Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

Abstract

An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole‐exome sequencing (WES), are identifying the genetic basis of disease for 25–40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation‐wide effort to identify mutations for childhood‐onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.

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.…”

“…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. a Two costutility analyses, six cost-effectiveness analyses.…”

“…Seven of these studies investigated WES; 5,6,[8][9][10]46,47 the eighth evaluated WGS. 48 Four publications used the traditional care pathway in the investigated condition as a comparator.…”

“…3 Given this, several studies have investigated the benefits arising from the application of WES and WGS in the clinic. These studies have primarily focused on intellectual learning disability 4 or Mendelian conditions more broadly, 3,[5][6][7][8][9] consistently reporting diagnostic yields between 25 and 30%. In addition, WES and WGS have often informed prognoses or treatment of patients, for example in inflammatory bowel disease 10 and epilepsies.…”

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.…”