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Updated: Jul 27, 2025
Candidate Gene Testing in Clinical Cohort Studies with Multiplexed Genotyping and Mass Spectrometry
Published on: June 21, 2018
Integrated multi-omics for rapid rare disease diagnosis on a national scale
Sebastian Lunke1,2,3, Sophie E Bouffler3, Chirag V Patel4
1Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
Insights
Rapid whole-genome sequencing aids critically ill children with rare diseases, achieving a 54% diagnosis rate. This genomic testing significantly changed clinical management for most diagnosed patients.
Area of Science:
- Genomics
- Rare Diseases
- Critical Care Medicine
Background:
- Critically ill infants and children with rare diseases require timely and accurate diagnoses for effective clinical management.
- Equitable access to advanced diagnostic tools is crucial for this vulnerable population.
Purpose of the Study:
- To evaluate the clinical utility and diagnostic yield of whole-genome sequencing and multi-omic approaches in critically ill children with suspected genetic conditions.
- To assess the impact of rapid genomic testing on clinical management decisions.
Main Methods:
- Whole-genome sequencing was performed on 290 families of critically ill infants and children.
- Bioinformatic analyses, transcriptome sequencing, long-read sequencing, and functional assays were employed for undiagnosed cases.
- Clinically accredited enzyme analysis and quantitative proteomics were utilized in selected patients.
Main Results:
- The initial diagnostic yield was 47% with an average turnaround time of 2.9 days.
- An overall diagnostic yield of 54% was achieved after implementing multi-omic analyses.
- Clinical management was altered in 77% of diagnosed patients, with 60% experiencing major impacts on treatment and care decisions.
Conclusions:
- Integrating multi-omic approaches into mainstream diagnostic practice offers significant clinical utility for rare disease genomic testing.
- Rapid and accurate genomic diagnosis in critical care settings can substantially improve patient management and outcomes.
- The study provides preliminary evidence for the effectiveness of comprehensive genomic testing in critically ill pediatric populations.
Abstract:
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.
