Genetic counselors and next-generation sequencing: The clinical implications of NGS patient data
By: Roche Life Science
Posted: March 09, 2016 | Lab Life - Next-Gen Sequencing
The 21st century has seen advancements in genetic technologies that revolutionized sequencing capacity with the rise of next-generation sequencing (NGS, also known as massively parallel or second-generation sequencing). These discoveries have fostered unprecedented scientific inquiry, diagnostic capabilities and clinical genetic inquiry.
The robust evolution of NGS platforms in the past decade has driven the cost of large-scale DNA sequencing (including whole-genome and whole-exome sequencing) down by more than 100,000-fold compared to the nearly $3 billion it cost to sequence the first human genome in 2004.1,2 Indeed, at the time of Sanger-based or "first-generation" sequencing, genomic sequencing capacity was approximately 3 to 4 million base pairs per day, in contrast to the capacity of today's NGS platforms at more than 60 billion base pairs per day.3
Thus, the costs of clinical whole-genome or targeted sequencing analyses are no longer prohibitive to clinical availability and application. This has dramatically changed the landscape of genetic analysis, testing and counseling, placing sequencing capabilities once only attainable by select scientists at major genetic institutes into the hands of individual investigators, clinicians, and third-party enterprises all over the world. Importantly, as the wave of NGS clinical genetic applications and availability continues to rise, we must remain aware of the significant challenges that need to be addressed. In particular, there should be an emphasis on the growing need for "next-generation genetic counseling" and the clinical implications of storing, interpreting, and communicating NGS patient data.
In this article, we will discuss the current landscape of next-generation genetic counseling, including the clinical testing and interpretation of NGS patient data, as well as the infrastructure to support NGS applications and the future direction of the field.
Clinical testing and interpretation
The clinical availability of NGS testing highlights several areas of uncertainty, namely the issue of variant interpretation, which is often unclear, as well as the potential to find results that are incidental to the initial intended application for testing. Indeed, assigning clinical significance to variants obtained via NGS testing is a dynamic challenge. The process for evaluating potential pathogenicity of a variant involves what is frequently referred to as annotation and interpretation.4
Annotation, as the name implies, involves assignment of the genetic variation (i.e. the base or amino acid change and type of change, chromosome coordinates and gene name, and population frequency) which is frequently performed semi-automatically. Interpretation involves the evaluation of these variations in combination with available clinical, pre-clinical, and database information to determine the clinical significance of the variant. This process often requires establishment of certain variance thresholds and filters to separate out likely benign or unrelated variants. Frequently used filters include allele frequency less than 1-5 percent (based on known population data) and certain types of variants, such as non-coding or synonymous variants.4
The potential magnitude of this data means there not only must be sufficient counseling prior to obtaining results, but substantial discussion in each clinical practice about how to make informed decisions regarding use, threshold of uncertainty for disclosure, and unclear results. Expectedly, the growing availability and applicability of NGS data has ushered in a new era of genetic counseling that will need to adapt dynamically to this ever-expanding field.
NGS patient data infrastructure
The necessary infrastructure to address patient needs effectively is multifactorial as it includes technical, educational, practical, and medical aspects. Importantly, there remain significant barriers to implementation and optimization of each of these needs. Perhaps the most straightforward to conceptualize is the technical infrastructure; namely, the ability to acquire and store NGS data and how to implement the results into the electronic medical record.
While seemingly obvious, there remain significant limitations at each practice and institution regarding this component and the manner in which it is performed varies drastically from site to site. The educational component is both patient- and provider-based, so there needs to be effective patient-directed education from a clinical or molecular geneticist and genetic counselors as described above, as well as an appropriate level of education at the provider level in order to do so effectively. This includes a working knowledge base and practical familiarity with testing methodology, genetic theories, and probabilistic reasoning, including Bayesian statistics. In turn, individuals can skillfully interpret diagnostic and risk-associated variants, and navigate what can be murky and confusing results.
In part, some of this interpretation can be obtained from the genome-specific software from the testing company itself and used in conjunction with interpretive software at a given institution. Medically, there must be infrastructure to support continued education for providers and trainees for the appropriate incorporation of genetic testing into preventative health and diagnostic-based applications.
There is no question that NGS technology has changed the landscape of clinical genetic testing in the present and for years to come. A rapidly increasing demand for genetic counseling is apparent as NGS applications become ubiquitous in clinical practice. This means that providers at various levels should be exposed to and trained in an appropriate amount of bioinformatics and genetics to be cognizant of the limitations and implications of patient NGS data. This includes being familiar with available NGS testing methodologies and clinical options , practical methods for managing variants of uncertain significant and incidental results, as well as determining when further testing or analysis is warranted. Most importantly, given the explosive growth in clinical NGS applications, the field will need to remain dynamic and continue to adapt to new and diverse clinical needs as they arise.
1. International Human Genome Consortium. Finishing the euchromatic sequence of the human genome. Nature 431, 931 945 (2004).
2. Green, E. D., & Guyer, M. S. (2011). Charting a course for genomic medicine from base pairs to bedside. Nature, 470(7333), 204 213
3. Biesecker, L. G. (2012). Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project. Genetics in Medicine, 14(4), 393 398.
4. Facio FM. (2014). A genetic counselor's guide to using next-generation sequencing in clinical practice. J Genet Couns. 2014 Aug;23(4):455-62.
5. Biesecker LG (2012). Next-generation sequencing in the clinic: are we ready? Nat Rev Genet. 2012 Nov;13(11):818-24.