• Bingbing Wu, Wenqing Kang, Yingyuan Wang, Deyi Zhuang, Liping Chen, Long Li, Yajie Su, Xinnian Pan, Qiufen Wei, Zezhong Tang, Yangfang Li, Jin Gao, Rui Cheng, Wei Zhou, Zhangxing Wang, Gang Qiu, Jian Wang, Lin Yang, Ping Zhang, Xuemei Zhao, Yao Wang, Mingyu Gan, Gang Li, Renchao Liu, Qi Ni, Feifan Xiao, Kai Yan, Yun Cao, Guoping Lu, Yulan Lu, Huijun Wang, and Wenhao Zhou.
• Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, China.
• Crit. Care Med. 2021 Oct 1; 49 (10): 1674-1683.

ObjectivesTo determine the diagnostic and clinical utility of trio-rapid genome sequencing in critically ill infants.DesignIn this prospective study, samples from critically ill infants were analyzed using both proband-only clinical exome sequencing and trio-rapid genome sequencing (proband and biological parents). The study occurred between April 2019 and December 2019.SettingThirteen member hospitals of the China Neonatal Genomes Project spanning 10 provinces were involved.ParticipantsCritically ill infants (n = 202), from birth up until 13 months of life were enrolled based on eligibility criteria (e.g., CNS anomaly, complex congenital heart disease, evidence of metabolic disease, recurrent severe infection, suspected immune deficiency, and multiple malformations).InterventionsNone.Measurements And Main ResultsOf the 202 participants, neuromuscular (45%), respiratory (22%), and immunologic/infectious (18%) were the most commonly observed phenotypes. The diagnostic yield of trio-rapid genome sequencing was higher than that of proband-only clinical exome sequencing (36.6% [95% CI, 30.1-43.7%] vs 20.3% [95% CI, 15.1-26.6%], respectively; p = 0.0004), and the average turnaround time for trio-rapid genome sequencing (median: 7 d) was faster than that of proband-only clinical exome sequencing (median: 20 d) (p < 2.2 × 10-16). The metagenomic analysis identified pathogenic or likely pathogenic microbes in six infants with symptoms of sepsis, and these results guided the antibiotic treatment strategy. Sixteen infants (21.6%) experienced a change in clinical management following trio-rapid genome sequencing diagnosis, and 24 infants (32.4%) were referred to a new subspecialist.ConclusionsTrio-rapid genome sequencing provided higher diagnostic yield in a shorter period of time in this cohort of critically ill infants compared with proband-only clinical exome sequencing. Precise and fast molecular diagnosis can alter medical management and positively impact patient outcomes.Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.

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