Abstract
Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS.
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Data availability
The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
We thank the families for taking part in the study, the CNRGH (Évry) for genome sequencing, the CCuB for technical support and management of the computing platform, and GeneMatcher for data sharing. Several authors are members of the ERN ITHACA. We acknowledge Suzan Rankin, Cyrille Chopelet and Jérémie Roquet for proofreading the manuscript.
Funding
This work was supported by grants from the Dijon Bourgogne University Hospital, the Regional Council of Bourgogne Franche-Comté, the Sanofi Genzyme laboratory and the European Union through the FEDER programs. This work was supported by the France Génomique National infrastructure, funded as part of the “Investissements d’Avenir” program managed by the Agence Nationale pour la Recherche (ANR-10-INBS-09). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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ASDP: data collection, data production, data analysis, manuscript writing, study coordination. AV/FTMT/ALB/PC/CP data analysis. RO data production, study conception. JFD study conception. AZ/MJ/TB/CF/AT/AS data collection, manuscript editing. BI/JD/SN/MG/MN/MV/SM/MF/AL/PR/YC/JVG/SS/LP/MB/CP/DB/CC data collection. CR data collection, data analysis, manuscript editing. AG/AP/AJ data collection, data analysis. RO/VC/CP/TJ/BF/DBD/CB/PG/ET data production. AB data production, manuscript editing. YD data production, manuscript editing, study conception. LF/CTR data collection, manuscript writing, study conception, study coordination.
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This study was approved by the appropriate French ethics committee (2016-A01347-44).
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Denommé-Pichon, AS., Vitobello, A., Olaso, R. et al. Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network. Eur J Hum Genet 30, 567–576 (2022). https://doi.org/10.1038/s41431-021-00998-4
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DOI: https://doi.org/10.1038/s41431-021-00998-4
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