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

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?