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GENOMIC MEDICINE
Advances in sequencing technologies will contribute to rapid gains in knowledge by Cheryl Guttman Krader in Fort Lauderdale
In just two years since exome sequencing was introduced, to date it has been used to identify more than 30 diseases. This is remarkable progress...
Roderick R McInnes MD, PhD
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for maximising the potential of genomic medicine, the capabilities of this technique will have a huge impact on medicine,” said Dr McInnes. The power of next-generation sequencing for identifying the causative gene is illustrated by recent research using high-throughput DNA sequencing to resolve the complex genetics of retinitis pigmentosa. As reported in a recent paper [J Med Genet 2011;48:145-51], application of this technology identified the involved gene in four of five unrelated patients with classical RP phenotypes. The same technology also led to identification of a new RP-associated gene, that for dehydrodolichol diphosphate synthase (DHDDS), in three siblings with RP. The disease gene in this family had not been identifiable using earlier techniques. “This technology does not always find the mutant gene, but it is a great improvement over what has been done until now. In just two years since exome sequencing was introduced, to date it has been used to identify more than 30 disease genes. This is remarkable progress and I think the rate of discovery of disease genes using this technology will be exponential.” There has also been encouraging recent progress in understanding the genetic basis of common diseases, including eye diseases. The focus in genomic medicine research of common diseases is to identify the variant forms of genes, i.e. alleles that confer disease susceptibility or resistance. This is done by using microarrays to identify single nucleotide polymorphisms (SNPs) throughout the genome. This approach has allowed genome-wide association studies in large populations, ESCRS
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and identified disease-associated variants in more than a hundred common disorders. “In studies including hundreds to thousands of people and looking at millions of SNPs for disease associations, more than 1,000 genetic variants for polygenic traits, most of them for diseases, had been identified by the end of 2010,” Dr McInnes reported. “For ocular diseases, at least 15 genome-wide association studies have been done to date and identified loci for AMD, exfoliation glaucoma, myopia and refractive errors, and primary open angle glaucoma, among others,” he said. For common diseases, recent studies indicate that variations in multiple genes typically contribute to risk, and most of the individual gene variants have modest effects, increasing the relative risk of
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elivering the ARVO/Alcon Keynote Lecture during the annual meeting of the Association for Research in Vision and Ophthalmology, Roderick R McInnes MD, PhD predicted major advances in understanding of the genetics of eye diseases are forthcoming within the next decade. “Trying to predict the future can be hazardous. However, considering the extensive amount of exciting research under way in genetics and biology, I think it is safe to say that patients and physicians have a great deal to look forward to,” said Dr McInnes, Alva chair in human genetics, director, Lady Davis Research Institute, and Canada research chair in neurogenetics, at the Jewish General Hospital of McGill University, Montreal, Canada. Interestingly, about 2,500 of the 7,000 known human single gene diseases involve the eye, and although all parts of the eye are represented among the monogenic diseases, it is also remarkable that the number of genes (190 loci, at which the gene has been identified in 155) in which mutations cause retinal degeneration is much greater than the number affecting any other part of the eye, noted Dr McInnes, who is also professor, departments of human genetics and biochemistry, McGill University, Montreal. So far, the causative gene has been identified for fewer than half of known single gene diseases, and it is believed that another 4,500 to 7,000 more single gene diseases will eventually be identified. While these numbers suggest a monumental challenge, Dr McInnes predicted that the causative gene for virtually all presently known monogenic disease will be identified within the next five to 10 years, thanks to developments in sequencing technologies. “Recently introduced sequencing technologies are very fast compared with the old tedious methods and relatively inexpensive. Consequently, whole genome sequencing can often find a mutation in a single affected individual without any family history pattern. As the cost per sample for this sequencing continues to fall and reaches $1000 per genome, which geneticists have considered a Holy Grail
disease development perhaps by just 1.1- to 1.4-fold. Therefore, in general, information on gene variants cannot be used to guide patient care. However, there are some exceptions, including AMD, for which the finding of certain combinations of alleles in the alternative complement factor pathway confer a 90 per cent risk of getting the disease, and exfoliation glaucoma, for which certain alleles of the gene for lysyl oxidase-like 1 (LOXL1) increase risk by about 100-fold. Although the discovery of genetic variant(s) in any individual may not be useful for predicting disease development, identification of these susceptibility genes is important as it can provide valuable insight into the pathophysiology of the disease. To this end, researchers worldwide are working to identify the cohorts of genes that confer risk to various common diseases and will be trying to weave this information together to construct a genetic and biologic network to explain the genetic risk for each disease. “This will be hard and slow work for biologists in addition to geneticists, but the task will be facilitated by worldwide consortiums that are creating and phenotyping mouse and yeast knockouts, to allow a systems approach to elucidating the biology of newly identified diseaserelated genes,” Dr McInnes said.
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