Application of Full-Spectrum Rapid Clinical Genome Sequencing Improves Diagnostic Rate and Clinical Outcomes in Critically Ill Infants in the China Neonatal Genomes Project

Bingbing Wu^{1

2}, Wenqing Kang³, Yingyuan Wang³, Deyi Zhuang⁴, Liping Chen⁵, Long Li⁶, Yajie Su⁶, Xinnian Pan⁷, Qiufen Wei⁷, Zezhong Tang⁸, Yangfang Li⁹, Jin Gao⁹, Rui Cheng¹⁰, Wei Zhou¹¹, Zhangxing Wang¹², Gang Qiu¹³, Jian Wang¹⁴, Lin Yang¹, Ping Zhang¹, Xuemei Zhao¹, Yao Wang¹, Mingyu Gan¹, Gang Li¹, Renchao Liu¹, Qi Ni¹, Feifan Xiao¹, Kai Yan¹⁵, Yun Cao^{2

15}, Guoping Lu¹⁶, Yulan Lu¹, Huijun Wang¹, Wenhao Zhou^{1

2

15}

Affiliations

¹ Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, China.
² Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China.
³ Department of Neonatology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
⁴ Department of Pediatrics, Xiamen Children's Hospital, Xiamen, China.
⁵ Department of Neonatology, Jiangxi Provincial Children's Hospital, Nanchang, China.
⁶ Department of Neonatology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
⁷ Department of Neonatology, Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
⁸ Department of Pediatrics, Peking University First Hospital, Beijing, China.
⁹ Department of Neonatology, Kunming Children's Hospital, Kunming, China.
¹⁰ Department of Neonatal Center, Children's Hospital of Nanjing Medical University, Nanjing, China.
¹¹ Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
¹² Department of Neonatology, Shenzhen Longhua People's Hospital, Guangdong, China.
¹³ Department of Neonatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
¹⁴ Department of Genetics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹⁵ Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
¹⁶ Pediatric intensive care unit, Children's Hospital of Fudan University, Shanghai, China.

PMID: 33935161
DOI: 10.1097/CCM.0000000000005052

Application of Full-Spectrum Rapid Clinical Genome Sequencing Improves Diagnostic Rate and Clinical Outcomes in Critically Ill Infants in the China Neonatal Genomes Project

Bingbing Wu et al. Crit Care Med. 2021.

. 2021 Oct 1;49(10):1674-1683.

doi: 10.1097/CCM.0000000000005052.

Authors

Affiliations

¹ Center for Molecular Medicine, Children's Hospital of Fudan University, Shanghai, China.
² Key Laboratory of Neonatal Diseases, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China.
³ Department of Neonatology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
⁴ Department of Pediatrics, Xiamen Children's Hospital, Xiamen, China.
⁵ Department of Neonatology, Jiangxi Provincial Children's Hospital, Nanchang, China.
⁶ Department of Neonatology, People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
⁷ Department of Neonatology, Maternal and Child Health Care Hospital of Guangxi Zhuang Autonomous Region, Nanning, China.
⁸ Department of Pediatrics, Peking University First Hospital, Beijing, China.
⁹ Department of Neonatology, Kunming Children's Hospital, Kunming, China.
¹⁰ Department of Neonatal Center, Children's Hospital of Nanjing Medical University, Nanjing, China.
¹¹ Department of Neonatology, Guangzhou Women and Children's Medical Center, Guangzhou, China.
¹² Department of Neonatology, Shenzhen Longhua People's Hospital, Guangdong, China.
¹³ Department of Neonatology, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai, China.
¹⁴ Department of Genetics, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai, China.
¹⁵ Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
¹⁶ Pediatric intensive care unit, Children's Hospital of Fudan University, Shanghai, China.

PMID: 33935161
DOI: 10.1097/CCM.0000000000005052

Abstract

Objectives: To determine the diagnostic and clinical utility of trio-rapid genome sequencing in critically ill infants.

Design: In 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.

Setting: Thirteen member hospitals of the China Neonatal Genomes Project spanning 10 provinces were involved.

Participants: Critically 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).

Interventions: None.

Measurements and main results: Of 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.

Conclusions: Trio-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.

PubMed Disclaimer

Conflict of interest statement

The authors have disclosed that they do not have any potential conflicts of interest.

Comment in

Whole Genome Sequencing as a First-Line Clinical Test: Almost Ready for Prime Time.
Dahmer MK. Dahmer MK. Crit Care Med. 2021 Oct 1;49(10):1815-1817. doi: 10.1097/CCM.0000000000005077. Crit Care Med. 2021. PMID: 34529612 No abstract available.

References

1. Wojcik MH, Schwartz TS, Yamin I, et al.: Genetic disorders and mortality in infancy and early childhood: Delayed diagnoses and missed opportunities. Genet Med. 2018; 20:1396–1404
1. Smith LD, Willig LK, Kingsmore SF: Whole-exome sequencing and whole-genome sequencing in critically ill neonates suspected to have single-gene disorders. Cold Spring Harb Perspect Med. 2015; 6:a023168
1. Willig LK, Petrikin JE, Smith LD, et al.: Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: A retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015; 3:377–387
1. Lionel AC, Costain G, Monfared N, et al.: Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2018; 20:435–443
1. Wang H, Lu Y, Dong X, et al.: Optimized trio genome sequencing (OTGS) as a first-tier genetic test in critically ill infants: Practice in China. Hum Genet. 2020; 139:473–482

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

LinkOut - more resources

Full Text Sources
Other Literature Sources
- scite Smart Citations
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Application of Full-Spectrum Rapid Clinical Genome Sequencing Improves Diagnostic Rate and Clinical Outcomes in Critically Ill Infants in the China Neonatal Genomes Project

Affiliations

Application of Full-Spectrum Rapid Clinical Genome Sequencing Improves Diagnostic Rate and Clinical Outcomes in Critically Ill Infants in the China Neonatal Genomes Project

Authors

Affiliations

Abstract

Conflict of interest statement

Comment in

References

MeSH terms

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous