Nanopore long-read sequencing for the critically ill facilitates ultrarapid diagnostics and urgent clinical decision making.
Smits DJ, Ferraro F, Drost M, van der Linde HC, de Graaf BM, van Bever Y, Brooks AS, Bardina L, Brüggenwirth HT, Debuy C, Donker Kaat L, van Dijk BT, van Engelen N, Geeven G, van de Graaf R, van Haaften-Visser DY, van Hasselt PM, Heijsman D, Hendriks YMC, Hitti-Malin RJ, Hoefsloot LH, Huijbregts G, IJspeert H, Lamballais S, Mijalkovic J, Mol MO, Nawawi D, Nederpelt N, Nibbeling EAR, Te Rijdt W, Schot R, van Slegtenhorst M, Sleutels F, Ulenkate ELM, Van Veghel-Plandsoen M, Verhagen JMA, Vos D, Wauters E, Wilke M, Sylva M, Barakat TS, van Ham TJ, Kleefstra T, Rots D, Verhoeven VJM
European journal of human genetics : EJHG, 2025 Oct 20
Abstract
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.