Miniaturized Nanopore DNA Sequencing: Accelerating the Path to Precision Medicine.

Abstract

On January 30, 2015, President Barack Obama announced the launch of a Precision Medicine Initiative—“a bold new research effort to revolutionize how we improve health and treat disease” (1). The success of this bold new initiative depends upon continued improvements in the genomics space. Arguably, the key technological player in precision medicine is next generation sequencing (NGS),2 an extremely powerful technology for detection of genetic variation. NGS has enabled a multitude of impressive research discoveries that have been translated toward more rapid, cost-effective, and comprehensive analyses for inherited conditions and cancer. However, despite its achievements, NGS analysis is still too expensive and time-consuming of a process to be carried out routinely on all patients. The technological platform and the clinical-grade reagents themselves are both costly, as is the scientific know-how to perform the benchwork, bioinformatics, and variant interpretation. Reducing the time, cost, and effort to perform clinical NGS is essential to achieve further adoption of personalized medicine. Current NGS sequencing technologies generally use expensive and slow optic-based measurements of short copies of PCR-amplified DNA. Additionally, 3 major groups of genomic variation that are important for clinical diagnostics cannot be efficiently detected by de novo assembly of sequencing data from short DNA strands. The first of these, and closest to clinical optimization, are the copy number alterations that remove or add single or multiple exons, such as those commonly encountered in Duchene muscular dystrophy. The next major class is the trinucleotide repeat disorders. The classical example here is Fragile X, whereby a repeating CGG motif expansion (growing to over thousands of nucleotides in some cases) causes disease. Finally, regions of low sequence complexity, known as pseudogenes, or highly related gene family members, like members of the CYP family of genes, can be challenging to detect a real pathogenic change from …