University of Washington in Seattle, wrote in the journal Nature: “These observations are consistent with the hypothesis that the modest increased risk for children of older fathers to develop ASD is the result of an increased mutation rate.”

The study was one of three autism investigations published in the latest edition of Nature which highlighted the role of “de novo” mutations.

Another paper identified three new genes linked to autism. The third focused on multiple disruptive mutations in autism-linked brain genes.

British expert Dr Rosa Hoekstra, lecturer in psychology and genetics at the Open University, said: “We already knew that there isn’t a ’single gene for autism’, but these new research publications suggest that the underlying genetic mechanisms may be even more complex than previously thought.

“These studies show that de novo point mutations – small gene changes that are not inherited from either parent – in the protein coding part of our DNA are common, and that some of these new genetic changes may be implicated in the risk for developing autism.

“A striking result from these studies is the association between new genetic changes and paternal age: de novo mutations seem to be more common in children of older dads; and if a child with autism has such a new genetic mutation, it seems to be much more often of paternal than maternal origin.”

Dr Kevin Mitchell, from the Smurfit Institute of Genetics at Trinity College Dublin, said:

“These studies reinforce the fact that autism is not one disorder – not clinically and not genetically either. Like intellectual disability or epilepsy or many other conditions, it can be caused by mutations in any of a very large number of genes. The ones we know about so far make up maybe 20-25% of cases - these new studies add to that list and also show how far we have to go to complete it.”

Read more: http://www.irishexaminer.com/breakingnews/world/older-fathers-link-to-austism-546362.html#ixzz1rBuwMIFf

Older dads have autistic kids

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Older dads have autistic kids (Thinkstock photos/Getty Images)

Times of India

Researchers have offered a new clue to the workings of a possible environmental factor in autism spectrum disorders (ASDs): fathers were four times more likely than mothers to transmit tiny, spontaneous mutations to their children with the disorders.

Moreover, the number of such transmitted genetic glitches increased with paternal age.

The discovery may help to explain earlier evidence linking autism risk to older fathers.

The results are among several from a trio of new studies, supported in part by the National Institutes of Health, finding that such sequence changes in parts of genes that code for proteins play a significant role in ASDs.

One of the studies determined that having such glitches boosts a child's risk of developing autism five to 20 fold.

Taken together, the three studies represent the largest effort of its kind, drawing upon samples from 549 families to maximize statistical power. They reveal sporadic mutations widely distributed across the genome, sometimes conferring risk and sometimes not.

While the changes identified don't account for most cases of illness, they are providing clues to the biology of what are likely multiple syndromes along the autism spectrum.

"These results confirm that it''s not necessarily the size of a genetic anomaly that confers risk, but its location - specifically in biochemical pathways involved in brain development and neural connections. Ultimately, it''s this kind of knowledge that will yield potential targets for new treatments," explained Thomas, R. Insel, M.D., director of the NIH''s National Institute of Mental Health (NIMH), which funded one of the studies and fostered development of the Autism Sequencing Consortium, of which all three groups are members.

All three teams sequenced the protein coding parts of genes in parents and an affected child - mostly in families with only one member touched by autism.

One study also included comparisons with healthy siblings. Although these protein-coding areas represent only about 1.5 percent of the genome, they harbor 85 percent of disease-causing mutations.

This strategy optimized the odds for detecting the few spontaneous errors in genetic transmission that confer autism risk from the "background noise" generated by the many more benign mutations.

Like larger deletions and duplications of genetic material previously implicated in autism and schizophrenia, the tiny point mutations identified in the current studies are typically not inherited in the conventional sense - they are not part of parents'' DNA, but become part of the child's DNA.

Most people have many such glitches and suffer no ill effects from them. But evidence is building that such mutations can increase risk for autism if they occur in pathways that disrupt brain development.

State's team found that 14 percent of people with autism studied had suspect mutations - five times the normal rate. Eichler and colleagues traced 39 percent of such mutations likely to confer risk to a biological pathway known to be important for communications in the brain.

Although Daly and colleagues found evidence for only a modest role of the chance mutations in autism, those pinpointed were biologically related to each other and to genes previously implicated in autism.

The Eichler team turned up clues to how environmental factors might influence genetics.

The high turnover in a male's sperm cells across the lifespan increases the chance for errors to occur in the genetic translation process.

These can be passed-on to the offspring's DNA, even though they are not present in the father's DNA. This risk may worsen with aging. The researchers discovered a four-fold marked paternal bias in the origins of 51 spontaneous mutations in coding areas of genes that was positively correlated with increasing age of the father.

So such spontaneous mutations could account for findings of an earlier study that found fathers of boys with autism were six times - and of girls 17 times - more likely to be in their 40's than their 20's.

"We now have a path forward to capture a great part of the genetic variability in autism - even to the point of being able to predict how many mutations in coding regions of a gene would be needed to account for illness," said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funded the Daly study and helped to create the Autism Sequencing Consortium.

"These studies begin to tell a more comprehensive story about the molecular underpinnings of autism that integrates previously disparate pieces of evidence," Lehner added.

The study has been published in the journal Nature.