Studies Investigate Role of De Novo Mutations in Autism

Exome sequencing used to describe de novo mutations, their origin, contribution to ASD risk

THURSDAY, April 5 (HealthDay News) -- The contribution of de novo mutations to the risk of autism spectrum disorders (ASDs) is complex, according to three sequencing studies published online April 4 in Nature.

Stephan J. Sanders, Ph.D., 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 single nucleotide variants 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.

Brian J. O'Roak, Ph.D., 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. Recurrent protein-altering mutations were seen in proband exomes in CHD8 and NTNG1. In a third study, Benjamin M. Neale, Ph.D., from Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues sequenced 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 write.

Several authors of the second study disclosed financial ties to biotechnology companies and/or involvement with patents related to the study subject matter.

Abstract - Sanders
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Abstract - O'Roak
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Abstract - Neale
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