X-linked intellectual disability is caused by defective genes on the X chromosome. As males only have one X chromosome and the disease is passed on in a recessive manner, the disorder mainly occurs in boys.
Women are affected only if both their X chromosomes carry the defective genes. Women with one healthy and one mutated X chromosome are usually healthy but have a 50 per cent chance of passing the mutated X chromosome on to their offspring.
Because of the high variability of the clinical picture, the search for the responsible genetic defect was, until a few years ago, very tedious.
An international research team headed by Vera Kalscheuer from the Max Planck Institute for Molecular Genetics in Berlin has now analysed 405 families, in which cases of X-linked intellectual disability occur.
The researchers have discovered changes in a number of genes that were already known to be related to the disorder.
In addition, they discovered that X-linked intellectual disability can also be caused by mutations in seven other genes that, until now, were not associated with the disorder.
For some years now, scientists have been aided in their research of genetic diseases by high-throughput sequencing.
This technology allows to sequence a large number of DNA segments simultaneously and to more easily identify genetic defects.
Using this method, the scientists investigated all DNA regions of the X chromosome containing protein-relevant information.
“In addition to known disease-related genes, we have discovered seven novel genes as the cause of X-linked intellectual disability and analysed what signalling pathways in the cells each protein is involved in,” said Kalscheuer.
According to the researchers, the clinical presentation and severity of the disorder depend on the responsible gene and the nature of the mutation.
For example, if the mutation is located in a region that is important for brain development and protein function, the result is likely to be a more severe disease progression.
With the help of systematic re-sequencing of all X-linked genes, the responsible genetic defect can be identified in around 60 per cent of families with X-linked intellectual disability.