Gene hunt is on for mental disability
25 Apr 2012 - Pioneering clinical genome-sequencing projects focus on patients with developmental delay. Medical geneticists are giving genome sequencing its first big test in the clinic by applying it to some of their most baffling cases. By the end of this year, hundreds of children with unexplained forms of intellectual disability and developmental delay will have had their genomes decoded as part of the first large-scale, national clinical sequencing projects.
These programmes, which were discussed last month at a rare-diseases conference held at the Wellcome Trust Genome Campus in Hinxton, UK, aim to provide a genetic diagnosis that could end years of uncertainty about a child’s disability. In the longer term, they could provide crucial data that will underpin efforts to develop therapies. The projects are also highlighting the logistical and ethical challenges of bringing genome sequencing to the consulting room. “The overarching theme is that genome-based diagnosis is now hitting mainstream medicine,” says Han Brunner, a medical geneticist at the Radboud University Nijmegen Medical Centre in the Netherlands, who leads one of the projects.
About 2% of children experience some form of intellectual disability. Many have disorders such as Down’s syndrome and fragile X syndrome, which are linked to known genetic abnormalities and so are easily diagnosed. Others have experienced environmental risk factors, such as fetal alcohol exposure, that rule out a simple genetic explanation. However, a large proportion of intellectual disability cases are thought to be the work of single, as-yet-unidentified mutations.
Scientists estimate that about 1,000 genes are involved in the function of the healthy brain. “There are so many genes that can go wrong and give you intellectual disability,” says André Reis, a medical geneticist at Erlangen University Hospital in Germany. Reis’s group, the German Mental Retardation Network, has already sequenced the exomes — the 1–2% of the genome that contains instructions for building proteins — of about 50 patients with severe intellectual disability.
Joining the hunt is a UK-based programme called Deciphering Developmental Disorders, which expects to sequence 1,000 exomes by the year’s end, with an ultimate goal of diagnosing up to 12,000 British children with developmental delay. A Canadian project called FORGE (finding of rare disease genes) aims to sequence children and families with 200 different disorders this year. And in the United States, the National Human Genome Research Institute in Bethesda, Maryland, recently funded three Mendelian Disorders Sequencing Centers that will apply genome sequencing to diagnosing thousands of patients with a wider range of rare diseases, including intellectual disability and developmental delay.