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New De Novo Gene Mutations Implicated in Intellectual Disability

NEW YORK (GenomeWeb) – A team from the Netherlands identified 10 new candidate genes for intellectual disability through a meta-analysis of de novo mutations in exome sequences from thousands of affected families.

Starting with exome sequences generated through Radboud University Medical Center's genetic testing program for 820 children with mild to severe intellectual disability and their parents, the researchers subsequently folded in information from nearly 1,300 other parent-child trios sequenced for published studies.

When the team brought together and analyzed all 2,637 de novo mutations identified in all 2,104 parent-child trios, it uncovered ten genes in which de novo loss-of-function mutations were over-represented — a set that included genes from chromatin modification, fragile X, synaptic plasticity, and embryonic development-related pathways. Results of the study were published this week in Nature Neuroscience.

"Our study underscores the impact of [de novo mutations] on a continuum of neurodevelopmental phenotypes that impinge on a broad spectrum of processes," co-senior author Christian Gilissen, a human genetics researcher at Radboud University Medical Center, and his colleagues wrote, noting that "a large number of rare dominant developmental disorder genes may remain to be identified."

Using the Illumina HiSeq instrument, the team sequenced protein-coding portions of the genome isolated by Agilent SureSelect enrichment in 461 boys and 359 girls with intellectual disability, and their parents.

In these exomes, covered to a median depth of 75-fold, the researchers found 1,083 suspicious de novo mutations affecting 915 genes. Through an analysis that took into account gene-specific mutation rates, they saw 18 known intellectual disability genes that appeared to be disproportionately affected by de novo mutations in the patient group.

To tease out new candidate genes, the team repeated its analysis after removing individuals with mutations in established intellectual disability genes, narrowing in on four genes with frequent de novo mutations in the intellectual disability-affected children: DLG4, PPM1D, SOX5, and TCF20.

Another six candidate genes turned up when the researchers brought the collection of parent-child trios up to 2,104 using data from published studies of sequenced families.

Their meta-analysis of 1,235 genes impacted by 1,400 de novo mutations in the 1,471 individuals who did not have mutations in known intellectual disability genes led them to the four genes found in the smaller sample set as well as RAC1, SMAD6, SON, TLK2, TRIP12, and SYNCRIP, which also contained more loss-of-function de novo mutations in individuals with intellectual disability than in those without.

De novo mutations in at least some of these genes seemed to produce overlapping clinical features, the team noted, including mutations in the TLK2 gene detected in two children tested at Radboud who had similar facial dysmorphisms.

Many of the genes or pathways affected by de novo mutations in the new analysis overlapped with genes that have been discovered in other individuals with intellectual disability, autism spectrum disorder, or other neurodevelopmental conditions.

Still, the study's authors noted that just two of the new genes they identified overlapped with genes affected by de novo mutations in a developmental disorder study by a Sanger-led team reporting in a bioRxiv preprint, arguing against the notion that researchers have identified most of the genes that can produce neurodevelopmental disorders when mutated de novo.