En-Ting Wu1, Wuh-Liang Hwu1,2, Yin-Hsiu Chien1,2, Ching Hsu3, Ting-Fu Chen3, Nai-Qi Chen2, Hung-Chieh Chou1, Po-Nien Tsao1, Pi-Chuan Fan1, I-Jung Tsai1, Shuan-Pei Lin4, Wu-Shiun Hsieh1,5, Tung-Ming Chang6,7, Chi-Nien Chen8, Chen-Hao Lee9, Yen-Yin Chou10, Pao-Chin Chiu11, Wen-Hui Tsai12, Hann-Chang Hsiung13, Feipei Lai3, Ni-Chung Lee1,2. 1. Department of Paediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. 2. Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan. 3. Department of Computer Science and Information Engineering, National Taiwan University, Taipei, Taiwan. 4. Department of Pediatrics, Mackay Memorial Hospital, Taipei, Taiwan. 5. Department of Pediatrics, Cathay General Hospital, Taipei, Taiwan. 6. Department of Pediatrics, Changhua Christian Hospital, Changhua, Taiwan. 7. Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan. 8. Department of Pediatrics, National Taiwan University Hospital, Hsin-Chu Branch, Hsinchu, Taiwan. 9. Department of Pediatrics, E-Da Hospital, Kaohsiung, Taiwan. 10. Department of Pediatrics, National Cheng Kung University Hospital, Tainan, Taiwan. 11. Department of Pediatrics, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan. 12. Department of Pediatrics, Chi Mei Medical Center, Tainan, Taiwan. 13. Information Technology Office, National Taiwan University Hospital, Taipei, Taiwan.
Abstract
OBJECTIVES: Critical illnesses caused by undiagnosed genetic conditions are challenging in PICUs. Whole-exome sequencing is a powerful diagnostic tool but usually costly and often fail to arrive at a final diagnosis in a short period. We assessed the feasibility of our whole-exome sequencing as a tool to improve the efficacy of rare diseases diagnosis for pediatric patients with severe illness. DESIGN: Observational analysis. METHOD: We employed a fast but standard whole-exome sequencing platform together with text mining-assisted variant prioritization in PICU setting over a 1-year period. SETTING: A tertiary referral Children's Hospital in Taiwan. PATIENTS: Critically ill PICU patients suspected of having a genetic disease and newborns who were suspected of having a serious genetic disease after newborn screening were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Around 50,000 to 100,000 variants were obtained for each of the 40 patients in 5 days after blood sampling. Eleven patients were immediately found be affected by previously reported mutations after searching mutation databases. Another seven patients had a diagnosis among the top five in a list ranked by text mining. As a whole, 21 patients (52.5%) obtained a diagnosis in 6.2 ± 1.1 working days (range, 4.3-9 d). Most of the diagnoses were first recognized in Taiwan. Specific medications were recommended for 10 patients (10/21, 47.6%), transplantation was advised for five, and hospice care was suggested for two patients. Overall, clinical management was altered in time for 81.0% of patients who had a molecular diagnosis. CONCLUSIONS: The current whole-exome sequencing algorithm, balanced in cost and speed, uncovers genetic conditions in infants and children in PICU, which helps their managements in time and promotes better utilization of PICU resources.
OBJECTIVES: Critical illnesses caused by undiagnosed genetic conditions are challenging in PICUs. Whole-exome sequencing is a powerful diagnostic tool but usually costly and often fail to arrive at a final diagnosis in a short period. We assessed the feasibility of our whole-exome sequencing as a tool to improve the efficacy of rare diseases diagnosis for pediatricpatients with severe illness. DESIGN: Observational analysis. METHOD: We employed a fast but standard whole-exome sequencing platform together with text mining-assisted variant prioritization in PICU setting over a 1-year period. SETTING: A tertiary referral Children's Hospital in Taiwan. PATIENTS: Critically ill PICUpatients suspected of having a genetic disease and newborns who were suspected of having a serious genetic disease after newborn screening were enrolled. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Around 50,000 to 100,000 variants were obtained for each of the 40 patients in 5 days after blood sampling. Eleven patients were immediately found be affected by previously reported mutations after searching mutation databases. Another seven patients had a diagnosis among the top five in a list ranked by text mining. As a whole, 21 patients (52.5%) obtained a diagnosis in 6.2 ± 1.1 working days (range, 4.3-9 d). Most of the diagnoses were first recognized in Taiwan. Specific medications were recommended for 10 patients (10/21, 47.6%), transplantation was advised for five, and hospice care was suggested for two patients. Overall, clinical management was altered in time for 81.0% of patients who had a molecular diagnosis. CONCLUSIONS: The current whole-exome sequencing algorithm, balanced in cost and speed, uncovers genetic conditions in infants and children in PICU, which helps their managements in time and promotes better utilization of PICU resources.
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Authors: Claudia C Y Chung; Gordon K C Leung; Christopher C Y Mak; Jasmine L F Fung; Mianne Lee; Steven L C Pei; Mullin H C Yu; Vivian C C Hui; Joshua C K Chan; Jeffrey F T Chau; Marcus C Y Chan; Mandy H Y Tsang; Wilfred H S Wong; Joanna Y L Tung; Kin Shing Lun; Yiu Ki Ng; Cheuk Wing Fung; Mabel S C Wong; Rosanna M S Wong; Yu Lung Lau; Godfrey C F Chan; So Lun Lee; Kit San Yeung; Brian H Y Chung Journal: Lancet Reg Health West Pac Date: 2020-07-24