Published online before print October 2, 2008

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Journal of Molecular Diagnostics 2008, Vol. 10, No. 6
Copyright © 2008 American Society for Investigative Pathology & Association for Molecular Pathology
DOI: 10.2353/jmoldx.2008.080027

Keeping Up With the Next Generation

Massively Parallel Sequencing in Clinical Diagnostics

John R. ten Bosch, Ph.D.^* and Wayne W. Grody, M.D., Ph.D.^*

From the Departments of Human Genetics, * Pathology & Laboratory Medicine, and Pediatrics, University of California at Los Angeles School of Medicine, Los Angeles, California

The speed, accuracy, efficiency, and cost-effectiveness of DNA sequencing have been improving continuously since the initial derivation of the technique in the mid-1970s. With the advent of massively parallel sequencing technologies, DNA sequencing costs have been dramatically reduced. No longer is it unthinkable to sequence hundreds or even thousands of genes in a single individual with a suspected genetic disease or complex disease predisposition. Along with the benefits offered by these technologies come a number of challenges that must be addressed before wide-scale sequencing becomes accepted medical practice. Molecular diagnosticians will need to become comfortable with, and gain confidence in, these new platforms, which are based on radically different technologies compared to the standard DNA sequencers in routine use today. Experience will determine whether these instruments are best applied to sequencing versus resequencing. Perhaps most importantly, along with increasing read lengths inevitably comes increased ascertainment of novel sequence variants of uncertain clinical significance, the postanalytical aspects of which could bog down the entire field. But despite these obstacles, and as a direct result of the promises these sequencing advances present, it will likely not be long before next-generation sequencing begins to make an impact in molecular medicine. In this review, technical issues are discussed, in addition to the practical considerations that will need to be addressed as advances push toward personal genome sequencing.

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