Next generation sequencing
Next generation sequencing (NGS) allows the simultaneous sequencing of all genes in the human genome, or of a selected subset of these genes, to identify variations known to cause disorders. NGS is available through specialised genetic services and may be recommended for people with intellectual disability of unknown aetiology, when chromosome microarray testing has been normal.
The main next generation sequencing tests that are available clinically are whole genome sequencing and exome sequencing. Although whole genome sequencing is considered the ‘gold standard’, the clinical uptake of exome sequencing is greater due to lower cost and detection rates that are only slightly inferior. Exome sequencing does not sequence all DNA, but targets the 1 to 2% of the human genome that comprises actual genes, and ignores the remainder of the genome. Although there are in excess of 20 000 genes in the human genome, when the indication for testing is developmental disability, testing laboratories will target analysis of data to approximately 1500 genes so far linked to neurodevelopmental disorders.
An unexpected discovery from next generation sequencing is new gene mutations, described as the ‘de novo paradigm of intellectual disability’. Of all genetic diagnoses made in individuals with developmental disability, the majority are de novo autosomal mutations, with autosomal recessive and X-linked inheritance accounting for minor proportions.
The diagnostic yield of next generation sequencing in individuals with developmental disability will depend on patient selection, being highest in those with severe intellectual disability and syndromic features. Currently, the diagnostic yield in individuals with intellectual disability is around 50%. Genetics services can provide more information on next generation sequencing1.
Although next generation sequencing is a relatively expensive test, it has been shown to be cost-effective, particularly when applied early in the patient’s diagnostic journey (due to the avoidance of other investigations and health service costs, and where applicable, the early institution of treatment).
Test results should be clearly recorded in the person’s medical history.