Opportunities and Challenges Associated with Clinical Diagnostic Genome Sequencing

Abstract

This report of the Whole Genome Analysis group of the Association for Molecular Pathology illuminates the opportunities and challenges associated with clinical diagnostic genome sequencing. With the reality of clinical application of next-generation sequencing, technical aspects of molecular testing can be accomplished at greater speed and with higher volume, while much information is obtained. Although this testing is a next logical step for molecular pathology laboratories, the potential impact on the diagnostic process and clinical correlations is extraordinary and clinical interpretation will be challenging. We review the rapidly evolving technologies; provide application examples; discuss aspects of clinical utility, ethics, and consent; and address the analytic, postanalytic, and professional implications.

Navigating the current landscape of clinical genetic testing for inherited retinal dystrophies

“…49,61 By searching for variants in known positive controls, Audo et al 31 studied the robustness of NGS panels and found lower coverage for two genes associated with congenital stationary night blindness, NYX (OMIM 300278) and GRM6 (OMIM 604096), as a result of GC-rich regions. In addition, because of low coverage of the PRPF31 gene, a known one-base pair deletion was undetectable.…”

The Promise and Pitfalls of Genomics-Driven Cancer Medicine

“…First, the quality of the data generated depends heavily on the quality of the sample provided. The percentage of tumor cells within a given sample can vary widely, and furthermore one tumor may harbor different genetic changes in different geographic regions ("tumor heterogeneity") [4,5]. Availability of ample, representative, high-quality biospecimens may prove scarce in real-time oncology NGS diagnostics.…”

“…Bioinformatics and computational biology are rapidly evolving, but considerable risk remains of false positive results, false negative results, and misinterpretation of gene mutations [4,9]. Because almost all malignancies are genetically unstable, tumors accumulate a large number of random genetic alterations not related to their pathogenesis.…”

“…The many thousands to millions of DNA strands are then sequenced simultaneously. All NGS sequencing results in a huge volume of raw data, generating hundreds of millions to even trillions of data points, in a single instrument run [4]. These data must then be processed and interpreted by comparison with a reference genome (e.g., the human genome in the case of medical genomics) requiring complex biostatistical and bioinformatics analysis [5].…”

“…To put the impact of NGS in context, sequencing of the first human genome was completed in 2001 after more than two decades of work and at the cost of $2.7 billion [4,6]. With the introduction of NGS in 2005 and continued improvement in NGS instrumentation, we can now sequence a human genome within days at a cost of approximately $5,000 [7].…”