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Smits, D.J.; Ferraro, F.; Drost, M.; Linde, H.C. van der; Graaf, B.M. de; Bever, Y. van; ... ; Verhoeven, V.J.M. (2025)

Nanopore long-read sequencing for the critically ill facilitates ultrarapid diagnostics and urgent clinical decision making

Article / Letter to editor
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...Show moreCritically 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.Show less
All authors
Smits, D.J.; Ferraro, F.; Drost, M.; Linde, H.C. van der; Graaf, B.M. de; Bever, Y. van; Brooks, A.S.; Bardina, L.; Brüggenwirth, H.T.; Debuy, C.; Kaat, L.D.; Dijk, B.T. van; Engelen, N. van; Geeven, G.; Graaf, R. van de; Haaften-Visser, D.Y. van; Hasselt, P.M. van; Heijsman, D.; Hendriks, Y.M.C.; Hitti-Malin, R.J.; Hoefsloot, L.H.; Huijbregts, G.; Ijspeert, H.; Lamballais, S.; Mijalkovic, J.; Mol, M.O.; Nawawi, D.; Nederpelt, N.; Nibbeling, E.A.R.; Rijdt, W. te; Schot, R.; Slegtenhorst, M. van; Sleutels, F.; Ulenkate, E.L.M.; Plandsoen, M.; Verhagen, J.M.A.; Vos, D.; Wauters, E.; Wilke, M.; Sylva, M.; Barakat, T.S.; Ham, T.J. van; Kleefstra, T.; Rots, D.; Verhoeven, V.J.M.
Date
2025-10-20
Journal
European Journal of Human Genetics
Volume
34
Pages
108 - 118
DOI
doi:10.1038/s41431-025-01959-x