Rare genetic diseases in infants and children are frequent causes of or risk factors for admission to the intensive care unit (ICU). These diseases may be suspected but are typically not identified on admission and can be challenging to diagnose. Genomic and exome sequencing are two modalities that have been studied recently and that could help diagnose and provide guidance on therapies for these genetic diseases.1-4 However, the sequencing process takes longer and costs more because it involves having geneticists and genetic counselors alongside the medical team.
Freed et al sought to evaluate a standardized process of using rapid exome sequencing to help diagnose critically ill children with genetic diseases in neonatal, pediatric, and pediatric cardiac ICUs.5 For this study, physicians caring for a patient with a suspected genetic disorder consulted a geneticist. The geneticist determined suitability and completed a standardized form that listed a phenotype-driven list of candidate genes, suspected mode of inheritance, and likely proposed changes to clinical management. This form was then sent to a laboratory genetic counselor who presented the case to a committee of board-certified geneticists. It was required that the committee’s decision be unanimous and and that the committee provide the review within one business day for the study to proceed.
Patients’ parents were provided counseling by clinical genetic counselors before peripheral blood samples were collected from the patient and from both biological parents and sent to an outside laboratory. Once verbal results returned from the laboratory, the consulting geneticist informed the critical care team and family of the results and, for the purposes of the study, classified the results as molecularly diagnosed, uncertain, or negative (if no disease-associated variants were identified). Freed et al used this complicated enrollment process to minimize cost and potential errors in diagnosis and sent the samples to an outside laboratory to allow for applicability to other pediatric institutions.
The main purpose of this study was to evaluate the clinical utility of the genetic findings to ICU physicians. During an almost 3-year process, 60 cases were referred to the laboratory genetic counselor, which ultimately lead to 46 approved and completed cases. The median patient age was 25 days, with a range of 1 day to 15 years. Fifty-six percent of the patients came from the neonatal ICU while 22% came from the pediatric ICU and 22% from the pediatric cardiac ICU. The median turnaround time from request to verbal result was 9 days, with 6 days required between sending the samples and the verbal result. A molecular diagnosis was made in 20 out of 46 patients (43%), but 24 out of 46 patients (52%) had a change in clinical management, including some with a negative finding.
This study provides an effective method for using rapid exome sequencing to make clinically useful decisions in critically ill infants and children. The authors discuss the speed at which the results were obtained and note that the biggest delay was parental coordination before sample collection. Other impediments to obtaining results included the need for committee approval of the request for genetic testing, which can be eliminated or modified, and laboratory technology, which may improve over time. The authors did not comment on the ultimate cost of each case (including laboratory studies, counseling costs, and costs saved by making timely clinical decisions in the ICU); these ultimate costs should be determined. If the costs prove to be less than exorbitant and if further studies continue to demonstrate utility, this process could be become a standard of care for all critically ill pediatric patients.
Author of this installment of Concise Critical Appraisal:
Daniel E. Sloniewsky, MD, FCCM, is an associate professor in the Division of Pediatric Critical Care Medicine in the Department of Pediatrics at Stony Brook Long Island Children’s Hospital. Dr. Sloniewsky is an editor of Concise Critical Appraisal.
- Hill M, Hammond J, Lewis C, Mellis R, Clement E, Chitty LS. Delivering genome sequencing for rapid genetic diagnosis in critically ill children: parent and professional views, experiences and challenges. Eur J Hum Genet. 2020 Jun 19. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32561901/
- Friedman JM, Bombard Y, Cornel MC, et al; Paediatric Task Team of the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream. Genome-wide sequencing in acutely ill infants: genomic medicine’s critical application? Genet Med. 2019 Feb;21(2):498-504. https://pubmed.ncbi.nlm.nih.gov/29895853/
- Mestek-Boukhibar L, Clement E, Jones WD, et al. Rapid Paediatric Sequencing (RaPS): comprehensive real-life workflow for rapid diagnosis of critically ill children. J Med Genet. 2018 Nov;55(11):721-728. https://pubmed.ncbi.nlm.nih.gov/30049826/
- Wang H, Qian Y, Lu Y, et al. Clinical utility of 24-h rapid trio-exome sequencing for critically ill infants. NPJ Genom Med. 2020 May 5;5:20. https://pubmed.ncbi.nlm.nih.gov/32411386/
- Freed AS, Candadai SVC, Sikes MC, et al. The impact of rapid exome sequencing on medical management of critically ill children. J Pediatr. 2020 Jun 15;S0022-3476(20)30721-6. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/32553838/