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Trio of Exome-Sequencing Studies ID Autism-related De Novo Mutations

NEW YORK (GenomeWeb News) – A trio of papers from researchers associated with the ARRA Autism Sequencing Collaborative appearing in this week's issue of Nature outline exome sequencing studies that have identified de novo mutations associated with autism spectrum disorders.

In the first of these studies, researchers from Yale University and elsewhere performed whole-exome sequencing on 238 families from the Simons Simplex Collection, a comprehensively phenotyped ASD cohort that consists of pedigrees with two unaffected parents, an affected proband, and in 200 families an unaffected sibling. The exome sequences were captured with Roche NimbleGen oligonucleotide libraries and sequenced using the Illumina GAIIx and HiSeq systems. In all, researchers sequenced the exomes of 928 individuals, which included 200 phenotypically discordant sibling pairs.

Among the 279 de novo coding mutations they identified, there was a single instance in probands and none in siblings in which two independent nonsense variants disrupted the same gene: SCN2A. The researchers said this result is "highly unlikely by chance."

In addition, they found that the rate of de novo single nucleotide variants increases with paternal age, which may offer at least a partial explanation for the increased risk of autism in children of older parents.

A second study, led by University Washington researchers, looked at data from 677 individuals from 209 families that had a single child with autism. They sequenced all coding regions of the genome for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that had been previously reported.

In the 189 new probands, they validated 248 de novo events, 225 single nucleotide variants, 17 small insertions/deletions, and six copy number variants. Among the de novo events, the researchers identified 62 top ASD risk-contributing mutations, and among these observed recurrent, protein-disruptive mutations in two genes: NTNG1 and CHD8.

According to the researchers, their investigation also found that de novo point mutations were overwhelmingly paternal in origin and positively correlated with paternal age. In addition, they found that 39 percent (49 out of 126) of the most disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodeling protein network ranked significantly for autism candidate genes.

"We find it intriguing that 49 proteins found to be mutated here have critical roles in fundamental developmental pathways, including β-catenin and p53 signalling, and that patients have been identified with multiple disruptive de novo mutations in interconnected pathways," the study authors wrote. "The latter observations are consistent with an oligogenic model of autism where both de novo and extremely rare inherited SNV and CNV mutations contribute in conjunction to the overall genetic risk."

Their research follows on a study published last year in Nature Genetics by researchers in the labs of Evan Eichler and Jay Shendure, which found potentially causative de novo mutations for autism, including mutations in genes that have previously been associated with autism, intellectual disability, and epilepsy.

Overall, the scientists in that study identified 21 de novo mutations, about half of them protein-changing. Four patients carried potentially causative de novo mutations — in the genes FOXP1, GRIN2B, SCN1A and LAMC3 — based on the gene being previously implicated in autism or a related disease, or in a biological pathway involved in autism.

The third research group, led by researchers at Massachusetts General Hospital and the Broad Institute, performed exome sequencing on 175 autism spectrum disorder probands and their parents in an effort to assess the role of de novo mutations in ASD.

The researchers observed 161 coding region point mutations, consisting of 101 missense, 50 silent, and 10 nonsense mutations, with an additional two conserved splice site single nucleotide variants, and six frameshift insertions/deletions. The observed mutation rate of 0.92 per exome was slightly, but not significantly elevated, versus expectation, they said.

The researchers found three genes with two de novo mutations: BRCA2, FAT1, and KCNMA1. But, they said, simulations demonstrate that two such hits are inadequate to define a gene as a conclusive risk factor.

In addition, they said that paternal and maternal age was a strong predictor of the number of de novo events per offspring. There also was an increased rate of de novo mutation in female versus male cases, though the difference was not significant, owing to limited sample size, they said.

In conducting further protein-interaction studies, the researchers found that "the proteins encoded by genes that harbored de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens."

The authors of the study said that considering the other two papers from the ARRA Autism Sequencing Collaborative, there were 18 genes with two functional de novo mutations observed in the complete data. Again, they said that "two or more hits is not quite significant," but matching loss-of-function variants at SCNA2, KATNAL2, and CHD8 are unlikely to occur by chance.

They subsequently evaluated these three candidates using exome sequencing on 935 cases and 870 controls. At both KATNAL2 and CHD8 they observed three additional loss-of-function mutations in cases with none in controls.

The researchers compared this data to 5,000 individuals in the NHLBI Exome Variant Server as additional controls. While they found three loss-of-function mutations in KATNAL2, none were seen in CHD8, "making the additional observation of three CHD8 loss-of-function mutations in our cases significant evidence of this being a genuine autism susceptibility gene."

The results from all three groups suggest modest roles for hundreds of genes in the development of autism, with a few specific genes presenting as genuine risk factors.

The ARRA Autism Sequencing Collaborative was formed by researchers from the Broad Institute, MGH, Baylor College of Medicine, Mount Sinai School of Medicine, Vanderbilt University, Carnegie Mellon University, and the University of Pittsburgh.

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