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Study Implicates De Novo Mutations in Mental Retardation

By Andrea Anderson

NEW YORK (GenomeWeb News) – De novo mutations that spring up in children but are absent in their parents are likely the culprit in many unexplained cases of mental retardation, according to a Dutch team.

Using exome sequencing in 10 parent-child trios, the researchers found nine non-synonymous mutations in children with mental retardation that were not found in their parents, including half a dozen mutations that appear to be pathogenic. The research, which appeared online yesterday in Nature Genetics, hints at an under-appreciated role for sporadic mutations in mental retardation — and underscores the notion that mental retardation can stem from changes in a wide variety of genes.

"Even though de novo mutation is a very rare event — the chance of a particular gene being mutated is very low — if there are a thousand genes [that can cause mental retardation], then collectively if you add them all up, there's enough of these events to explain a significant portion of mental retardation," co-corresponding author Han Brunner, a human genetics researcher at Radboud University Nijmegen Medical Centre, told GenomeWeb Daily News.

Mental retardation is a heterogeneous set of conditions that can stem from genetic syndromes, chromosomal abnormalities, or problems during pregnancy or at birth, Brunner explained. But such known causes explain no more than half of mental retardation cases, he added. And many of the cases that can't be explained represent single cases within families, consistent with the possibility that these affected children carry mutations not found in other members of their family.

To begin testing this, the researchers sequenced the exomes of eight male and two female children with moderate to severe mental retardation, along with their parents.

The parent-child trios selected did not have known family histories of mental retardation, the researchers noted. None of the affected children had been diagnosed with mental retardation-related syndromes, nor did they carry detectable chromosomal rearrangements or copy number changes.

"We really focused on the [cases] that we had no clue whatsoever as to what might be the cause of their problem," Brunner said.

After targeting exome sequences with the Agilent SureSelect Human Exome Kit array, the team used the SOLiD 3 Plus platform to sequence targeted exons to an average of nearly 80 percent coverage and a median depth of 42 times.

When they analyzed this sequence data, the researchers detected an average of 21,755 variants per individual. And after tossing out synonymous changes and mutations that fell inside introns or outside of gene coding regions, they were left with 51 candidate mutations for mental retardation.

They subsequently verified 13 of these mutations by using Sanger sequencing to look specifically at these 51 genes within the trios.

Their analyses suggest that nine of the mutations — eight affecting genes on autosomal chromosomes and one in a gene on the X chromosome — had appeared de novo in affected children, since corresponding mutations did not turn up in either parent from the same trio. Similarly, the researchers didn't find any of nine mutations in a panel of more than 1,600 control chromosomes.

Of the nine genes in which mutations were identified, six seem to be potentially causative, Brunner said. Two genes had been previously linked to mental retardation, he explained, while four are known to be active in the brain and lead to brain abnormalities when knocked out in mice.

"For those six, the evidence is solid for two of them and the other four look very, very suspicious," he said.

The team also uncovered one male child who carries a recessive non-synonymous mutation in the previously identified X-linked mental retardation gene JARID1C that he inherited from his mother. Her mutation, in turn, appears to have arisen de novo, they noted, and isn't present in either of the affected child's grandparents.

"Our findings provide strong experimental support for a de novo paradigm for mental retardation," Brunner and co-authors wrote. "Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population."

While the extent to which de novo mutations contribute to mental retardation is still unclear, Brunner suspects these changes might explain a quarter of mental retardation cases. Still, he noted, exome sequencing of many more affected families will be needed to get a handle on the prevalence and types of de novo mutations involved in mental retardation.

For their part, he and his colleagues eventually hope to sequence the exomes of about 500 parent-child trios, Brunner said. They are also exploring the possibility of using exome sequencing as a diagnostic tool for mental retardation cases with no known cause.

"The quality of the [sequencing] machines is increasing so rapidly, and therefore the cost of the sequencing is decreasing so rapidly, that I would hope that we could offer this as a diagnostic test sometime next year," Brunner said. "If we can convert our scientific results into a diagnostic test, which we do hope to do, that might transform the diagnostic process for these children."

Such improved diagnostic tools are expected to help provide answers to families who have a child with unexplained mental retardation and provide insights for those seeking genetic counseling, Brunner explained. In the long run, he noted, unraveling the spectrum of genetic changes that can lead to mental retardation may also lead to more precise clinical definitions of the condition and the identification of mental retardation sub-groups that may benefit from different management strategies.