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Genetic Diagnostic Technologies

By David N. Finegold, MD, Professor of Human Genetics, Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh

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(See also Overview of Genetics.)

Genetic diagnostic technology is rapidly improving. DNA or RNA can be amplified, producing many copies of a gene or gene segment, using PCR.

Gene probes can be used to locate specific segments of normal or mutated DNA. Different types of probes may investigate a broad range of sizes of DNA sequence. A known DNA segment may be cloned and then fluorescently tagged (using fluorescent in situ hybridization [FISH]); this segment is then combined with a test specimen. The tagged DNA binds to its complementary DNA segment and can be detected by measuring the amount and type of fluorescence. Gene probes can detect a number of disorders before and after birth.

Oligonucleotide arrays (probes) are another type of probe now routinely utilized to identify deleted or duplicated regions of DNA sequence in specific chromosomes on a genomewide basis. DNA from a patient is compared to a reference genome using many oligonucleotide probes. Using such probes, the entire genome can be tested (queried).

Microchips are powerful new tools that can be used to identify DNA mutations, pieces of RNA, or proteins. A single chip can test for millions of different DNA changes using only one sample. Microchips provide finer resolution for genome queries than oligonucleotide arrays.

Next-generation sequencing technologies have dramatically changed the approach to genetic diagnosis. This technology involves breaking the entire genome into small segments, sequencing the segments, and then reassembling the sequences using intensive computational techniques to provide the base-by-base sequence of the entire genome or more limited regions, such as the expressed portion of the genome known as the exome. This process helps identify single or multiple nucleotide variations as well as areas of insertion or deletion. The costs of this technology have dramatically fallen and continue to fall. The equipment and computational methods also continue to improve.

This revolutionary technology has moved a significant portion of the technical aspects of genetic diagnosis to next-generation sequencing. It is conceivable that as this technology continues to rapidly evolve it will become the mainstay of genetic diagnosis. However, the sheer volume of information generated by sequencing the exome or genome results in a variety of interpretive problems that complicate understanding of the results. Despite these issues, these techniques appear to be the technology of the future.