Published online 15 September 2008 | Nature | doi:10.1038/455274b

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Gene chips unmask cryptic diseases

Microarrays zero in on small DNA defects.

Microarrays are an early genomic success story — the technology is already being used in the clinic.Phototake/BSIP/Chagnon

People with diverse symptoms including mental retardation, small head size, heart problems and cataracts have genomic rearrangements on the same region of chromosome 1, researchers reported last week.

A team led by genome scientist Evan Eichler at the University of Washington in Seattle linked deletions and duplications in a region of chromosome 1 that is 1.35 million DNA bases long to the abnormalities and cases of autism and learning difficulties1. Two studies published in July linked the same genomic region to schizophrenia2,3.

The findings are just the latest in a spate of studies using microarrays, which measure genetic make-up and activity, to identify small DNA defects in patients with complex disorders. Doctors are already using the technique to diagnose genetic causes of unexplained developmental conditions after clinical tests have proven inconclusive, making microarray tests an early clinical success story in the genomic revolution.

"The technology is moving rapidly from research to clinical labs, and what's research information today is becoming part of our clinical practice tomorrow," says David Ledbetter, an expert in chromosomal abnormalities at Emory University in Atlanta, Georgia.

“What's research information today is becoming part of our clinical practice tomorrow”

David Ledbetter
Emory University

Microarrays are glass slides embedded with fragments of DNA selected from entire genomes. Scientists can detect abnormalities in a patient's DNA — such as losses or gains of hundreds or a thousand bases — by comparing it with the normal material on the microarray. These deletions or duplications, also called copy-number changes, can change the dosage of a gene. They were invisible to older techniques such as karyotype analysis and fluorescence in situ hybridization, both of which involve examining whole chromosomes.

Over the past two years, microarray-based DNA comparisons have become routine in clinics around the world. Microarray supplier Agilent, based in Santa Clara, California, estimates that the worldwide market in this form of microarray analysis approaches US$200 million and is growing rapidly.

But a new appreciation of the amount of genetic variation found in healthy people means it can be difficult to tell whether a particular change is causing a patient's symptoms.

In Eichler's study, for example, eight patients had spontaneous deletions in the chromosome 1 region, but nine patients inherited their abnormalities from a parent, some of whom showed no symptoms. It's not clear how rearrangements in the region, which contains nine genes, cause the many symptoms seen in the study.

Such findings complicate the use of microarray tests in prenatal diagnostics, an area that is proceeding cautiously. On 1 October, doctors will begin enrolling 4,000 patients in a study funded by the US National Institute of Child Health and Human Development in Bethesda, Maryland, to compare microarray-based tests with traditional prenatal diagnosis techniques.

Scientists worldwide are trying to decrease uncertainty by pooling their samples in databases of copy-number aberrations, including Canada's Database of Genomic Variants, DECIPHER in the United Kingdom, and the European Union-funded ECARUCA. The databases help scientists link rare DNA changes to conditions ranging from autism and schizophrenia to kidney disease.

Eventually, scientists and doctors hope to understand why changes in gene copy number cause disease. But Eichler warns that this will require studies with perhaps tens of thousands of patients, as well as consultations with patients and their families for follow-up analyses, something that isn't part of most large genome-wide association studies today.

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It will also require US geneticists to share samples as freely as their European colleagues, says Eichler, who is grateful to his European collaborators, but laments his US colleagues' reluctance to pool their resources on a large scale. Ledbetter is trying to coax US geneticists to share with the help of a grant from the American College of Medical Genetics Foundation in Rockville, Maryland. Eichler hopes the plan will succeed: "We are going to need a sea change." 

  • References

    1. Mefford, H. C. et al. New Engl. J. Med. doi:10.1056/NEJMoa0805384 (2008).
    2. Stefansson, H. et al. Nature 455, 232–236 (2008).
    3. International Schizophrenia Consortium Nature 455, 237–241 (2008).
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