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

被引：39

作者：

Wu, Bingbing ^{[1
,2
]}

Kang, Wenqing ^{[3
]}

Wang, Yingyuan ^{[3
]}

Zhuang, Deyi ^{[4
]}

Chen, Liping ^{[5
]}

Li, Long ^{[6
]}

Su, Yajie ^{[6
]}

Pan, Xinnian ^{[7
]}

Wei, Qiufen ^{[7
]}

Tang, Zezhong ^{[8
]}

Li, Yangfang ^{[9
]}

Gao, Jin ^{[9
]}

Cheng, Rui ^{[10
]}

Zhou, Wei ^{[11
]}

Wang, Zhangxing ^{[12
]}

Qiu, Gang ^{[13
]}

Wang, Jian ^{[14
]}

Yang, Lin ^{[1
]}

Zhang, Ping ^{[1
]}

Zhao, Xuemei ^{[1
]}

Wang, Yao ^{[1
]}

Gan, Mingyu ^{[1
]}

Li, Gang ^{[1
]}

Liu, Renchao ^{[1
]}

Ni, Qi ^{[1
]}

Xiao, Feifan ^{[1
]}

Yan, Kai ^{[15
]}

Cao, Yun ^{[2
,15
]}

Lu, Guoping ^{[16
]}

Lu, Yulan ^{[1
]}

Wang, Huijun ^{[1
]}

Zhou, Wenhao ^{[1
,2
,15
]}

机构：

[1] Fudan Univ, Ctr Mol Med, Childrens Hosp, Shanghai, Peoples R China

[2] Fudan Univ, Key Lab Neonatal Dis, Minist Hlth, Childrens Hosp, Shanghai, Peoples R China

[3] Zhengzhou Univ, Dept Neonatol, Childrens Hosp, Zhengzhou, Peoples R China

[4] Xiamen Childrens Hosp, Dept Pediat, Xiamen, Peoples R China

[5] Jiangxi Prov Childrens Hosp, Dept Neonatol, Nanchang, Jiangxi, Peoples R China

[6] Peoples Hosp Xinjiang Uygur Autonomous Reg, Dept Neonatol, Urumqi, Peoples R China

[7] Maternal & Child Hlth Care Hosp Guangxi Zhuang Au, Dept Neonatol, Nanning, Peoples R China

[8] Peking Univ First Hosp, Dept Pediat, Beijing, Peoples R China

[9] Kunming Childrens Hosp, Dept Neonatol, Kunming, Yunnan, Peoples R China

[10] Nanjing Med Univ, Dept Neonatal Ctr, Childrens Hosp, Nanjing, Peoples R China

[11] Guangzhou Women & Childrens Med Ctr, Dept Neonatol, Guangzhou, Peoples R China

[12] Shenzhen Longhua Peoples Hosp, Dept Neonatol, Shenzhen, Guangdong, Peoples R China

[13] Shanghai Jiao Tong Univ, Shanghai Childrens Hosp, Dept Neonatol, Shanghai, Peoples R China

[14] Shanghai Jiao Tong Univ, Shanghai Childrens Med Ctr, Dept Genet, Sch Med, Shanghai, Peoples R China

[15] Fudan Univ, Dept Neonatol, Childrens Hosp, Shanghai, Peoples R China

[16] Fudan Univ, Pediat Intens Care Unit, Childrens Hosp, Shanghai, Peoples R China

来源：

CRITICAL CARE MEDICINE | 2021年 / 49卷 / 10期

关键词：

clinical outcomes; critically ill infants; diagnostic rate; genetic disease; proband-only clinical exome sequencing; trio-rapid genome sequencing; DISORDERS;

D O I：

10.1097/CCM.0000000000005052

中图分类号：

R4 [临床医学];

学科分类号：

1002 ; 100602 ;

摘要：

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 x 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.

引用

页码：1674 / 1683

页数：10

共 25 条

[1] Whole-genome sequencing offers additional but limited clinical utility compared with reanalysis of whole-exome sequencing [J].

Alfares, Ahmed ;

Aloraini, Taghrid ;

Al Subaie, Lamia ;

Alissa, Abdulelah ;

Al Qudsi, Ahmed ;

Alahmad, Ahmed ;

Al Mutairi, Fuad ;

Alswaid, Abdulrahman ;

Alothaim, Ali ;

Eyaid, Wafaa ;

Albalwi, Mohammed ;

Alturki, Saeed ;

Alfadhel, Majid .

GENETICS IN MEDICINE, 2018, 20 (11) :1328-1333

[2] ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions [J].

Dolzhenko, Egor ;

Deshpande, Viraj ;

Schlesinger, Felix ;

Krusche, Peter ;

Petrovski, Roman ;

Chen, Sai ;

Emig-Agius, Dorothea ;

Gross, Andrew ;

Narzisi, Giuseppe ;

Bowman, Brett ;

Scheffler, Konrad ;

van Vugt, Joke J. F. A. ;

French, Courtney ;

Sanchis-Juan, Alba ;

Ibanez, Kristina ;

Tucci, Arianna ;

Lajoie, Bryan R. ;

Veldink, Jan H. ;

Raymond, F. Lucy ;

Taft, Ryan J. ;

Bentley, David R. ;

Eberle, Michael A. .

BIOINFORMATICS, 2019, 35 (22) :4754-4756

[3] Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort [J].

Dong, Xinran ;

Liu, Bo ;

Yang, Lin ;

Wang, Huijun ;

Wu, Bingbing ;

Liu, Renchao ;

Chen, Hongbo ;

Chen, Xiang ;

Yu, Sha ;

Chen, Bin ;

Wang, Sujuan ;

Xu, Xiu ;

Zhou, Wenhao ;

Lu, Yulan .

JOURNAL OF MEDICAL GENETICS, 2020, 57 (08) :558-566

[4] Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization [J].

Farnaes, Lauge ;

Hildreth, Amber ;

Sweeney, Nathaly M. ;

Clark, Michelle M. ;

Chowdhury, Shimul ;

Nahas, Shareef ;

Cakici, Julie A. ;

Benson, Wendy ;

Kaplan, Robert H. ;

Kronick, Richard ;

Bainbridge, Matthew N. ;

Friedman, Jennifer ;

Gold, Jeffrey J. ;

Ding, Yan ;

Veeraraghavan, Narayanan ;

Dimmock, David ;

Kingsmore, Stephen F. .

NPJ GENOMIC MEDICINE, 2018, 3

[5] Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children [J].

French, Courtney E. ;

Delon, Isabelle ;

Dolling, Helen ;

Sanchis-Juan, Alba ;

Shamardina, Olga ;

Megy, Karyn ;

Abbs, Stephen ;

Austin, Topun ;

Bowdin, Sarah ;

Branco, Ricardo G. ;

Firth, Helen ;

Rowitch, David H. ;

Raymond, F. Lucy ;

Tuna, Salih ;

Aitman, Timothy J. ;

Ashford, Sofie ;

Astle, Willian J. ;

Bennet, David L. ;

Bleda, Marta ;

Carss, Keren J. ;

Chinnery, Patrick F. ;

Deevi, Sri V. V. ;

Fletcher, Debra ;

Gale, Daniel P. ;

Graf, Stefan F. ;

Hu, Fengyuan ;

James, Roger ;

Kasanicki, Mary A. ;

Kingston, Nathalie ;

Koziell, Ania B. ;

Allen, Hana Lango ;

Maher, Eamonn R. ;

Markus, Hugh S. ;

Meacham, Stuart ;

Morrell, Nicholas W. ;

Penkett, Christopher J. ;

Roberts, Irene ;

Sanchis-Juan, Alba ;

Smith, Kenneth G. C. ;

Stark, Hannah ;

Stirrups, Kathleen E. ;

Turro, Ernest ;

Watkins, Hugh ;

Williamson, Catherine ;

Young, Timothy ;

Bradley, John R. ;

Ouwehand, Willem H. ;

Raymond, F. Lucy ;

Agrawal, Shruti ;

Armstrong, Ruth .

INTENSIVE CARE MEDICINE, 2019, 45 (05) :627-636

[6] Relationship between phenotype and genotype of 102 Chinese newborns with Prader-Willi syndrome [J].

Ge, Meng-Meng ;

Gao, Yan-Yan ;

Wu, Bing-Bing ;

Yan, Kai ;

Qin, Qian ;

Wang, HuiJun ;

Zhou, WenHao ;

Yang, Lin .

MOLECULAR BIOLOGY REPORTS, 2019, 46 (05) :4717-4724

[7] Copy-number variants in clinical genome sequencing: deployment and interpretation for rare and undiagnosed disease [J].

Gross, Andrew M. ;

Ajay, Subramanian S. ;

Rajan, Vani ;

Brown, Carolyn ;

Bluske, Krista ;

Burns, Nicole J. ;

Chawla, Aditi ;

Coffey, Alison J. ;

Malhotra, Alka ;

Scocchia, Alicia ;

Thorpe, Erin ;

Dzidic, Natasa ;

Hovanes, Karine ;

Sahoo, Trilochan ;

Dolzhenko, Egor ;

Lajoie, Bryan ;

Khouzam, Amirah ;

Chowdhury, Shimul ;

Belmont, John ;

Roller, Eric ;

Ivakhno, Sergii ;

Tanner, Stephen ;

McEachern, Julia ;

Hambuch, Tina ;

Eberle, Michael ;

Hagelstrom, R. Tanner ;

Bentley, David R. ;

Perry, Denise L. ;

Taft, Ryan J. .

GENETICS IN MEDICINE, 2019, 21 (05) :1121-1130

[8] Clinical Metagenomic Next-Generation Sequencing for Pathogen Detection [J].

Gu, Wei ;

Miller, Steve ;

Chiu, Charles Y. .

ANNUAL REVIEW OF PATHOLOGY: MECHANISMS OF DISEASE, VOL 14, 2019, 14 :319-338

[9]

Hagen Cathrine Monrad, 2004, Pediatr Crit Care Med, V5, P463

[10] A Randomized, Controlled Trial of the Analytic and Diagnostic Performance of Singleton and Trio, Rapid Genome and Exome Sequencing in III Infants [J].

Kingsmore, Stephen F. ;

Cakici, Julie A. ;

Clark, Michelle M. ;

Gaughran, Mary ;

Feddock, Michele ;

Batalov, Sergey ;

Bainbridge, Matthew N. ;

Carroll, Jeanne ;

Caylor, Sara A. ;

Clarke, Christina ;

Ding, Yan ;

Ellsworth, Katarzyna ;

Farnaes, Lauge ;

Hildreth, Amber ;

Hobbs, Charlotte ;

James, Kiely ;

Kint, Cyrielle I. ;

Lenberg, Jerica ;

Nahas, Shareef ;

Prince, Lance ;

Reyes, Iris ;

Salz, Lisa ;

Sanford, Erica ;

Schols, Peter ;

Sweeney, Nathaly ;

Tokita, Mari ;

Veeraraghavan, Narayanan ;

Watkins, Kelly ;

Wigby, Kristen ;

Wong, Terence ;

Chowdhury, Shimul ;

Wright, Meredith S. ;

Dimmock, David ;

Bezares, Zaira ;

Bloss, Cinnamon ;

Braun, Joshua J. A. ;

Diaz, Carlos ;

Mashburn, Dana ;

Tamang, Dorjee ;

Orendain, Daniken ;

Friedman, Jenni ;

Gleeson, Joe ;

Barea, Jaime ;

Chiang, George ;

Cohenmeyer, Casey ;

Coufal, Nicole G. ;

Evans, Marva ;

Honold, Jose ;

Hovey, Raymond L. ;

Kimball, Amy .

AMERICAN JOURNAL OF HUMAN GENETICS, 2019, 105 (04) :719-733

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