A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.
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.
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
Lisenka E L M
0000-0001-6470-5497
LELM
Vissers
Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Kirsten J M
KJM
van Nimwegen
Department of Pediatric Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
Jolanda H
0000-0003-1605-0128
JH
Schieving
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
Erik-Jan
EJ
Kamsteeg
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
Tjitske
T
Kleefstra
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
Helger G
HG
Yntema
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
Rolph
R
Pfundt
Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Gert Jan
GJ
van der Wilt
Department of IQ Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands.|Institute for Science, Innovation and Society, Radboud University, Nijmegen, The Netherlands.
Lotte
0000-0002-5856-762X
L
Krabbenborg
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
Han G
HG
Brunner
Department of IQ Healthcare, Radboud University Medical Center, Nijmegen, The Netherlands.
Simone
0000-0002-6733-6305
S
van der Burg
Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
Janneke
J
Grutters
Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Clinical Genetics, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
Joris A
0000-0002-3218-8250
JA
Veltman
Department of Pediatric Neurology, Radboud University Medical Center, Nijmegen, The Netherlands.
Michèl A A P
MAAP
Willemsen
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003362:Cost-Benefit Analysis; D005260:Female; D005820:Genetic Testing / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D007223:Infant; D008297:Male; D009462:Neurology / Q000379:methods* / Q000706:statistics & numerical data*; D010342:Patient Acceptance of Health Care / Q000706:statistics & numerical data*; D010372:Pediatrics / Q000379:methods* / Q000706:statistics & numerical data*; D059039:Standard of Care / Q000191:economics / Q000592:standards / Q000706:statistics & numerical data; D000073359:Exome Sequencing / Q000379:methods / Q000706:statistics & numerical data