Clinical Impact and Cost-Effectiveness of Whole Exome Sequencing as a Diagnostic Tool: A Pediatric Center’s Experience

Abstract

BackgroundThere are limited reports of the use of whole exome sequencing (WES) as a clinical diagnostic tool. Moreover, there are no reports addressing the cost burden associated with genetic tests performed prior to WES.ObjectiveWe demonstrate the performance characteristics of WES in a pediatric setting by describing our patient cohort, calculating the diagnostic yield, and detailing the patients for whom clinical management was altered. Moreover, we examined the potential cost-effectiveness of WES by examining the cost burden of diagnostic workups.MethodsTo determine the clinical utility of our hospital’s clinical WES, we performed a retrospective review of the first 40 cases. We utilized dual bioinformatics analyses pipelines based on commercially available software and in-house tools.ResultsOf the first 40 clinical cases, we identified genetic defects in 12 (30%) patients, of which 47% of the mutations were previously unreported in the literature. Among the 12 patients with positive findings, seven have autosomal dominant disease and five have autosomal recessive disease. Ninety percent of the cohort opted to receive secondary findings and of those, secondary medical actionable results were returned in three cases. Among these positive cases, there are a number of novel mutations that are being reported here. The diagnostic workup included a significant number of genetic tests with microarray and single-gene sequencing being the most popular tests. Significantly, genetic diagnosis from WES led to altered patient medical management in positive cases.ConclusionWe demonstrate the clinical utility of WES by establishing the clinical diagnostic rate and its impact on medical management in a large pediatric center. The cost-effectiveness of WES was demonstrated by ending the diagnostic odyssey in positive cases. Also, in some cases it may be most cost-effective to directly perform WES. WES provides a unique glimpse into the complexity of genetic disorders.

Precision treatment with sirolimus in a case of activated phosphoinositide 3-kinase δ syndrome

“…cases such as this demonstrate the powerful impact that the integration of genomic medicine can have on the diagnosis and treatment for patients across medical specialities [9].…”

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). [18][19][20][21][28][29][30] Of these publications, the study by Soden et al 29 did not directly report WES costs but estimated Population unclear 2 (6) No study population 6 (17) WES, whole-exome sequencing; WGS, whole-genome sequencing.…”

“…48 Four publications used the traditional care pathway in the investigated condition as a comparator. 6,10,46,48 Three publications were retrospective analyses 6,47,48 and three were diagnostic studies, estimating the diagnostic yield of WES in a variety of conditions. 5,8,9 The final two studies were case studies on single probands and families.…”

Against all odds: blended phenotypes of three single-gene defects

“…Its cost-effectiveness and utility in clinical diagnosis are increasingly recognized. 22,23 Even without clinical clues and a working hypothesis, unbiased comprehensive genetic analysis may deliver pathogenic variants. Promoted by success and falling costs, however, widespread use of clinical WES may interfere with clinical judgment.…”