Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders

Abstract

Neurodevelopmental disorders (NDDs) affect more than 3% of children and are attributable to single-gene mutations at more than 1000 loci. Traditional methods yield molecular diagnoses in less than one-half of children with NDD. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) can enable diagnosis of NDD, but their clinical and cost-effectiveness are unknown. One hundred families with 119 children affected by NDD received diagnostic WGS and/or WES of parent-child trios, wherein the sequencing approach was guided by acuity of illness. Forty-five percent received molecular diagnoses. An accelerated sequencing modality, rapid WGS, yielded diagnoses in 73% of families with acutely ill children (11 of 15). Forty percent of families with children with nonacute NDD, followed in ambulatory care clinics (34 of 85), received diagnoses: 33 by WES and 1 by staged WES then WGS. The cost of prior negative tests in the nonacute patients was $19,100 per family, suggesting sequencing to be cost-effective at up to $7640 per family. A change in clinical care or impression of the pathophysiology was reported in 49% of newly diagnosed families. If WES or WGS had been performed at symptom onset, genomic diagnoses may have been made 77 months earlier than occurred in this study. It is suggested that initial diagnostic evaluation of children with NDD should include trio WGS or WES, with extension of accelerated sequencing modalities to high-acuity patients.

Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability

“…32 High prices for additional diagnoses were also reported by Shashi et al 33 to be $25,000 per diagnosis if no diagnosis was obtained after a first visit. Soden et al 34 recently estimated that negative diagnostic tests for a group of neurodevelopmental disorder patients cost $19,100. In our study, patient 10 thus far has accrued a total of $47,841 in costs and still requires a diagnosis.…”

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

“…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.…”

“…Soden et al 29 estimated that WES would be cost-effective in pediatric neurodevelopmental disorders, compared with existing nongenomic investigative approaches (including laboratory tests, radiologic procedures, and electromyograms) on a cost-per-diagnosis basis if the cost of WES was no more than £2,123 ($3,063) per individual.…”

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

“…1 DES offers a cost-effective and comprehensive method to detect underlying alterations in presumed genetic disorders and may significantly shorten the so-called diagnostic odyssey that many patients with rare disorders experience, resulting in a faster time to diagnosis and overall reduction in health-care costs. 2,3 In a 2012 policy statement, the American College of Medical Genetics and Genomics endorsed the use of genomic sequencing technologies in clinical practice for patients with suspected genetic disorders when (i) the patient presents with a phenotype that is inconsistent with currently testable syndromes, (ii) the patient presents with a phenotype that is consistent with a disorder with many genetic causes, or (iii) no cause has been discovered despite extensive testing. 4 Although the overall diagnostic yield from smaller selected patient cohorts varies widely in neurodevelopmental disorders, data from large unselected laboratory cohorts estimate that the overall diagnostic yield of DES ranges from 25 to 37% (refs.…”

“…This is in line with a reported diagnostic yield of 27-45% for patients with a broad spectrum of neurodevelopmental disorders. 3,8,9 However, initial studies also demonstrate that the diagnostic yield of DES may depend on the particular patient phenotype. [10][11][12] Seizures are a common comorbidity of many known Mendelian disorders, and many epilepsy syndromes have a strong genetic component.…”