Integrated multi-omics for rapid rare disease diagnosis on a national scale

• Published in: Nature medicine Vol. 29; no. 7; pp. 1681 - 1691
• Main Authors: Lunke, Sebastian, Bouffler, Sophie E., Patel, Chirag V., Sandaradura, Sarah A., Wilson, Meredith, Pinner, Jason, Hunter, Matthew F., Barnett, Christopher P., Wallis, Mathew, Kamien, Benjamin, Tan, Tiong Y., Freckmann, Mary-Louise, Chong, Belinda, Phelan, Dean, Francis, David, Kassahn, Karin S., Ha, Thuong, Gao, Song, Arts, Peer, Jackson, Matilda R., Scott, Hamish S., Eggers, Stefanie, Rowley, Simone, Boggs, Kirsten, Rakonjac, Ana, Brett, Gemma R., de Silva, Michelle G., Springer, Amanda, Ward, Michelle, Stallard, Kirsty, Simons, Cas, Conway, Thomas, Halman, Andreas, Van Bergen, Nicole J., Sikora, Tim, Semcesen, Liana N., Stroud, David A., Compton, Alison G., Thorburn, David R., Bell, Katrina M., Sadedin, Simon, North, Kathryn N., Christodoulou, John, Stark, Zornitza
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2023; Nature Publishing Group
• Subjects: 692/308/2056; 692/308/575; 692/699; Abnormalities; Biomedical and Life Sciences; Biomedicine; Cancer Research; Child; Children; Chromosome aberrations; Critical Illness; Decision analysis; Diagnosis; Diagnostic systems; Exome Sequencing; Gene sequencing; Genomes; Genomics; Humans; Infant; Infants; Infectious Diseases; Metabolic Diseases; Molecular Medicine; Multiomics; Neurosciences; Palliation; Patients; Proteomics; Rare diseases; Rare Diseases - diagnosis; Rare Diseases - genetics; Rare Diseases - therapy; Transcriptomes; Whole genome sequencing; Whole Genome Sequencing - methods
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/s41591-023-02401-9

Critically 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. A report from the Australian Acute Care Genomics programme shows that the integration of rapid whole-genome sequencing and multi-omic analyses informs diagnoses and treatment decisions in a prospective cohort of 290 critically ill infants and children.