Conference Summary

Clinical Applications for Technological Advances in Genetic Testing

Shelley D. Smith, PhD


December 11, 2009

In This Article

"Next Generation" Sequencing

Because current SNP panels are not designed to pick up rare variants, and comparative genome hybridization arrays may miss some regions, sequencing is needed to pick up other types of mutations. However, traditionally it has been financially impractical to sequence large regions without previous evidence of association, so many rare variants are probably never detected. This is changing with new DNA sequencing technologies, commonly referred to as "next generation" or massively parallel sequencing, available on several different platforms such as the Roche 454, Illumina Genome Analyzer (formerly called Solexa®), Applied Biosystems SOLiD™, and Helicos® Genetic Analysis Platform.

These systems are enabling much cheaper sequencing of large regions of DNA or large collections of genes, and even whole genomes. For example, Nicholas Campbell,[4] from Vanderbilt University in Nashville, Tennessee, reported that sequencing of the SLC6A4 transporter, which has been associated with autism and is a target of selective serotonin reuptake inhibitor medications, was performed in 120 probands with autism. Campbell and colleagues found several new variants that produced gain of function in the resulting protein and hypothesized that another gene, the adenosine A3 receptor, which up-regulates serotonin transport, would also be involved in autism and sequenced this gene in 172 autistic probands. They found that 3 individuals had a mutation that was predicted to affect ligand binding; when they tested additional families, they found 11 more families with the same mutation. Functional testing in Chinese hamster ovary cells confirmed that the mutation affected persistence of the receptor at the cell membrane.

In another study, Florence Demenais,[5] from the Institut National de la Santé et de la Recherche Médicale (INSERM) in Paris, France, sequenced a gene, MCR1, which was known to be involved in some cases of malignant melanoma, but had not been picked up on GWAS analysis because SNPs in the gene were not included on the SNP panels. Sequencing found 75 variants, 3 of which were in coding regions with significant effects. Finally, in a study by James Lupski,[6] from Baylor College of Medicine, Houston, Texas, a set of neuropathy genes were selected and sequenced in a family with the dominantly inherited Charcot-Marie-Tooth disease. The family had previously undergone clinically available testing, but all of the tested genes had shown normal sequences; his study detected a previously missed mutation in the gene SH3TC2.

Many clinical tests focus on regions of genes most likely to contain mutations to decrease costs, but the new technology should make it possible to cover all of a gene so that fewer causal mutations will be missed.


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