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Severe intellectual disability diagnosed by analysis of entire genome

With a new technique, which at once studies the whole genome, a genetic cause can be identified in six out of ten children with severe intellectual disability. This makes the method more successful than all the usual methods together. Moreover, almost all mental impairments are caused by new mutations that have not yet occurred in father or mother. This is reported by researchers of the Radboud university medical center in an article appearing in Nature.

Almost one in two hundred children is severely intellectually disabled. Often the cause is difficult to detect, because more than a thousand genes may play a role in the development of intellectual disability. Despite extensive research the quest of parents, who’d desperately like to know what is happening in their child, usually ends without an identifiable cause.

The complete genome

Having now used a very powerful new approach called whole genome sequencing (WGS) in collaboration with Complete Genomics, Inc. a BGI Company, that is based in California, researchers of the Radboudumc could study the entire genetic material of a child and his or her unaffected parents. “Compared to whole exome sequencing – a technique that we used before – WGS delivers nearly a hundred times more data,” says Han Brunner, professor of Clinical Genetics and head of the departments of Genetics in both Nijmegen and Maastricht. “Before, we could detect the cause of intellectual disability in up to four of 10 children with all the genetic techniques together. If we now only use WGS this increased to 6 of 10 children. For the patients and families involved this is a huge step forward.”

New mutations

Joris Veltman, professor of Translational Genomics in Radboudumc and also associated to the Maastricht UMC+: “The WGS study makes clear that virtually all known genetic causes of intellectual disability are based on new mutations in the genetic material of the patient. The parents do not have the mutation. Only in exceptional cases it is a hereditary cause and the mutation is found in the genes of father, mother or both. To detect the remaining causes we will probably have to look into the non-coding DNA in the genome, something we will do in the coming years”.

Widespread use

WGS shows tremendous effectiveness in detecting the genetic causes of intellectual disabilities. Although the costs are now a little higher than with traditional techniques, the demand for large-scale use of technology is imperative. “The price of WGS is still dropping very fast,” says Veltman. “Ten years ago sequencing a single genome amounted to hundred million euros; now we can not only sequence but also clinically interpret the genome for several thousand euros. If we combine efforts in The Netherlands we may soon be able to offer diagnostic WGS for around thousand euros. WGS is not only useful for diagnosing intellectual disability, but also shows enormous potential for diagnosing cancer and other disorders.”


Research was financed by European Research Council and Dutch Scientific Organisation

Genome sequencing identifies major causes of severe intellectual disability, Christian Gilissen, Jayne Y. Hehir-Kwa, Djie Tjwan Thung, Maartje van de Vorst, Bregje W. M. van Bon, Marjolein H.Willemsen, Michael Kwint, Irene M. Janssen, Alexander Hoischen, Annette Schenck, Richard Leach, Robert Klein, Rick Tearle, Tan Bo, Rolph Pfundt, Helger G. Yntema, Bert B.A. de Vries, Tjitske Kleefstra, Han G. Brunner, Lisenka E. L. M. Vissers & Joris A. Veltman, Nature, doi:10.1038/nature13394, Published online 4 June 2014.

Radboud University Nijmegen