PerspectiveGenetic Diseases

# Deep Sequencing of Patient Genomes for Disease Diagnosis: When Will It Become Routine?

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Science Translational Medicine  15 Jun 2011:
Vol. 3, Issue 87, pp. 87ps23
DOI: 10.1126/scitranslmed.3002695

## Abstract

Next-generation sequencing technologies have greatly lowered the cost of whole-genome sequencing (WGS) and related approaches. Thus, comprehensive sequencing for diagnostic purposes may clear this financial hurdle in the near future. The report by Bainbridge and colleagues in this issue of Science Translational Medicine illustrates the diagnostic power of WGS. In this Perspective, we discuss whether and how genome sequencing might become routine for clinical diagnosis.

## NOT SO FAST

Before a sense of euphoria sinks in, however, we offer perspectives on the four most important hurdles to broad use of NGS-based diagnostic testing in clinical laboratories. First, no clinical-grade general database of disease-associated mutations currently exists. Interpreting the clinical significance of mutations relies on information found in the primary literature and general and locus-specific databases (5, 8); disturbingly, 27% of literature-cited mutations may be incorrect (13). Consortia organized by leading reference laboratories, the National Center for Biotechnology Information, the Human Genome Variation Society, and the Human Variome Project are beginning to develop plans and recommendations to address these issues and create a clinical-grade general database (31).

Second, consensus strategies for standardized, high-throughput interpretation of genetic variants of unknown significance (VUS) must be developed and implemented. The current guidelines for clinical interpretation and reporting of disease variants (5, 8) are largely extensible to NGS but may warrant several considerations for future revisions: (i) Current guidelines for reporting VUS are necessarily conservative, written in the context of testing one or a few candidate genes. There is a high burden to report variants that are unlikely to be causative for fear of under-calling a pathogenic genotype, a fear perhaps less relevant in the context of sequencing all potentially causal genes rather than a single locus. As more public genomic data become available, the knowledge of variant frequencies and improved global insights into their correlation with disease should yield less-ambiguous reports for VUS. (ii) Mutation interpretation guidelines must be extended to include provisions for reporting genotypes and paired haplotypes (genetic constituents of each individual chromosome) with future extensibility to epistasis (gene-gene interactions resulting in modified phenotypes). (iii) Consensus software tools are needed for automated in-process VUS annotation to accommodate increasing test volumes and the numbers of all variants generated by NGS. (iv) In light of ongoing advancements in NGS, the way in which clinical laboratories report incidental findings—genomic variants perceived to be immaterial to the illness for which a diagnosis is sought—requires reassessment in terms of the increasing knowledge of the occurrence of pleiotropy, epistasis, and genetic heterogeneity. For example, broader genetic backgrounds of patients, including variants categorized as incidental, will likely explain why the same disease mutation may result in variable symptoms in distinct individuals. (v) Broader genomic testing creates a much greater need for clinical correlation than was necessary for conventional molecular testing. Adapting to this reality will require both careful collection of phenotypic information and use of a controlled vocabulary when genomic level–sequencing testing is ordered.

Third, genomic training programs must be designed for use in medical school curricula, residency training, and the reeducation of mature physicians. Health care providers will need better interpretive and communication skills regarding genetic information. Clearly, the numbers of clinical geneticists and genetic counselors are, and will continue to be, insufficient to serve as the sole providers of genomic medicine. Thus, a standard for genomic medicine certification for other subspecialists is urgently needed, as are genomic medicine training tracks for physician assistants and nurse practitioners. In addition, as genomic medicine becomes the standard of care, the role of interpretation and reporting will likely expand to pathologists, who will also require education. Without such initiatives, genomic medicine lacks the infrastructure for broad deployment.

Finally, before clinical practice guidelines can be defined for NGS-based diagnosis, many questions must be answered: What are the analytical gold standards? What are the benefits and harms of using genomic information in health care, and how are these maximized and minimized, respectively? Which sets of disorders benefit from NGS-based diagnostic testing in terms of cost and improved outcomes? What are the implications for preconception carrier testing and neonatal screening? How can improved rates of ascertainment and earlier diagnoses be leveraged to reinvigorate clinical trials of new therapies for orphan disorders? Although NGS has only recently arrived in the clinic and shows great potential as a diagnostic tool, the technology has outpaced the modes of analysis. To remedy this imbalance moving forward will require thoughtful planning by clinical and laboratory geneticists, researchers, bioinformaticians, and ethicists.

## Footnotes

• Citation: S. F. Kingsmore, C. J. Saunders, Deep Sequencing of Patient Genomes for Disease Diagnosis: When Will It Become Routine? Sci. Transl. Med. 3, 87ps23 (2011).

## References and Notes

1. Acknowledgments: We thank D. Dinwiddie, N. Miller, and S. Soden for their insights. This work was funded by the Beyond Batten Disease Foundation and Children’s Mercy Hospital. A deo lumen, ab amicis auxilium. Competing interests: The authors declare no competing interests.
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