Abstract
Genetic diseases are a leading cause of death in infants in the intensive care setting; therefore, rapid and accurate genetic diagnosis is desired. To validate 24-h trio-exome sequencing (TES), samples from probands and their parents were processed by the AmpliSeq /Ion S5XL platform in a hospital clinical laboratory. Infants from the intensive care unit (ICU) suspected of having a genetic disease were enrolled. Regular and 24-h TES using the Agilent SureSelect capture kit/Illumina platform were performed on all samples in parallel. Of 33 enrolled infants, 23 received positive results with rapid TES, and an additional two diagnoses were achieved with regular TES. Among the 23 diagnosed patients, 10 experienced changes in medical management, such as hematopoietic stem cell transplant. Ten diagnosed cases were discharged prior to receiving the regular TES results; six received timely symptom control, and four withdrew medical support. Rapid TES enabled faster time to diagnosis, which resulted in an overall decrease in length of hospital stay. The 24-h TES can serve as a rapid response tool for patients with suspected monogenic disorders and can guide clinical decision-making in urgent cases.
Highlights
Genetic disease diagnosis in infants can be extremely challenging to diagnose because the symptoms and characteristics may not appear early in life and may progress rapidly[1,2,3]
A systematic literature review (January 2011–August 2017) and meta-analysis in 37 studies, comprising 20,068 children with suspected genetic diseases, showed that the diagnostic rate and clinical utility of WGS/WES were greater than CMA18
The time window for which many life-saving treatments can be most effective for some diseases is very limited
Summary
Genetic disease diagnosis in infants can be extremely challenging to diagnose because the symptoms and characteristics may not appear early in life and may progress rapidly[1,2,3]. It is critical to diagnose these children as soon as possible to enable timely interventions, reducing mortality and unessential intensive care, as well as minimizing the anxiety of patient families. Comprehensive clinical panel testing or exome sequencing requires weeks to obtain genetic test results[6,7]. It is difficult to break the 1-week turn-around-time (TAT) barrier because conventional high throughput sequencing platforms run cases by batch, reducing flexibility for individual cases. Current rapid trio-genome sequencing is cost-prohibitive for most patients in developing countries. Because rapid trio-exome sequencing can, by comparison, produce results in a short amount of time and is less expensive, it is the ideal testing strategy for critically ill infants in the pediatrics/neonate intensive care unit (PICU/NICU)
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