Implementation of novel genetic diagnostic tests is generally driven by technological advances because they promise shorter turnaround times and/or higher diagnostic yields. Other aspects, including impact on clinical management or cost-effectiveness, are often not assessed in detail prior to implementation.
We studied the clinical utility of whole-exome sequencing (WES) in complex pediatric neurology in terms of diagnostic yield and costs. We analyzed 150 patients (and their parents) presenting with complex neurological disorders of suspected genetic origin. In a parallel study, all patients received both the standard diagnostic workup (e.g., cerebral imaging, muscle biopsies or lumbar punctures, and sequential gene-by-gene–based testing) and WES simultaneously.
Our unique study design allowed direct comparison of diagnostic yield of both trajectories and provided insight into the economic implications of implementing WES in this diagnostic trajectory. We showed that WES identified significantly more conclusive diagnoses (29.3%) than the standard care pathway (7.3%) without incurring higher costs. Exploratory analysis of WES as a first-tier diagnostic test indicates that WES may even be cost-saving, depending on the extent of other tests being omitted.
Our data support such a use of WES in pediatric neurology for disorders of presumed genetic origin.
Genet Med advance online publication 23 March 2017
diagnostic yield; health-care resource use; Prospective Clinical Utility Study; pediatric neurology; whole-exome sequencing
- The National Institutes of Health Undiagnosed Diseases Program: insights into rare diseases. Genet Med 2012;14:51–59. , , , et al.
- The diagnostic pathway in complex paediatric neurology: a cost analysis. Eur J Paediatr Neurol 2015;19:233–239. , , , et al.
- The economic cost of brain disorders in Europe. Eur J Neurol 2012;19:155–162. , , , , ; .
- Exome sequencing: a transformative technology. Lancet Neurol 2011;10:942–946.
- Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol 2010;9:885–894.
- Clinical whole exome sequencing in child neurology practice. Ann Neurol 2014;76:473–483. , , , et al.
- Whole exome sequencing in pediatric neurology patients: clinical implications and estimated cost analysis. J Child Neurol 2016;31:887–894. ,
- Use of next-generation sequencing as a diagnostic tool for congenital myasthenic syndrome. Pediatr Neurol 2014;51:717–720. , ,
- The usefulness of whole-exome sequencing in routine clinical practice. Genet Med 2014;16:922–931. , , , et al.
- Outcome of whole exome sequencing for diagnostic Odyssey cases of an individualized medicine clinic: The Mayo Clinic Experience. Mayo Clin Proc 2016;91: 297–307. , , , et al.
- Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–424. , , , et al.; .
- Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012;367:1921–1929. , , , et al.
- Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders. Genet Med 2016; e-pub ahead of print 27 October 2016. , , , et al.
- https://www.radboudumc.nl/Informatievoorverwijzers/Genoomdiagnostiek/en/Pages/Exomesequencing.aspx. . Radboudumc, Human Genetics.
- Pulling cost-effectiveness analysis up by its bootstraps: a non-parametric approach to confidence interval estimation. Health Econ 1997;6:327–340. , ,
- A post-hoc comparison of the utility of sanger sequencing and exome sequencing for the diagnosis of heterogeneous diseases. Hum Mutat 2013;34:1721–1726. , , , et al.
- FORGE Canada Consortium: outcomes of a 2-year national rare-disease gene-discovery project. Am J Hum Genet 2014;94:809–817. , , , et al.; .
- Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369:1502–1511. , , , et al.
- Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet 2012;380:1674–1682. , , , et al.
- An incomplete understanding of human genetic variation. Genetics 2016;202:1251–1254. ,
- Unlocking Mendelian disease using exome sequencing. Genome Biol 2011;12:228. , , ,
- Genetic studies in intellectual disability and related disorders. Nat Rev Genet 2016;17:9–18. , ,
- KDM6A point mutations cause Kabuki syndrome. Hum Mutat 2013;34:108–110. , , , et al.
- Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet 2014;46:1063–1071. , , , et al.
- De novo mutations in PDE10A cause childhood-onset chorea with bilateral striatal lesions. Am J Hum Genet 2016;98:763–771. , , , et al.
- Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med 2014;6:265ra168. , , , et al.
- Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med 2012;4:154ra135. , , , et al.
- Evaluating a counselling strategy for diagnostic WES in paediatric neurology: an exploration of parents’ information and communication needs. Clin Genet 2016;89:244–250. , , , et al.
- Understanding the psychosocial effects of WES test results on parents of children with rare diseases. J Genet Couns 2016;25:1207–1214. , , , et al.
- Patient experiences with gene panels based on exome sequencing in clinical diagnostics: high acceptance and low distress. Clin Genet 2015;87:319–326. , , , , ,
- ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 2013;15:565–574. , , , et al.; .
- ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med 2015;17: 68–9. .
- Societal preferences for the return of incidental findings from clinical genomic sequencing: a discrete-choice experiment. CMAJ 2015;187:E190–E197. , , , et al.
- Towards a European consensus for reporting incidental findings during clinical NGS testing. Eur J Hum Genet 2015;23:1601–1606. , , , et al.
- Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014;312:1870–1879. , , , et al.
- Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am J Hum Genet 2013;93:631–640. , , , et al.; .
- Feedback of individual genetic results to research participants: in favor of a qualified disclosure policy. Hum Mutat 2011;32:861–867. , ,
- Focus group discussions on secondary variants and next-generation sequencing technologies. Eur J Med Genet 2015;58:249–257. , , ,