Studies confirm genetic complexity of autism

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Studies Investigate Role of De Novo Mutations in Autism
Studies Investigate Role of De Novo Mutations in Autism

HealthDay News -- The genetic basis of autism may be so complicated that there may not be a distinct pattern of genetic variation to explain the condition, results of three studies published online in Nature suggest.

All three studies compared exomes, the DNA that codes for proteins, in people with autism to exomes in their parents and unaffected siblings in an attempt to detect single nucleotide polymorphisms (SNPs) that occurred at or near conception in autistic individuals that could account for the developmental disorder.

Although "de novo" mutations were discovered in all three studies, only a few occurred in the same genes and few participants experienced the same changes, the researchers found.

In one study, Stephan J. Sanders, PhD, from the Yale University School of Medicine in New Haven, Conn., and colleagues used whole exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, to investigate the frequency and distribution of de novo SNPs and their contribution to the risk of ASDs.

The researchers found that highly disruptive de novo mutations were seen in brain-expressed genes and were correlated with ASDs. Based on the mutation rate in uninfected individuals, in unrelated probands, multiple, independent de novo single nucleotide variants in the same gene reliably identified risk alleles.

In a second study Brian J. O'Roak, PhD, from the University of Washington School of Medicine in Seattle, and colleagues sequenced the exome for parent-child trios with sporadic ASD and unaffected siblings, for a total of 677 individual exomes within 209 families.De novo mutations showed a paternal bias (4:1) and correlated positively with paternal age. This finding suggests that genetic mutations associated with autism are much more likely to come from the father's side. Recurrent protein-altering mutations were seen in proband exomes in CHD8 and NTNG1.

In a third study, Benjamin M. Neale, PhD, from Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues sequenced the exomes of 175 parent-child trios for ASD cases and found that the de novo missense or nonsense mutations associated with ASD were distributed across many genes and were incompletely penetrant.

"Overall, these data underscore the challenge of establishing individual genes as conclusive risk factors for ASD, a challenge that will require larger sample sizes and deeper analytical integration with inherited variation," Neale and colleagues wrote.


  1. Neale BM et al. Nature 2012; doi:10.1038/nature11011.
  2. O'Roak BJ et al. Nature 2012; doi:10.1038/nature10989.
  3. Sanders SJ et al. Nature 2012; doi: 10.1038/nature10945.
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