The ClinSeq Project: Piloting large-scale genome sequencing for research in genomic medicine

Abstract

ClinSeq is a pilot project to investigate the use of whole-genome sequencing as a tool for clinical research. By piloting the acquisition of large amounts of DNA sequence data from individual human subjects, we are fostering the development of hypothesis-generating approaches for performing research in genomic medicine, including the exploration of issues related to the genetic architecture of disease, implementation of genomic technology, informed consent, disclosure of genetic information, and archiving, analyzing, and displaying sequence data. In the initial phase of ClinSeq, we are enrolling roughly 1000 participants; the evaluation of each includes obtaining a detailed family and medical history, as well as a clinical evaluation. The participants are being consented broadly for research on many traits and for wholegenome sequencing. Initially, Sanger-based sequencing of 300-400 genes thought to be relevant to atherosclerosis is being performed, with the resulting data analyzed for rare, high-penetrance variants associated with specific clinical traits. The participants are also being consented to allow the contact of family members for additional studies of sequence variants to explore their potential association with specific phenotypes. Here, we present the general considerations in designing ClinSeq, preliminary results based on the generation of an initial 826 Mb of sequence data, the findings for several genes that serve as positive controls for the project, and our views about the potential implications of ClinSeq. The early experiences with ClinSeq illustrate how large-scale medical sequencing can be a practical, productive, and critical component of research in genomic medicine.

Intentions to receive individual results from whole-genome sequencing among participants in the ClinSeq study

“…A description of the original ClinSeq cohort and study design is published. 9 Since that publication, the study has generated exome sequence data for most participants. 21 The National Human Genome Research Institute's Institutional Review Board approved this study.…”

“…[6][7][8] At the National Institutes of Health, ClinSeq is a clinical study that aims to enroll a cohort of 41000 participants who consent to WGS and have a choice about what types of information they want returned to them. 9 This longitudinal study provides a novel opportunity for baseline assessment of preferences to learn personal health-related information from WGS.…”

Research participants’ attitudes towards the confidentiality of genomic sequence information

“…9 The Whole Genome Medical Sequencing (WGMS) study enrolls children and adults for genomic sequencing with the aim of discovering the genetic aetiology of rare conditions. The two studies are overseen by the same primary investigator and involve overlapping approaches to informed consent.…”

“…In both protocols, sequence variants deemed clinically relevant are validated in a Clinical Laboratory Improvement Amendmentscertified laboratory and returned to the corresponding participant, or their parent if the proband is a minor. 9 …”

Returning pharmacogenetic secondary findings from genome sequencing: let’s not put the cart before the horse

“…DNA sequencing was introduced to enable the molecular diagnosis of congenital disorders and rare syndromes, followed by several studies that explored the introduction of sequencing in various clinical settings. 1,2 Given the role of DNA in many diseases and outcomes, it is understandable that there is research interest in the secondary use of sequencing data and in the preemptive sequencing of healthy individuals in the event that DNA data are needed for a later medical decision.…”