TY - JOUR
T1 - Rapid exome sequencing as a first-tier test in neonates with suspected genetic disorder
T2 - results of a prospective multicenter clinical utility study in the Netherlands
AU - Olde Keizer, Richelle A C M
AU - Marouane, Abderrahim
AU - Kerstjens-Frederikse, Wilhelmina S
AU - Deden, A Chantal
AU - Lichtenbelt, Klaske D
AU - Jonckers, Tinneke
AU - Vervoorn, Marieke
AU - Vreeburg, Maaike
AU - Henneman, Lidewij
AU - de Vries, Linda S
AU - Sinke, Richard J
AU - Pfundt, Rolph
AU - Stevens, Servi J C
AU - Andriessen, Peter
AU - van Lingen, Richard A
AU - Nelen, Marcel
AU - Scheffer, Hans
AU - Stemkens, Daphne
AU - Oosterwijk, Cor
AU - van Amstel, Hans Kristian Ploos
AU - de Boode, Willem P
AU - van Zelst-Stams, Wendy A G
AU - Frederix, Geert W J
AU - Vissers, Lisenka E L M
N1 - Funding Information:
The authors would like to thank all families who participated to this research. Radicon-NL Consortium Authorlist: L Henneman1,2, MM van Haelst1,2, EA Sistermans1,2, MC Cornel1,2,3, M Misra-Isrie1, MMAM Mannens2,4, Q Waisfisz1, JM van Hagen4, AS Brooks5, TS Barakat6, EH Hoefsloot6, RA van Lingen7, CAL Ruivenkamp8, A van Haeringen8, S Koene8, GWE Santen8, JW Rutten9, B de Koning10, SJC Stevens10,11, A van den Wijngaard10,11, M Sinnema10,11, APA Stegmann10,11, M Vreeburg10, M Vervoorn12, P Andriessen12,13, D Kasteel14, EM Adang15, AC Deden16, 17, HG Brunner10, 11, 16, 17, WP de Boode18, 19, HG Yntema16, H Scheffer16,19, W van Zelst-Stams16,19, R Pfundt16, T Kleefstra16,17, A Marouane16,17, LELM Vissers16,17, T Rigter3,20, W Rodenburg20, MA Swertz21, VVAM Knoers21, WS Kerstjens-Frederikse21, RJ Sinke21, KJ van der Velde21, IM van Langen21, ME van Gijn21, JP van Tintelen22, LS de Vries23, GWJ Frederix22,24, JK Ploos van Amstel22, KD Lichtenbelt22, RACM Olde Keizer16,17,22,24, R Oegema22, C Oosterwijk25, D Stemkens25. 1. Department of Human Genetics, Amsterdam UMC, Location Vrije Universiteit Amsterdam, The Netherlands; 2. Amsterdam Reproduction & Development, Amsterdam, The Netherlands; 3. Amsterdam Public Health research institute, personalized medicine program, Amsterdam, The Netherlands; 4. Department of Human Genetics, Amsterdam UMC, location University of Amsterdam, The Netherlands; 5. Department of Clinical Genetics, Erasmus University Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands; 6. Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands; 7. Department of Neonatology, Isala Women and Children's Hospital, Zwolle, The Netherlands; 8. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands; 9. Department Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; 10. Department of Clinical Genetics, Maastricht University Medical Center+ (MUMC+), Maastricht, The Netherlands; 11. Research School for Developmental Biology (GROW), Maastricht University, Maastricht, The Netherlands; 12. Department of Neonatology, Máxima Medical Center, Veldhoven, The Netherlands; 13. Department of Applied Physics, School of Medical Physics and Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands; 14. Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; 15. Department of Health Evidence, Radboudumc Technology Center for Health Economics Nijmegen, The Netherlands; 16. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands; 17. Donders Institute for Brain Cognition and Behaviour, 6500 HB Nijmegen, The Netherlands; 18. Department of Neonatology, Radboud University Medical Center, Nijmegen, The Netherlands; 19. Radboud Institute for Health Sciences, Amalia Children's Hospital, Nijmegen, Netherlands; 20. Centre for Health Protection, National Institute for Public Health and the Environment, Bilthoven, The Netherlands; 21. Department of Genetics, University of Groningen, the Netherlands, University Medical Center, Groningen, the Netherlands; 22. Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands; 23. Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands; 24. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; 25. VSOP - National Patient Alliance for Rare and Genetic Diseases, Soest, The Netherlands.
Funding Information:
The aims of this study contribute to the Solve-RD project (to L. E. L. M. Vissers) which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 779257. This study is financially supported by grants from the Netherlands Organisation for Health Research and Development (ZonMw; 843002608, 846002003 to HKPvA, HS, LV, WvZ, GF, WdB, RS, PA, and RvL).
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10–20) vs. 59 days (95% CI 23–98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). Conclusion: Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin.What is Known:• Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used.• Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing.What is New:• This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests.• Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.
AB - The introduction of rapid exome sequencing (rES) for critically ill neonates admitted to the neonatal intensive care unit has made it possible to impact clinical decision-making. Unbiased prospective studies to quantify the impact of rES over routine genetic testing are, however, scarce. We performed a clinical utility study to compare rES to conventional genetic diagnostic workup for critically ill neonates with suspected genetic disorders. In a multicenter prospective parallel cohort study involving five Dutch NICUs, we performed rES in parallel to routine genetic testing for 60 neonates with a suspected genetic disorder and monitored diagnostic yield and the time to diagnosis. To assess the economic impact of rES, healthcare resource use was collected for all neonates. rES detected more conclusive genetic diagnoses than routine genetic testing (20% vs. 10%, respectively), in a significantly shorter time to diagnosis (15 days (95% CI 10–20) vs. 59 days (95% CI 23–98, p < 0.001)). Moreover, rES reduced genetic diagnostic costs by 1.5% (€85 per neonate). Conclusion: Our findings demonstrate the clinical utility of rES for critically ill neonates based on increased diagnostic yield, shorter time to diagnosis, and net healthcare savings. Our observations warrant the widespread implementation of rES as first-tier genetic test in critically ill neonates with disorders of suspected genetic origin.What is Known:• Rapid exome sequencing (rES) enables diagnosing rare genetic disorders in a fast and reliable manner, but retrospective studies with neonates admitted to the neonatal intensive care unit (NICU) indicated that genetic disorders are likely underdiagnosed as rES is not routinely used.• Scenario modeling for implementation of rES for neonates with presumed genetic disorders indicated an expected increase in costs associated with genetic testing.What is New:• This unique prospective national clinical utility study of rES in a NICU setting shows that rES obtained more and faster diagnoses than conventional genetic tests.• Implementation of rES as replacement for all other genetic tests does not increase healthcare costs but in fact leads to a reduction in healthcare costs.
KW - Clinical utility
KW - Diagnostic workflow
KW - Economic evaluation
KW - Neonates
KW - Rapid exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85151442453&partnerID=8YFLogxK
U2 - 10.1007/s00431-023-04909-1
DO - 10.1007/s00431-023-04909-1
M3 - Article
C2 - 36997769
SN - 0340-6199
VL - 182
SP - 2683
EP - 2692
JO - European Journal of Pediatrics
JF - European Journal of Pediatrics
IS - 6
ER -