TY - JOUR
T1 - Feasibility of Targeted Next-Generation DNA Sequencing for Expanding Population Newborn Screening
AU - Shum, Bennett Oh Vic
AU - Pretorius, Carel Jacobus
AU - Sng, Letitia Min Fen
AU - Henner, Ilya
AU - Barahona, Paulette
AU - Basar, Emre
AU - McGill, Jim
AU - Wilgen, Urs
AU - Zournazi, Anna
AU - Downie, Lilian
AU - Taylor, Natalie
AU - Cheney, Liam
AU - Wu, Sylvania
AU - Twine, Natalie Angela
AU - Bauer, Denis Carolin
AU - Watts, Gerald Francis
AU - Navilebasappa, Akash
AU - Kumar, Kishore Rajagopal
AU - Ungerer, Jacobus Petrus Johannes
AU - Bennett, Glenn
N1 - Publisher Copyright:
© American Association for Clinical Chemistry 2023. All rights reserved. For permissions, please e-mail: [email protected].
PY - 2023/8/1
Y1 - 2023/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85166442309&partnerID=8YFLogxK
U2 - 10.1093/clinchem/hvad066
DO - 10.1093/clinchem/hvad066
M3 - Article
C2 - 37443404
AN - SCOPUS:85166442309
SN - 0009-9147
VL - 69
SP - 890
EP - 900
JO - Clinical Chemistry
JF - Clinical Chemistry
IS - 8
ER -
