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Dutch Team IDs New Intellectual Disability Genes in Diagnostic Exome Sequencing Pilot

NEW YORK (GenomeWeb News) – A new study in the New England Journal of Medicine is underscoring the importance of de novo mutations in non-syndromic intellectual disability, while highlighting the potential of using exome sequencing to diagnose severe intellectual disability cases that can't be explained by other genetic tests.

As part of a pilot program at Radboud University Nijmegen Medical Center in the Netherlands, researchers turned to exome sequencing in an attempt to diagnose the genetic roots of intellectual disability in 100 children with severe, non-syndromic forms of the condition. Through exome sequencing on each child and his or her parents, followed by extensive analyses and validation testing, they were able to report causal mutations in 16 percent of the cases.

Ten of these cases stemmed from de novo mutations to intellectual disability-related genes identified in the past and three cases involved X-linked mutations affecting known intellectual disability genes. Another three cases were causally tied to de novo mutations to in new risk genes: DYNC1H1, GATAD2B, and CTNNB1.

"If we now go back and re-evaluate the patients in a few months time we may actually find a higher diagnostic yield," co-senior author Joris Veltman, a human genetics researcher at Radboud University Nijmegen Medical Center, told GenomeWeb Daily News.

"That's something that we expected from the start: you will have to go back to the data sometimes for those patients [for which] you've not found a diagnostic causal mutation," he said. "It's very important to continue with this and look at the data again."

Although it's possible for intellectual disability or mental retardation to arise as a consequence of infection, oxygen deprivation, or other non-genetic factors, the study authors explained, most of the cases that occur in developed countries are believed to have genetic causes.

Indeed, in a study appearing online last week in the Lancet, Swiss and German researchers found evidence that de novo mutations were likely behind roughly half of the severe, non-syndromic, non-familial cases of intellectual disability they tested by exome sequencing.

That comes on the heels of several other studies showing that such spontaneous mutations are found more frequently than usual in the genomes of individuals with intellectual disability, autism spectrum disorder, and other neurological conditions.

Even so, less than half of intellectual disability cases with an apparent genetic basis can be traced back to glitches in a specific gene. That is especially true when the intellectual disability symptoms aren't part of a larger genetic syndrome. Consequently, there has been a push to try to uncover additional genetic contributors to such conditions — and to find ways of achieving diagnoses for more affected individuals.

"An understanding of the genetic cause of intellectual disability can benefit patients and their families," Veltman and co-authors wrote, "because a diagnosis may provide information on the prognosis, preclude further unnecessary invasive testing, and may lead to appropriate therapy."

"Moreover, a diagnosis often facilitates access to appropriate medical and supportive care," they added. "Family members may benefit from knowledge of the risk of recurrence, reproductive counseling, and possible prenatal diagnosis."

As part of a pilot program on diagnostic sequencing at Radboud University Nijmegen Medical Center — and to find new genetic causes for intellectual disability — researchers used exome sequencing to test 100 individuals with severe, non-syndromic intellectual disability who scored below 50 on standardized IQ tests and their unaffected parents.

"We actually still don't know the majority of genes that can cause intellectual disability when they're mutated," Veltman explained. "So you really need this trio approach to identify de novo mutations in genes that you did not know were linked to intellectual disability."

The affected children had already been tested using conventional genetic tests as well as array-based tests for chromosomal duplications and deletions, which both failed to find obvious genetic culprits for their conditions.

For each member of the parent-child trios tested, the team captured coding sequences with Agilent's SureSelect kit before sequencing the exomes to a median of 64-fold coverage over 87 percent of the sequences targeted, on average, using Life Technologies' SOLiD 4 sequencing platform.

Data from these trio exomes were then funneled into a computational pipeline specialized for picking up not only de novo mutations, but also autosomal recessive and X-linked candidate alterations.

The researchers uncovered 79 suspicious de novo mutations that could be verified by Sanger sequencing overall. They then whittled away at this list by bringing in information on the nature of each mutation, its inheritance pattern, the gene affected, and so on.

Amongst the 16 mutations deemed causal following this analysis, 10 were de novo mutations affecting genes already implicated in intellectual disability, and three children carried maternally inherited, X-linked mutations to known risk genes.

The investigators also saw suspicious, de novo mutations in two-dozen candidate genes that had not been conclusively linked to intellectual disability previously. For the five most plausible candidate genes in that set, the team did targeted resequencing in another 765 individuals with intellectual disability, uncovering additional mutations in three of the genes.

DYNC1H1, GATAD2B, and CTNNB1 were all mutated in at least one other patient with intellectual disability in the validation group. The phenotypes described in these individuals fit with those found in cases carrying alterations to the same gene, supporting the notion that these mutations in these patients have authentic ties to their condition.

The remaining 19 de novo mutation-containing candidate genes are currently classified as potentially pathogenic, though that may change if other mutations in the same genes appear in more non-syndromic intellectual disability cases in the future, Veltman noted.

"As soon as we found a second patient with a mutation in one of these candidate genes and were more sure that it's really pathogenic, we would go back to them," he said.

In a related commentary appearing in NEJM, University of Washington researcher and physician Heather Mefford discussed the advantages and shortcomings of using exome sequencing to diagnose non-syndromic intellectual disability.

Exome sequencing may be an attractive alternative to more targeted diagnostic tests for conditions such as non-syndromic intellectual disability that have many possible causes, Mefford explained. But she cautioned that at this point it is still sometimes tricky to figure out which mutations are causal in a clinical setting — particularly for diagnostic labs that cannot do extensive validation testing or follow-up experiments on mutations in new genes or other variants of unknown significance.

Still, Mefford said, the diagnostic interpretation of exome data should become a clearer as more and more mutational data accumulates from clinical and research studies.

"All of us want to find those new genes that cause disease and be able to help families and patients," she told GWDN. "It's just going to take a little while."

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