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#Grand Rounds

Ultra-Rapid Exome Sequencing in Critically Ill Neonatal and Pediatric Patients

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BACKGROUND AND PURPOSE:

  • Genomic testing of neonatal and pediatric patients with suspected genetic conditions improves diagnoses and influences clinical management
  • The Australian Genomics Health Alliance Acute Care Flagship (JAMA, 2020) prospectively evaluated the performance of ultra-rapid genomic diagnosis in a public health care system

METHODS:

  • Descriptive feasibility study
  • Participants
    • Critically ill pediatric patients
    • Suspicion of monogenic conditions
  • Exposure
    • Ultra-rapid exome sequencing
  • Study design
    • Formal implementation strategy that emphasized
      • Communication and feedback | Standardized processes | Coordination | Distributed leadership | Collective learning
    • Patients seen by clinical genetics prior to testing
  • Primary outcome
    • Time from sample receipt to ultra-rapid exome sequencing report
  • Secondary outcome
    • Molecular diagnostic yield
    • Change in clinical management following result
    • The time from hospital admission to the report
    • Proportion of laboratory reports returned prior to death or hospital discharge

RESULTS:

  • 108 patients were included
    • Median age: 28 days (range 0 days to 17 years) | 34% female
    • From NICU: 57%
    • From pediatric ICU: 33%
    • From other hospital wards: 9%
  • Mean time to referral to clinical genetics service: 8.1 days following admission to ICU
  • Time from sample receipt to ultra-rapid exome sequencing
    • Mean time: 3.3 days (95% CI, 3.2 to 3.5 days)
    • Median time: 3 days (range 2 to 7 days)
  • Time from hospital admission to ultra-rapid exome sequencing report
    • Mean time: 17.5 days (95% CI, 14.6 to 21.1 days)
    • Reports issued prior to death or hospital discharge: 86%
  • Molecular diagnosis
    • Diagnosis returned: 51% of patients (55 patients)
    • 20% of these diagnoses had augmented testing beyond exome sequencing including
      • Mitochondrial genome sequencing analysis
      • Exome sequencing–based copy number analysis
      • Use of international databases to identify novel gene–disease associations
      • Additional phenotyping and RNA analysis
  • Influence on clinical management
    • Proportion of patients with a diagnosis where report influenced care: 76% 
    • Proportion of patients without a diagnosis where report influence care: 11%
  • Changes in Clinical Management
    • Targeted treatments initiated: 11% (12 patients)
    • Treatment redirected to palliative care: 13% (14 patients)
    • Surveillance for specific complications initiated: 18% (19 patients)

CONCLUSION:

  • Ultra-rapid genomic testing in critically ill neonatal and pediatric patients with suspected monogenic conditions is feasible
  • Accompanying editorial points out that
    • The bottleneck at this point is not the lab but arranging for the child to have a professional genetic evaluation prior to ordering the test
    • This study demonstrates feasibility; however requires a setting where structure is in place to ensure communication and appropriate processes 
  • The authors suggest that further studies should evaluate
    • The clinical value of such testing
    • The generalizability of the findings to other health care settings

Learn More – Primary Sources:

Feasibility of Ultra-Rapid Exome Sequencing in Critically Ill Infants and Children With Suspected Monogenic Conditions in the Australian Public Health Care System

JAMA Editorial: Clinical Genomics in Critically Ill Infants and Children

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Related ObG Topics:

Can Whole-Exome Sequencing Help Diagnose Otherwise Unexplained Fetal Structural Anomalies?
Is there a Role for Sequencing Otherwise Healthy Newborns? 
Can Whole Exome Sequencing Explain Prenatal Loss With Insufficient Fetal DNA?

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