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Diagnostic Rates of Rapid Exome Sequencing in Critical Settings

Runa, Samantha L (2023) Diagnostic Rates of Rapid Exome Sequencing in Critical Settings. Master's Thesis, University of Pittsburgh. (Unpublished)

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Introduction: Undiagnosed genetic diseases are one of the leading causes of infant morbidity and mortality, and can be a significant public health concern for both providers and patients alike. In a critical care setting, rapid and comprehensive genetic testing needs to be considered for patients to achieve equitable care. As Whole Exome Sequencing (WES) has slowly become the standard of care for many clinically complex patients, Rapid Whole Exome Sequencing (rWES) is quickly becoming a first step for many infants and children with acute medical issues in an inpatient setting.
Methods: Using data collected from 2015 to 2021 from a large clinical genetics laboratory, GeneDx, results from rWES were reviewed and the diagnostic rate was established. The diagnostic rate was stratified by the number of samples submitted for testing, clinical indication, age of the proband, and inclusion of mitochondrial genome sequencing and deletion/duplication studies (mtDNA) and the associated results. The significance of the results was assessed by the chi-squared statistical test.
Results: 2744 rWES cases were retrospectively reviewed and evaluated for the diagnostic rate . The overall diagnostic yield of rWES in this cohort is 33 .3%. Comparing Trios and Non-Trios, the diagnostic yield differs greatly with Trio cases having a diagnostic yield of 35.5% and Non-Trios a yield of 20% (p-value <0.0001). The highest diagnostic yield is seen in those under the age of 1 year and in cases of postmortem sample analysis, at 39% and 43%, respectively. Furthermore, the diagnostic rate is increased when patients have a multi-system clinical presentation with rates ranging from 31% to 38%.
Conclusion: Results of this large-scale review of over 2500 rWES cases provide concrete information about diagnostic rates to help guide ordering physicians caring for their patients. The overall diagnostic rate of 33% is similar to those previously reported, and this study demonstrates that diagnostic rates increase when both biological parents are submitted, and yields are higher within specific age and phenotype categories. These results prove the utility of rWES testing in critically ill patients and recommend a guideline for providers to provide comprehensive, rapid, and equitable testing.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Runa, Samantha Lslr120@pitt.eduslr120
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee MemberCyprych, Leslie KWleslie.walsh@chp.edulkc37
Committee MemberBertolet, Marniemhb12@pitt.edumhb12
Committee MemberMcWalter,
Thesis AdvisorVento, Jodieventojm@pitt.edujmvento
Date: 11 May 2023
Date Type: Publication
Defense Date: 7 April 2023
Approval Date: 11 May 2023
Submission Date: 27 April 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 75
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Genetic Counseling
Degree: MS - Master of Science
Thesis Type: Master's Thesis
Refereed: Yes
Uncontrolled Keywords: Genetics, Genetic Counseling, Whole Exome Sequencing, Rapid Whole Exome Sequencing
Date Deposited: 11 May 2023 16:25
Last Modified: 11 May 2023 16:25


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