Clinical Interpretation and Implications of Whole-Genome Sequencing

Abstract

IMPORTANCE Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication. OBJECTIVES To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings. DESIGN, SETTING, AND PARTICIPANTS An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings. MAIN OUTCOMES AND MEASURES Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up. RESULTS Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95%CI, 0.40-0.64), and reclassified 69%of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001). CONCLUSIONS AND RELEVANCE In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.

Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature

“…3,[31][32][33][34][35][36][37][38][39][40][41][42] Seven studies presented data on the costs of WES or WGS testing pathways, [24][25][26][27][43][44][45] and eight studies presented data on clinically relevant outcome measures for these tests. 5,6,[8][9][10][46][47][48] Of the eight full economic evaluations, two were CUAs 22,23 and six were CEAs, published between 2014 and 2017 in Australia (2), the United States (1), the UK (1), the Netherlands (1), and Canada (1).…”

“…Chrystoja and Diamandis 24 reviewed the potential of WGS and summarized cost data extracted from previously published scientific studies and commercial sources. Dewey et al 43 estimated the costs of WGS in the United States as well as the costs associated with curation and clinical follow-up. Weymann et al 45 estimated the costs of using WGS to inform treatment decisions in patients with advanced cancers.…”

“…40,41 Six studies estimated the cost of WGS, four of which used data from commercial sources. 24,26,28,43 Cost estimates ranged from £1,312 ($1,906) for sequencing using the HiSeq X in Germany 26 to £17,243 ($24,810) for an unspecified platform in Canada. 24 Four studies used a transparent bottom-up approach to estimate the cost of WGS.…”

“…24 Four studies used a transparent bottom-up approach to estimate the cost of WGS. 20,21,26,28,45 There was limited evidence of a reduction in the cost of WGS over time, with the lowest estimate declining from £10,497 ($15,146) 43 in 2013 to £1,312 ($1,906) 26 in 2017. However, this is based on a small sample.…”

Challenges of using next generation sequencing in newborn screening

“…In WGS this represents an even greater challenge in the non-coding parts of the genome where function is not yet clearly defined for many sequences. Thus, the clinical significance of thousands of genomic and exomic variants detected by NGS cannot presently be interpreted with complete certainty, preventing evidence-based decisions being made to guide treatment and clinical surveillance Koboldt et al, 2013;Dewey et al, 2014;Johansen Taber et al, 2014;Landau et al, 2014;Yang et al, 2014). If we also consider complex disorders that are caused by a combination of multiple genetic variations, each increasing disease risk only slightly, then the picture is even more complex.…”