Rapid Whole Genome Sequencing Decreases Morbidity and Healthcare Cost of Hospitalized Infants

ABSTRACTBACKGROUNDGenetic disorders are a leading cause of morbidity and mortality in infants. Rapid Whole Genome Sequencing (rWGS) can diagnose genetic disorders in time to change acute medical or surgical management (clinical utility) and improve outcomes in acutely ill infants.METHODSRetrospective cohort study of acutely ill inpatient infants in a regional children’s hospital from July 2016–March 2017. Forty-two families received rWGS for etiologic diagnosis of genetic disorders. Probands received standard genetic testing as clinically indicated. Primary end-points were rate of diagnosis, clinical utility, and healthcare utilization. The latter was modelled in six infants by comparing actual utilization with matched historical controls and/or counterfactual utilization had rWGS been performed at different time points.FINDINGSThe diagnostic sensitivity was 43% (eighteen of 42 infants) for rWGS and 10% (four of 42 infants) for standard of care (P=.0005). The rate of clinical utility for rWGS (31%, thirteen of 42 infants) was significantly greater than for standard of care (2%, one of 42; P=.0015). Eleven (26%) infants with diagnostic rWGS avoided morbidity, one had 43% reduction in likelihood of mortality, and one started palliative care. In six of the eleven infants, the changes in management reduced inpatient cost by $800, 000 to $2,000,000.DISCUSSIONThese findings replicate a prior study of the clinical utility of rWGS in acutely ill inpatient infants, and demonstrate improved outcomes and net healthcare savings. rWGS merits consideration as a first tier test in this setting.

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Clinical-grade whole-genome sequencing and 3′ transcriptome analysis of colorectal cancer patients

Genome Medicine ◽

10.1186/s13073-021-00852-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Agata Stodolna ◽

Miao He ◽

Mahesh Vasipalli ◽

Zoya Kingsbury ◽

Jennifer Becq ◽

...

Keyword(s):

Colorectal Cancer ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Transcriptome Analysis ◽

Variant Calling ◽

Standard Of Care ◽

Genomic Variation ◽

Whole Genome ◽

Clinical Grade ◽

Pathway Gene

Abstract Background Clinical-grade whole-genome sequencing (cWGS) has the potential to become the standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3′ transcriptome analysis would give new insights into colorectal cancer. Methods Patients underwent PCR-free whole-genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into the mutational signatures and tumour biology were gained by the use of 3′ RNA-seq. Results Fifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 30% of patients had a tumour mutational burden of > 10 mutations/Mb of DNA, suggesting suitability for immunotherapy. Conclusions Clinical whole-genome sequencing offers a potential avenue for the identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.

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Clinical utility of whole-genome sequencing in precision oncology

Seminars in Cancer Biology ◽

10.1016/j.semcancer.2021.06.018 ◽

2021 ◽

Author(s):

Richard Rosenquist ◽

Edwin Cuppen ◽

Reinhard Buettner ◽

Carlos Caldas ◽

Helene Dreau ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Precision Oncology ◽

Whole Genome

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Clinical utility of ultra-rapid whole-genome sequencing in an infant with atypical presentation of WT1-associated nephrotic syndrome type 4

Molecular Case Studies ◽

10.1101/mcs.a005470 ◽

2020 ◽

Vol 6 (4) ◽

pp. a005470

Author(s):

Erica Sanford ◽

Terence Wong ◽

Katarzyna A. Ellsworth ◽

Elizabeth Ingulli ◽

Stephen F. Kingsmore

Keyword(s):

Nephrotic Syndrome ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Whole Genome ◽

Atypical Presentation ◽

Syndrome Type

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Whole-genome sequencing offers additional but limited clinical utility compared with reanalysis of whole-exome sequencing

Genetics in Medicine ◽

10.1038/gim.2018.41 ◽

2018 ◽

Vol 20 (11) ◽

pp. 1328-1333 ◽

Cited By ~ 44

Author(s):

Ahmed Alfares ◽

Taghrid Aloraini ◽

Lamia Al subaie ◽

Abdulelah Alissa ◽

Ahmed Al Qudsi ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Whole Genome ◽

Whole Exome

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Genetics of neuropsychiatric disease

Oxford Textbook of Neuropsychiatry ◽

10.1093/med/9780198757139.003.0012 ◽

2020 ◽

pp. 127-140

Author(s):

Stefania Bruno ◽

Nayana Lahiri

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Genetic Disorders ◽

Single Gene ◽

Diagnostic Techniques ◽

Genetic Influences ◽

Whole Genome ◽

Neuropsychiatric Disease ◽

Genomic Technologies ◽

Whole Exome

To better understand the intricacies of genetic influences on neuropsychiatric disease, it is important first to have a grounding in the models of human inheritance and current diagnostic techniques. This chapter covers the fundamentals of genetic disorders, giving insights into chromosomal, single-gene, and mitochondrial disorders. Moreover, it explores the changing applications of genomic technologies, such as whole exome and whole genome sequencing, through the lens of their implications for neuropsychiatry. Clinical examples are provided to give an idea of the genetic underpinnings of Alzheimer’s disease, Parkinson’s disease, and other familiar disorders.

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Best practices for the analytical validation of clinical whole-genome sequencing intended for the diagnosis of germline disease

npj Genomic Medicine ◽

10.1038/s41525-020-00154-9 ◽

2020 ◽

Vol 5 (1) ◽

Author(s):

Christian R. Marshall ◽

◽

Shimul Chowdhury ◽

Ryan J. Taft ◽

Mathew S. Lebo ◽

...

Keyword(s):

Best Practices ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Test Performance ◽

Genetic Disorders ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Whole Genome ◽

Analytical Validation ◽

Whole Exome

Abstract Whole-genome sequencing (WGS) has shown promise in becoming a first-tier diagnostic test for patients with rare genetic disorders; however, standards addressing the definition and deployment practice of a best-in-class test are lacking. To address these gaps, the Medical Genome Initiative, a consortium of leading healthcare and research organizations in the US and Canada, was formed to expand access to high-quality clinical WGS by publishing best practices. Here, we present consensus recommendations on clinical WGS analytical validation for the diagnosis of individuals with suspected germline disease with a focus on test development, upfront considerations for test design, test validation practices, and metrics to monitor test performance. This work also provides insight into the current state of WGS testing at each member institution, including the utilization of reference and other standards across sites. Importantly, members of this initiative strongly believe that clinical WGS is an appropriate first-tier test for patients with rare genetic disorders, and at minimum is ready to replace chromosomal microarray analysis and whole-exome sequencing. The recommendations presented here should reduce the burden on laboratories introducing WGS into clinical practice, and support safe and effective WGS testing for diagnosis of germline disease.

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Read and assembly metrics inconsequential for clinical utility of whole-genome sequencing in mapping outbreaks

Nature Biotechnology ◽

10.1038/nbt.2616 ◽

2013 ◽

Vol 31 (7) ◽

pp. 592-594 ◽

Cited By ~ 20

Author(s):

Simon R Harris ◽

M E Török ◽

Edward J P Cartwright ◽

Michael A Quail ◽

Sharon J Peacock ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Genome Sequencing ◽

Clinical Utility ◽

Whole Genome

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A centralized rare disease database and whole-genome sequencing as a standard of care: two essential implementations for the future of health

FACETS ◽

10.1139/facets-2021-0065 ◽

2021 ◽

Vol 6 ◽

pp. 1831-1834

Author(s):

Sina Faraji ◽

Dimitri Patrinos ◽

Julie Hagan ◽

Bartha Maria Knoppers

Keyword(s):

Whole Genome Sequencing ◽

Rare Disease ◽

Genome Sequencing ◽

Standard Of Care ◽

Whole Genome ◽

The Future

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Clinical-grade whole genome sequencing of colorectal cancer and 3’ transcriptome analysis demonstrate targetable alterations in the majority of patients

10.1101/2020.04.26.20080887 ◽

2020 ◽

Author(s):

Agata Stodolna ◽

Miao He ◽

Mahesh Vasipalli ◽

Zoya Kingsbury ◽

Jennifer Becq ◽

...

Keyword(s):

Colorectal Cancer ◽

Whole Genome Sequencing ◽

Genome Sequencing ◽

Transcriptome Analysis ◽

Variant Calling ◽

Standard Of Care ◽

Genomic Variation ◽

Whole Genome ◽

Clinical Grade ◽

Pathway Gene

AbstractIntroductionClinical grade whole genome sequencing (cWGS) has the potential to become standard of care within the clinic because of its breadth of coverage and lack of bias towards certain regions of the genome. Colorectal cancer presents a difficult treatment paradigm, with over 40% of patients presenting at diagnosis with metastatic disease. We hypothesised that cWGS coupled with 3’ transcriptome analysis would give new insights into colorectal cancer.MethodsPatients underwent PCR-free whole genome sequencing and alignment and variant calling using a standardised pipeline to output SNVs, indels, SVs and CNAs. Additional insights into mutational signatures and tumour biology were gained by the use of 3’ RNAseq.ResultsFifty-four patients were studied in total. Driver analysis identified the Wnt pathway gene APC as the only consistently mutated driver in colorectal cancer. Alterations in the PI3K/mTOR pathways were seen as previously observed in CRC. Multiple private CNAs, SVs and gene fusions were unique to individual tumours. Approximately 20% of patients had a tumour mutational burden of >10 mutations/Mb of DNA, suggesting suitability for immunotherapy.ConclusionsClinical whole genome sequencing offers a potential avenue for identification of private genomic variation that may confer sensitivity to targeted agents and offer patients new options for targeted therapies.

Download Full-text