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Feasibility of Targeted Next-Generation DNA Sequencing for Expanding Population Newborn Screening
Bennett Oh Vic Shum1,2, Carel Jacobus Pretorius3,4, Letitia Min Fen Sng5,6
1Preventive Health Division, Genepath, Sydney, NSW, Australia.
Clinical Chemistry
|July 14, 2023
Summary
Targeted gene sequencing (TGS) offers a feasible method to expand newborn screening (NBS) for genetic diseases. This approach demonstrates high accuracy and cost-effectiveness, paving the way for broader NBS programs.
Area of Science:
- Genomics
- Public Health
- Clinical Diagnostics
Background:
- Newborn screening (NBS) is crucial for early detection of genetic disorders but is limited by the availability of suitable assays.
- Whole genome and whole exome sequencing present technical hurdles for population-level NBS.
- Targeted gene sequencing (TGS) is explored as a potential solution to expand NBS capabilities.
Purpose of the Study:
- To investigate the feasibility of targeted gene sequencing (TGS) for expanding newborn screening (NBS).
- To develop and validate a TGS assay for a broad range of inherited conditions.
- To assess the cost-effectiveness of TGS for NBS.
Main Methods:
- A TGS panel encompassing 164 genes was developed to screen for diverse inherited conditions.
- A high-throughput, low-turnaround laboratory and bioinformatics workflow was established, mitigating challenges of WGS/WES.
- Analytical validation and performance testing in 2552 newborns were conducted, alongside cost-effectiveness analysis.
Main Results:
- The TGS assay achieved analytical sensitivity greater than 99% and 100% specificity.
- 1.3% of newborns screened tested positive for a condition, with an average of 225 variants per individual requiring interpretation.
- Turnaround time was 7–10 days, with a maximum batch size of 1536 samples, and 1.8% variants of uncertain significance (VUS) were identified.
Conclusions:
- Targeted gene sequencing (TGS) is a viable method for enhancing newborn screening (NBS) programs.
- The TGS assay demonstrates potential for cost-effective implementation in NBS.
- This methodology could significantly increase the number of treatable genetic conditions identified through NBS.
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