Feasibility of Targeted Next-Generation DNA Sequencing for Expanding Population Newborn Screening

Bennett Oh Vic Shum, Carel Jacobus Pretorius, Letitia Min Fen Sng, Ilya Henner, Paulette Barahona, Emre Basar, Jim McGill, Urs Wilgen, Anna Zournazi, Lilian Downie, Natalie Taylor, Liam Cheney, Sylvania Wu, Natalie Angela Twine, Denis Carolin Bauer, Gerald Francis Watts, Akash Navilebasappa, Kishore Rajagopal Kumar, Jacobus Petrus Johannes Ungerer, Glenn Bennett

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Newborn screening (NBS) is an effective public health intervention that reduces death and disability from treatable genetic diseases, but many conditions are not screened due to a lack of a suitable assay. Whole genome and whole exome sequencing can potentially expand NBS but there remain many technical challenges preventing their use in population NBS. We investigated if targeted gene sequencing (TGS) is a feasible methodology for expanding NBS. METHODS: We constructed a TGS panel of 164 genes which screens for a broad range of inherited conditions. We designed a high-volume, low-turnaround laboratory and bioinformatics workflow that avoids the technical and data interpretation challenges associated with whole genome and whole exome sequencing. A methods-based analytical validation of the assay was completed and test performance in 2552 newborns examined. We calculated annual birth estimates for each condition to assess cost-effectiveness. RESULTS: Assay analytical sensitivity was >99% and specificity was 100%. Of the newborns screened, 1.3% tested positive for a condition. On average, each individual had 225 variants to interpret and 1.8% were variants of uncertain significance (VUS). The turnaround time was 7 to 10 days. Maximum batch size was 1536 samples. CONCLUSIONS: We demonstrate that a TGS assay could be incorporated into an NBS program soon to increase the number of conditions screened. Additionally, we conclude that NBS using TGS may be cost-effective.

Original languageEnglish
Pages (from-to)890-900
Number of pages11
JournalClinical Chemistry
Issue number8
Publication statusPublished - 2 Aug 2023

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