Integrated multi-omics for rapid rare disease diagnosis on a national scale.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
15
12
2022
accepted:
12
05
2023
medline:
21
7
2023
pubmed:
9
6
2023
entrez:
8
6
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37291213
doi: 10.1038/s41591-023-02401-9
pii: 10.1038/s41591-023-02401-9
pmc: PMC10353936
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1681-1691Informations de copyright
© 2023. The Author(s).
Références
Stark, Z. et al. Integrating genomics into healthcare: a global responsibility. Am. J. Hum. Genet. 104, 13–20 (2019).
pubmed: 30609404
pmcid: 6323624
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).
pubmed: 30002876
pmcid: 6037748
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).
pubmed: 32573669
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).
pubmed: 34089648
pmcid: 8322922
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).
pubmed: 34744166
Gorzynski, J. E. et al. Ultrarapid nanopore genome sequencing in a critical care setting. N. Engl. J. Med. 386, 700–702 (2022).
pubmed: 35020984
Goranitis, I. et al. Is faster better? An economic evaluation of rapid and ultra-rapid genomic testing in critically ill infants and children. Genet. Med. https://doi.org/10.1016/j.gim.2022.01.013 (2022).
Kingsmore, S. F. 2022: a pivotal year for diagnosis and treatment of rare genetic diseases. Cold Spring Harb. Mol. Case Stud. 8, a006204 (2022).
pubmed: 35217563
pmcid: 8958907
Smedley, D. et al. 100,000 Genomes pilot on rare-disease diagnosis in health care - preliminary report. N. Engl. J. Med. 385, 1868–1880 (2021).
pubmed: 34758253
Stranneheim, H. et al. Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients. Genome Med. 13, 40 (2021).
pubmed: 33726816
pmcid: 7968334
Kingsmore, S. F. et al. A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants. Am. J. Hum. Genet. 105, 719–733 (2019).
pubmed: 31564432
pmcid: 6817534
Brockman, D. G. et al. Randomized prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test. Genet Med. 23, 1689–1696 (2021).
pubmed: 33976420
pmcid: 8488861
Seaby, E. G., Rehm, H. L. & O’Donnell-Luria, A. Strategies to uplift novel Mendelian gene discovery for improved clinical outcomes. Front. Genet. 12, 674295 (2021).
pubmed: 34220947
pmcid: 8248347
Morales, J. et al. A standardized framework for representation of ancestry data in genomics studies, with application to the NHGRI-EBI GWAS catalog. Genome Biol. 19, 21 (2018).
pubmed: 29448949
pmcid: 5815218
Robinson, P. N. et al. The Human Phenotype Ontology: a tool for annotating and analyzing human hereditary disease. Am. J. Hum. Genet. 83, 610–615 (2008).
pubmed: 18950739
pmcid: 2668030
Alsina Casanova, M. et al. Maternal mutations of FOXF1 cause alveolar capillary dysplasia despite not being imprinted. Hum. Mutat. 38, 615–620 (2017).
pubmed: 28256047
Neilson, D. E. et al. Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2. Am. J. Hum. Genet. 84, 44–51 (2009).
pubmed: 19118815
pmcid: 2668029
Halman, A., Dolzhenko, E. & Oshlack, A. STRipy: a graphical application for enhanced genotyping of pathogenic short tandem repeats in sequencing data. Hum. Mutat. 43, 859–868 (2022).
pubmed: 35395114
pmcid: 9541159
Martinelli, S. et al. Heterozygous germline mutations in the CBL tumor-suppressor gene cause a Noonan syndrome-like phenotype. Am. J. Hum. Genet. 87, 250–257 (2010).
pubmed: 20619386
pmcid: 2917705
Niemeyer, C. M. et al. Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat. Genet. 42, 794–800 (2010).
pubmed: 20694012
pmcid: 4297285
Smallwood, K. et al. POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies. Am. J. Hum. Genet. 110, 809–825 (2023).
pubmed: 37075751
Fichtman, B. et al. Pathogenic variants in NUP214 cause ‘plugged’ nuclear pore channels and acute febrile encephalopathy. Am. J. Hum. Genet. 105, 48–64 (2019).
pubmed: 31178128
pmcid: 6612515
Gonorazky, H. D. et al. Expanding the boundaries of RNA sequencing as a diagnostic tool for rare Mendelian disease. Am. J. Hum. Genet. 104, 466–483 (2019).
pubmed: 30827497
pmcid: 6407525
Murdock, D. R. et al. Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing. J. Clin. Invest. 131, e14500 (2021).
Lee, H. et al. Diagnostic utility of transcriptome sequencing for rare Mendelian diseases. Genet Med. 22, 490–499 (2020).
pubmed: 31607746
Maddirevula, S. et al. Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics. Genome Biol. 21, 145 (2020).
pubmed: 32552793
pmcid: 7298854
Brnich, S. E. et al. Recommendations for application of the functional evidence PS3/BS3 criterion using the ACMG/AMP sequence variant interpretation framework. Genome Med. 12, 3 (2019).
pubmed: 31892348
pmcid: 6938631
Sobreira, N., Schiettecatte, F., Valle, D. & Hamosh, A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum. Mutat. 36, 928–930 (2015).
pubmed: 26220891
pmcid: 4833888
Stolz, J. R. et al. Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders. Am. J. Hum. Genet. 108, 1692–1709 (2021).
pubmed: 34375587
pmcid: 8456161
Cooper, M. S., Stark, Z., Lunke, S., Zhao, T. & Amor, D. J. IREB2-associated neurodegeneration. Brain 142, e40 (2019).
pubmed: 31243445
Lee, R. G. et al. Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease. Hum. Mol. Genet. https://doi.org/10.1093/hmg/ddac040 (2022).
Rehman, A. U. et al. Biallelic loss of function variants in PPP1R21 cause a neurodevelopmental syndrome with impaired endocytic function. Hum. Mutat. 40, 267–280 (2019).
pubmed: 30520571
Amarasekera, S. S. C. et al. Multi-omics identifies large mitoribosomal subunit instability caused by pathogenic MRPL39 variants as a cause of pediatric onset mitochondrial disease. Hum. Mol. Genet. https://doi.org/10.1093/hmg/ddad069 (2023).
Cloney, T. et al. Lessons learnt from multifaceted diagnostic approaches to the first 150 families in Victoria’s Undiagnosed Diseases Program. J. Med. Genet. 59, 748–758 (2022).
pubmed: 34740920
Osmond, M. et al. Outcome of over 1500 matches through the Matchmaker Exchange for rare disease gene discovery: the 2-year experience of Care4Rare Canada. Genet. Med. 24, 100–108 (2022).
pubmed: 34906465
Baxter, S. M. et al. Centers for Mendelian Genomics: a decade of facilitating gene discovery. Genet. Med. 24, 784–797 (2022).
pubmed: 35148959
pmcid: 9119004
McWalter, K., Torti, E., Morrow, M., Juusola, J. & Retterer, K. Discovery of over 200 new and expanded genetic conditions using GeneMatcher. Hum. Mutat. 43, 760–764 (2022).
pubmed: 35224800
pmcid: 9306743
Taylor, J. P. et al. A clinical laboratory’s experience using GeneMatcher-building stronger gene–disease relationships. Hum. Mutat. 43, 765–771 (2022).
pubmed: 35181961
Towne, M. C. et al. Diagnostic testing laboratories are valuable partners for disease gene discovery: 5-year experience with GeneMatcher. Hum. Mutat. 43, 772–781 (2022).
pubmed: 35143109
pmcid: 9313781
Goenka, S. D. et al. Accelerated identification of disease-causing variants with ultra-rapid nanopore genome sequencing. Nat. Biotechnol. 40, 1035–1041 (2022).
pubmed: 35347328
pmcid: 9287171
Lunke, S. & Stark, Z. Can rapid nanopore sequencing bring genomic testing to the bedside? Clin. Chem. https://doi.org/10.1093/clinchem/hvac111 (2022).
Best, S. et al. Learning from scaling up ultra-rapid genomic testing for critically ill children to a national level. NPJ Genom. Med. 6, 5 (2021).
pubmed: 33510162
pmcid: 7843635
Stark, Z. et al. Scaling national and international improvement in virtual gene panel curation via a collaborative approach to discordance resolution. Am. J. Hum. Genet. 108, 1551–1557 (2021).
pubmed: 34329581
pmcid: 8456155
Harris, P. A. et al. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inf. 42, 377–381 (2009).
Brett, G. R. et al. Co-design, implementation, and evaluation of plain language genomic test reports. NPJ Genom. Med. 7, 61 (2022).
pubmed: 36272999
pmcid: 9588009
Pedersen, B. S. et al. Somalier: rapid relatedness estimation for cancer and germline studies using efficient genome sketches. Genome Med. 12, 62 (2020).
pubmed: 32664994
pmcid: 7362544
Sadedin, S. P., Ellis, J. A., Masters, S. L. & Oshlack, A. Ximmer: a system for improving accuracy and consistency of CNV calling from exome data. Gigascience 7, giy112 (2018).
pubmed: 30192941
pmcid: 6177737
Rausch, T. et al. DELLY: structural variant discovery by integrated paired-end and split-read analysis. Bioinformatics 28, i333–i339 (2012).
pubmed: 22962449
pmcid: 3436805
Layer, R. M., Chiang, C., Quinlan, A. R. & Hall, I. M. LUMPY: a probabilistic framework for structural variant discovery. Genome Biol. 15, R84 (2014).
pubmed: 24970577
pmcid: 4197822
Abyzov, A., Urban, A. E., Snyder, M. & Gerstein, M. CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. Genome Res. 21, 974–984 (2011).
pubmed: 21324876
pmcid: 3106330
Roller, E., Ivakhno, S., Lee, S., Royce, T. & Tanner, S. Canvas: versatile and scalable detection of copy number variants. Bioinformatics 32, 2375–2377 (2016).
pubmed: 27153601
Chen, X. et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 32, 1220–1222 (2016).
pubmed: 26647377
Brechtmann, F. et al. OUTRIDER: A statistical method for detecting aberrantly expressed genes in RNA sequencing data. Am. J. Hum. Genet. 103, 907–917 (2018).
pubmed: 30503520
pmcid: 6288422
Akesson, L. S. et al. Distinct diagnostic trajectories in NBAS-associated acute liver failure highlights the need for timely functional studies. JIMD Rep. 63, 240–249 (2022).
pubmed: 35433172
pmcid: 8995841
Frazier, A. E. et al. Fatal perinatal mitochondrial cardiac failure caused by recurrent de novo duplications in the ATAD3 locus. Medicine 2, 49–73 (2021).
Fowler, K. J. Storage of skin biopsies at -70 degrees C for future fibroblast culture. J. Clin. Pathol. 37, 1191–1193 (1984).
pubmed: 6490956
pmcid: 498966
Van Bergen, N. J. et al. Pathogenic variants in nucleoporin TPR (translocated promoter region, nuclear basket protein) cause severe intellectual disability in humans. Hum. Mol. Genet. 31, 362–375 (2022).
pubmed: 34494102
Kumar, R. et al. Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder. NPJ Genom. Med. 7, 9 (2022).
pubmed: 35091571
pmcid: 8799713
Tyanova, S. et al. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 13, 731–740 (2016).
pubmed: 27348712
Stroud, D. A. et al. Accessory subunits are integral for assembly and function of human mitochondrial complex I. Nature 538, 123–126 (2016).
pubmed: 27626371
Lake, N. J. et al. Biallelic mutations in MRPS34 lead to instability of the small mitoribosomal subunit and Leigh syndrome. Am. J. Hum. Genet. 102, 713 (2018).
pubmed: 29625026
pmcid: 5985357
Shamseldin, H. E. et al. NUP214 deficiency causes severe encephalopathy and microcephaly in humans. Hum. Genet. 138, 221–229 (2019).
pubmed: 30758658