Integrated multi-omics for rapid rare disease diagnosis on a national scale
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Published:2023-06-08
Issue:7
Volume:29
Page:1681-1691
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ISSN:1078-8956
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Container-title:Nature Medicine
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language:en
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Short-container-title:Nat Med
Author:
Lunke SebastianORCID, Bouffler Sophie E.ORCID, Patel Chirag V., Sandaradura Sarah A., Wilson MeredithORCID, Pinner Jason, Hunter Matthew F., Barnett Christopher P., Wallis Mathew, Kamien Benjamin, Tan Tiong Y.ORCID, Freckmann Mary-Louise, Chong BelindaORCID, Phelan Dean, Francis David, Kassahn Karin S.ORCID, Ha ThuongORCID, Gao Song, Arts PeerORCID, Jackson Matilda R., Scott Hamish S.ORCID, Eggers Stefanie, Rowley Simone, Boggs Kirsten, Rakonjac Ana, Brett Gemma R.ORCID, de Silva Michelle G.ORCID, Springer Amanda, Ward Michelle, Stallard Kirsty, Simons Cas, Conway ThomasORCID, Halman AndreasORCID, Van Bergen Nicole J., Sikora TimORCID, Semcesen Liana N., Stroud David A., Compton Alison G.ORCID, Thorburn David R.ORCID, Bell Katrina M., Sadedin Simon, North Kathryn N., Christodoulou JohnORCID, Stark ZornitzaORCID
Abstract
AbstractCritically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.
Publisher
Springer Science and Business Media LLC
Subject
General Biochemistry, Genetics and Molecular Biology,General Medicine
Reference62 articles.
1. Stark, Z. et al. Integrating genomics into healthcare: a global responsibility. Am. J. Hum. Genet. 104, 13–20 (2019). 2. Clark, M. M. et al. Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. NPJ Genom. Med. 3, 16 (2018). 3. Lunke, S. et al. Feasibility of ultra-rapid exome sequencing in critically ill infants and children with suspected monogenic conditions in the Australian public health care system. JAMA 323, 2503–2511 (2020). 4. Dimmock, D. et al. Project Baby Bear: rapid precision care incorporating rWGS in 5 California children’s hospitals demonstrates improved clinical outcomes and reduced costs of care. Am. J. Hum. Genet. 108, 1231–1238 (2021). 5. Stark, Z. & Ellard, S. Rapid genomic testing for critically ill children: time to become standard of care? Eur. J. Hum. Genet. 30, 142–149 (2022).
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