Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project

Purpose:The debate surrounding the return of results from high-throughput genomic interrogation encompasses many important issues including ethics, law, economics, and social policy. As well, the debate is also informed by the molecular, genetic, and clinical foundations of the emerging field of clinical genomics, which is based on this new technology. This article outlines the main biomedical considerations of sequencing technologies and demonstrates some of the early clinical experiences with the technology to enable the debate to stay focused on real-world practicalities.Methods:These experiences are based on early data from the ClinSeq project, which is a project to pilot the use of massively parallel sequencing in a clinical research context with a major aim to develop modes of returning results to individual subjects.Results:The study has enrolled >900 subjects and generated exome sequence data on 572 subjects. These data are beginning to be interpreted and returned to the subjects, which provides examples of the potential usefulness and pitfalls of clinical genomics.Conclusion:There are numerous genetic results that can be readily derived from a genome including rare, high-penetrance traits, and carrier states. However, much work needs to be done to develop the tools and resources for genomic interpretation. The main lesson learned is that a genome sequence may be better considered as a health-care resource, rather than a test, one that can be interpreted and used over the lifetime of the patient.Genet Med 2012:14(4):393–398

[1]  Jamie K Teer,et al.  A mosaic activating mutation in AKT1 associated with the Proteus syndrome. , 2011, The New England journal of medicine.

[2]  James C. Mullikin,et al.  Exome sequencing: the sweet spot before whole genomes , 2010, Human molecular genetics.

[3]  Identification of a novel LDLR mutation (c.261_262invGA, p.Trp87X): Importance of specifying DNA and protein mutations. , 2010, Atherosclerosis.

[4]  Leslie G Biesecker,et al.  Motivators for participation in a whole-genome sequencing study: implications for translational genomics research , 2011, European Journal of Human Genetics.

[5]  George Church,et al.  Ethical and Practical Guidelines for Reporting Genetic Research Results to Study Participants: Updated Guidelines from a National Heart, Lung, and Blood Institute Working Group , 2010, Circulation. Cardiovascular genetics.

[6]  Kenneth D. Mandl,et al.  Reestablishing the Researcher-Patient Compact , 2007, Science.

[7]  C. Férec,et al.  Revealing the human mutome , 2010, Clinical genetics.

[8]  S. Antonarakis,et al.  Vogel and Motulsky's Human Genetics , 2010 .

[9]  M. Guyer,et al.  Charting a course for genomic medicine from base pairs to bedside , 2011, Nature.

[10]  Jamie K Teer,et al.  Massively parallel sequencing of exons on the X chromosome identifies RBM10 as the gene that causes a syndromic form of cleft palate. , 2010, American journal of human genetics.

[11]  G. Geller,et al.  Public perspectives on informed consent for biobanking. , 2009, American journal of public health.

[12]  Jamie K Teer,et al.  Systematic comparison of three genomic enrichment methods for massively parallel DNA sequencing. , 2010, Genome research.

[13]  Alexander F. Wilson,et al.  Research in Genomic Medicine the Clinseq Project: Piloting Large-scale Genome Sequencing for Material Supplemental , 2009 .

[14]  Leslie G. Biesecker,et al.  Exome sequencing identifies ACSF3 as the cause of Combined Malonic and Methylmalonic Aciduria , 2011, Nature genetics.