Exome Sequencing Provides Diagnostic Assay for Intellectual Disability

A molecular based diagnostic assay has been used determine whether one or more genetic mutations explain a patient's intellectual disability.

Exome sequencing, which deciphers over 21,000 protein-coding genes and not the entire human genome, can be used as a diagnostic assay to determine the genetic mutations that may elucidate why some patients suffer from significant limitations both in intellectual functioning and in adaptive behavior.

A team of scientists at Radboud University (Nijmegen, The Netherlands) performed exome sequencing of 100 patients with unexplained cognitive impairment, and uncovered 79 genes with unique de novo mutations. These de novo mutations were present in the DNA of the patients but not in that of their parents whose exomes also were sequenced.

The diagnostic interpretation revealed that 16 of the 100 mutations were causative, or pathogenic. Ten of these mutations occurred in genes already known to be involved in intellectual disability, and three X-linked maternally inherited mutations were identified. In addition, de novo mutations were uncovered in three novel candidate genes, which after follow-up were found to be more frequently mutated in patients with intellectual disability. Furthermore, disruptive de novo mutations were identified in 19 additional genes with a functional link to intellectual disability. Because 19 genes were found in only a single patient, a conclusive diagnosis based on these findings could not be made.

Joseph de Ligt, MSc, bioinformatician and PhD student in human genetics, said, “The child with a cognitive disability is often an isolated case without family history of the condition, and that intellectual disability occurs in about 1% of the population. All de novo as well as X-linked mutations identified in this study were interpreted in the context of the clinical diagnosis.” The results of this study were presented on November 8, 2012, at the American Society of Human Genetics meeting, held in San Francisco, (CA, USA).

Related Links:
Radboud University