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Comparative Study
. 2020 Sep 1;3(9):e2018109.
doi: 10.1001/jamanetworkopen.2020.18109.

Genome Sequencing as a Diagnostic Test in Children With Unexplained Medical Complexity

Gregory Costain  1   2 , Susan Walker  3   4 , Maria Marano  5 , Danielle Veenma  1 , Meaghan Snell  2 , Meredith Curtis  2 , Stephanie Luca  6 , Jason Buera  5 , Danielle Arje  5 , Miriam S Reuter  3   4 , Bhooma Thiruvahindrapuram  3 , Brett Trost  3 , Wilson W L Sung  3 , Ryan K C Yuen  4   7 , David Chitayat  1   8   9 , Roberto Mendoza-Londono  1   2   9 , D James Stavropoulos  2   10   11   9 , Stephen W Scherer  3   5   7 , Christian R Marshall  2   3   10   11   9 , Ronald D Cohn  1   5   7   9 , Eyal Cohen  5   6   9   12 , Julia Orkin  5   6   9 , M Stephen Meyn  1   2   7   9   13 , Robin Z Hayeems  2   6   12
Affiliations
Comparative Study

Genome Sequencing as a Diagnostic Test in Children With Unexplained Medical Complexity

Gregory Costain et al. JAMA Netw Open. .

Abstract

Importance: Children with medical complexity (CMC) represent a growing population in the pediatric health care system, with high resource use and associated health care costs. A genetic diagnosis can inform prognosis, anticipatory care, management, and reproductive planning. Conventional genetic testing strategies for CMC are often costly, time consuming, and ultimately unsuccessful.

Objective: To evaluate the analytical and clinical validity of genome sequencing as a comprehensive diagnostic genetic test for CMC.

Design, setting, and participants: In this cohort study of the prospective use of genome sequencing and comparison with standard-of-care genetic testing, CMC were recruited from May 1, 2017, to November 30, 2018, from a structured complex care program based at a tertiary care pediatric hospital in Toronto, Canada. Recruited CMC had at least 1 chronic condition, technology dependence (child is dependent at least part of each day on mechanical ventilators, and/or child requires prolonged intravenous administration of nutritional substances or drugs, and/or child is expected to have prolonged dependence on other device-based support), multiple subspecialist involvement, and substantial health care use. Review of the care plans for 545 CMC identified 143 suspected of having an undiagnosed genetic condition. Fifty-four families met inclusion criteria and were interested in participating, and 49 completed the study. Probands, similarly affected siblings, and biological parents were eligible for genome sequencing.

Exposures: Genome sequencing was performed using blood-derived DNA from probands and family members using established methods and a bioinformatics pipeline for clinical genome annotation.

Main outcomes and measures: The primary study outcome was the diagnostic yield of genome sequencing (proportion of CMC for whom the test result yielded a new diagnosis).

Results: Genome sequencing was performed for 138 individuals from 49 families of CMC (29 male and 20 female probands; mean [SD] age, 7.0 [4.5] years). Genome sequencing detected all genomic variation previously identified by conventional genetic testing. A total of 15 probands (30.6%; 95% CI 19.5%-44.6%) received a new primary molecular genetic diagnosis after genome sequencing. Three individuals had novel diseases and an additional 9 had either ultrarare genetic conditions or rare genetic conditions with atypical features. At least 11 families received diagnostic information that had clinical management implications beyond genetic and reproductive counseling.

Conclusions and relevance: This study suggests that genome sequencing has high analytical and clinical validity and can result in new diagnoses in CMC even in the setting of extensive prior investigations. This clinical population may be enriched for ultrarare and novel genetic disorders. Genome sequencing is a potentially first-tier genetic test for CMC.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Costain reported receiving grants from the McLaughlin Centre–University of Toronto; and funding support in the form of personnel support and payment for some of the sequencing costs from SickKids Centre for Genetic Medicine during the conduct of the study. Ms Snell reported receiving grants from Norm Saunders Complex Care Initiative and Centre for Genetic Medicine during the conduct of the study. Ms Curtis reported receiving grants from the Norm Saunders Complex Care Initiative–The Hospital for Sick Children, The Hospital for Sick Children–Centre for Genetic Medicine, and University of Toronto–McLaughlin Centre during the conduct of the study. Ms Luca reported receiving grants from Norm Saunders Complex Care Initiative–The Hospital for Sick Children, SickKids Centre for Genetic Medicine, and the McLaughlin Centre–University of Toronto during the conduct of the study. Dr Trost reported personal funding awards from Canadian Institutes of Health Research and personal funding awards from Canadian Open Neuroscience Platform during the conduct of the study. Dr Stavropoulos reported being co-inventor of PhenoTips and serving on the Scientific Advisory Board of Gene42. Dr Meyn reported receiving grants from University of Toronto McLaughlin Centre during the conduct of the study; serving as a member of the Gene42/PhenoTips Scientific Advisory Board; and having a patent to the PhenoTips software pending. Dr Hayeems reported receiving grants from Norm Saunders Complex Care Initiative and The Centre for Genetic Medicine, The Hospital for Sick Children during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Recruitment Flowchart
Figure 2.
Figure 2.. Timeline of the Diagnostic Process
Horizontal lines indicate the duration of the diagnostic process from initial suspicion for an underlying genetic condition to diagnosis by genome sequencing.
See this image and copyright information in PMC

References

    1. Cohen E, Kuo DZ, Agrawal R, et al. . Children with medical complexity: an emerging population for clinical and research initiatives. Pediatrics. 2011;127(3):529-538. doi:10.1542/peds.2010-0910 - DOI - PMC - PubMed
    1. Cohen E, Berry JG, Camacho X, Anderson G, Wodchis W, Guttmann A. Patterns and costs of health care use of children with medical complexity. Pediatrics. 2012;130(6):e1463-e1470. doi:10.1542/peds.2012-0175 - DOI - PMC - PubMed
    1. Kuo DZ, Houtrow AJ; Council on Children With Disabilities . Recognition and management of medical complexity. Pediatrics. 2016;138(6):e20163021. doi:10.1542/peds.2016-3021 - DOI - PubMed
    1. Cohen E, Berry JG, Sanders L, Schor EL, Wise PH. Status complexicus? the emergence of pediatric complex care. Pediatrics. 2018;141(suppl 3):S202-S211. doi:10.1542/peds.2017-1284E - DOI - PubMed
    1. Oei K, Hayeems RZ, Ungar WJ, Cohn RD, Cohen E. Genetic testing among children in a complex care program. Children (Basel). 2017;4(5):E42. doi:10.3390/children4050042 - DOI - PMC - PubMed

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