Nanopore long-read sequencing for the critically ill facilitates ultrarapid diagnostics and urgent clinical decision making
Critically ill pediatric patients often have genetic disorders requiring a rapid diagnosis to guide urgent care decisions. Standard genetic testing typically takes weeks and requires multiple tests. Nanopore long-read genome sequencing (LR-GS) delivers genome-wide results within days as a one-test-fits-all solution. As one of the first centers in Europe, we implement ultrarapid LR-GS for critically ill patients. We enrolled 26 critically ill patients (median age 2 months) suspected of having a genetic disorder at the intensive care unit to perform (ultra)rapid nanopore LR-GS alongside standard genomic care. We compared diagnostic yield, turnaround time (TAT), and evaluated the impact on clinical decision making. In 11/26 cases a genetic diagnosis was made with (ultra)rapid LR-GS. From sample receipt to result, the average TAT was 5.3 days (range 2.0-10.8) for LR-GS and 18.4 days (range 6.1-29.1) for standard genomic care. DNA methylation analysis from LR-GS expedited the diagnosis in 3/26 cases. In 7/11 solved cases ultrarapid LR-GS led to immediate adjustments in patient care, e.g., medication switch or termination of treatment. Our findings underscore the clinical impact of ultrarapid LR-GS, including added value of methylation analysis, for critically ill patients and highlight existing challenges, paving the way to ultrarapid LR-GS integration into standard diagnostics.
Authors
- Yolande van Bever (ORCID: https://orcid.org/0000-0003-2002-9145)
- Désirée Y. van Haaften–Visser (ORCID: https://orcid.org/0000-0002-5598-8840)
- Judith M.A. Verhagen (ORCID: https://orcid.org/0000-0002-0340-3433)
- Federico Ferraro (ORCID: https://orcid.org/0000-0003-1365-2529)
- Marc Sylva (ORCID: https://orcid.org/0000-0002-2315-5908)
- Wouter P. te Rijdt (ORCID: https://orcid.org/0000-0003-4852-9379)
- Tjakko J. van Ham (ORCID: https://orcid.org/0000-0002-2175-8713)
- Bianca M. de Graaf (ORCID: https://orcid.org/0000-0002-9564-0283)
- Nienke van Engelen (ORCID: https://orcid.org/0000-0002-2012-0611)
- Rachel Schot (ORCID: https://orcid.org/0000-0001-9578-4095)
- Dmitrijs Rots (ORCID: https://orcid.org/0000-0002-4890-9147)
- Laura Donker Kaat (ORCID: https://orcid.org/0009-0007-2436-0931)
- Virginie J. M. Verhoeven (ORCID: https://orcid.org/0000-0001-7359-7862)
- Bastiaan T van Dijk (ORCID: https://orcid.org/0000-0002-5161-6791)
- Esther Nibbeling (ORCID: https://orcid.org/0000-0001-8818-3232)
- Merel O. Mol (ORCID: https://orcid.org/0000-0003-2533-2530)
- Tahsin Stefan Barakat (ORCID: https://orcid.org/0000-0003-1231-1562)
- Rebekkah J. Hitti‐Malin (ORCID: https://orcid.org/0000-0002-7873-2880)
- Martina Wilke (ORCID: https://orcid.org/0000-0002-8115-8517)
- Daphne Heijsman
- Marjon van Slegtenhorst
- Sander Lamballais (ORCID: https://orcid.org/0000-0003-3118-6330)
- Hennie T. Brüggenwirth (ORCID: https://orcid.org/0000-0003-4303-8896)
- Raoul van de Graaf
- Peter M. van Hasselt (ORCID: https://orcid.org/0000-0001-9821-8398)
- Mark Drost
- Hanna IJspeert (ORCID: https://orcid.org/0000-0002-7061-5321)
- Els Wauters (ORCID: https://orcid.org/0000-0002-0115-0030)
- Frank Sleutels (ORCID: https://orcid.org/0000-0001-6813-5209)
- Herma C. van der Linde (ORCID: https://orcid.org/0009-0003-1472-6355)
- Jona Mijalkovic
- Dagmar I. Vos (ORCID: https://orcid.org/0000-0003-4581-5396)
- Daphne J. Smits (ORCID: https://orcid.org/0000-0003-0526-4825)
- Yvonne Hendriks
- Tjitske Kleefstra (ORCID: https://orcid.org/0000-0002-0956-0237)
- Alice S. Brooks (ORCID: https://orcid.org/0000-0003-1830-0821)
- Lies H. Hoefsloot (ORCID: https://orcid.org/0009-0000-3444-9955)
- Geert Geeven (ORCID: https://orcid.org/0000-0002-5603-0095)
- Christophe Debuy
- Līvija Bārdiņa (ORCID: https://orcid.org/0000-0002-8211-9798)
- Glenn Huijbregts
- Diënna Nawawi
- Nadine Nederpelt
- Eva L. M. Ulenkate
- Monique Van Veghel – Plandsoen
Institutions
- Radboud University Nijmegen (NL)
- Utrecht University (NL)
- Leiden University Medical Center (NL)
- Erasmus MC (NL)
- Radboud University Medical Center (NL)
- Vincent Van Gogh Voor Geestelijke Gezondheidszorg (NL)
- Willem-Alexander Kinderziekenhuis (NL)
- Erasmus MC - Sophia Children’s Hospital (NL)
- Wilhelmina Children's Hospital (NL)
- Erasmus University Rotterdam (NL)
Publication Details
- Journal
- European Journal of Human Genetics
- Published
- 2025-10-20
- DOI
- https://doi.org/10.1038/s41431-025-01959-x
- Citations
- 3
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 5.45
Funders
- ZonMw
- Hospital for Sick Children