Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions

Abstract

IMPORTANCE Optimal use of whole-exome sequencing (WES) in the pediatric setting requires an understanding of who should be considered for testing and when it should be performed to maximize clinical utility and cost-effectiveness.OBJECTIVES To investigate the impact of WES in sequencing-naive children suspected of having a monogenic disorder and evaluate its cost-effectiveness if WES had been available at different time points in their diagnostic trajectory. DESIGN, SETTING, AND PARTICIPANTS This prospective study was part of the MelbourneGenomics Health Alliance demonstration project. At the ambulatory outpatient clinics of the Victorian Clinical Genetics Services at the Royal Children's Hospital, Melbourne, Australia, children older than 2 years suspected of having a monogenic disorder were prospectively recruited from May 1 through November 30, 2015, by clinical geneticists after referral from general and subspecialist pediatricians. All children had nondiagnostic microarrays and no prior single-gene or panel sequencing.EXPOSURES All children underwent singleton WES with targeted phenotype-driven analysis. MAIN OUTCOMES AND MEASURESThe study examined the clinical utility of a molecular diagnosis and the cost-effectiveness of alternative diagnostic trajectories, depending on timing of WES. RESULTSOf 61 children originally assessed, 44 (21 [48%] male and 23 [52%] female) aged 2 to 18 years (mean age at initial presentation, 28 months; range, 0-121 months) were recruited, and a diagnosis was achieved in 23 (52%) by singleton WES. The diagnoses were unexpected in 8 of 23 (35%), and clinical management was altered in 6 of 23 (26%). The mean duration of the diagnostic odyssey was 6 years, with each child having a mean of 19 tests and 4 clinical genetics and 4 nongenetics specialist consultations, and 26 (59%) underwent a procedure while under general anesthetic for diagnostic purposes. Economic analyses of the diagnostic trajectory identified that WES performed at initial tertiary presentation resulted in an

Yield of whole exome sequencing in undiagnosed patients facing insurance coverage barriers to genetic testing

“…Further complicating the development of nuanced and appropriate policies on coverage for WES is the lack of data regarding its cost‐effectiveness. Existing data support the use of WES in patients with suspected genetic disorders early in the diagnostic process in order to shorten the diagnostic odyssey and improve efficiency of evaluations, especially in patients with neurologic conditions (Stark et al, ; Tan et al, ; Vissers et al, ; Walsh et al, ). However, such literature on WES utilization lacks clear presentation of cost data, is limited by small cohort sizes, and use outcome measures that are difficult to translate into health economic policy (Schwarze, Buchanan, Taylor, & Wordsworth, ).…”

Contribution of next generation sequencing in pediatric practice in Lebanon. A Study on 213 cases

“…The higher diagnostic rate for panels was expected, since panels were ordered mainly in the cases where the clinician was relatively more confident about characterizing the underlying genetic condition. Recent studies have noted higher diagnostic yields from WES in pediatric cohorts with suspected monogenic disorders (Charng et al, ; Dillon et al, ; Tan et al, ). This could be due to the fact that physicians in Lebanon tend to order WES analysis only for complex cases, and rarely when they have a relatively strong clinical suspicion to help them along.…”

What do parents expect from a genetic diagnosis of their child with intellectual disability?

“…Also, management and surveillance recommendations are now available for a growing number of genetic disorders, such as early onset of low‐vision training and monitoring of weight gain in patients with Cohen syndrome who are at risk of blindness and obesity (Dikow, Karch, Rohrschneider, & Moog, ). Clinical implications following an aetiologic genetic diagnosis have been reported in 26%–78% of cases (Evers et al, ; Meng et al, ; Tan et al, ). In this context, the clinician has to be aware that although these treatments may improve the patient's medical condition and the family's QoL, they do not cure ID/DD in the vast majority of cases.…”