First-Tier Next Generation Sequencing for Newborn Screening: An Important Role for Biochemical Second-Tier Testing

Overview

Journal Genet Med Open

Date 2024 Sep 6

PMID 39238532

Authors

Sarah L Stenton

Madelynn Campagna

Anthony Philippakis

Anne ODonnell-Luria

Michael H Gelb

Affiliations

Soon will be listed here.

Abstract

There is discussion of expanding newborn screening (NBS) through the use of genomic sequence data; yet, challenges remain in the interpretation of DNA variants. Population-level DNA variant databases are available, and it is possible to estimate the number of newborns who would be flagged as having a risk for a genetic disease (including rare variants of unknown significance, VUS) via next-generation sequencing (NGS) positive. Estimates of the number of newborns screened as NGS positive for monogenic recessive diseases were obtained by analysis of the Genome Aggregation Database (gnomAD). For a collection of diseases for which there is interest in NBS, we provided 2 estimates for the expected number of newborns screened as NGS positive. For a set of lysosomal storage diseases, we estimated that 100 to approximately 600 NGS screen positives would be found per disease per year in a large NBS laboratory (California), and this figure may be expected to rise to a limit of about 1000 if we account for the fact that gnomAD does not contain all worldwide variants. The number of positives would drop 2.5- to 10-fold if the 10 VUS with highest allele frequency were biochemically annotated as benign. It is proposed that a second-tier biochemical assay using the same dried blood spot could be carried out as a filter and as part of NBS to reduce the number of high-risk NGS positive newborns to a manageable number.

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References

De La Vega F, Chowdhury S, Moore B, Frise E, McCarthy J, Hernandez E . Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases. Genome Med. 2021; 13(1):153. PMC: 8515723. DOI: 10.1186/s13073-021-00965-0. View

Ceyhan-Birsoy O, Murry J, Machini K, Lebo M, Yu T, Fayer S . Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Am J Hum Genet. 2019; 104(1):76-93. PMC: 6323417. DOI: 10.1016/j.ajhg.2018.11.016. View

Trinidad M, Hong X, Froelich S, Daiker J, Sacco J, Nguyen H . Predicting disease severity in metachromatic leukodystrophy using protein activity and a patient phenotype matrix. Genome Biol. 2023; 24(1):172. PMC: 10360315. DOI: 10.1186/s13059-023-03001-z. View

Adhikari A, Gallagher R, Wang Y, Currier R, Amatuni G, Bassaganyas L . The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat Med. 2020; 26(9):1392-1397. PMC: 8800147. DOI: 10.1038/s41591-020-0966-5. View

Vaz F, Bootsma A, Kulik W, Verrips A, Wevers R, Schielen P . A newborn screening method for cerebrotendinous xanthomatosis using bile alcohol glucuronides and metabolite ratios. J Lipid Res. 2017; 58(5):1002-1007. PMC: 5408618. DOI: 10.1194/jlr.P075051. View

Guenzel A, Turgeon C, Nickander K, White A, Peck D, Pino G . The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease. Genet Med. 2020; 22(6):1108-1118. DOI: 10.1038/s41436-020-0764-y. View

Collins C, Yi F, Dayuha R, Duong P, Horslen S, Camarata M . Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease. Gastroenterology. 2021; 160(7):2367-2382.e1. PMC: 8243898. DOI: 10.1053/j.gastro.2021.02.052. View

Herbst Z, Urdaneta L, Klein T, Burton B, Basheeruddin K, Liao H . Evaluation of Two Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis Type II. Int J Neonatal Screen. 2022; 8(1). PMC: 8884011. DOI: 10.3390/ijns8010009. View

Ioannidis N, Rothstein J, Pejaver V, Middha S, McDonnell S, Baheti S . REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. Am J Hum Genet. 2016; 99(4):877-885. PMC: 5065685. DOI: 10.1016/j.ajhg.2016.08.016. View

10.

Findlay G, Daza R, Martin B, Zhang M, Leith A, Gasperini M . Accurate classification of BRCA1 variants with saturation genome editing. Nature. 2018; 562(7726):217-222. PMC: 6181777. DOI: 10.1038/s41586-018-0461-z. View

11.

Collins C, Chang I, Jung S, Dayuha R, Whiteaker J, Segundo G . Rapid Multiplexed Proteomic Screening for Primary Immunodeficiency Disorders From Dried Blood Spots. Front Immunol. 2018; 9:2756. PMC: 6288356. DOI: 10.3389/fimmu.2018.02756. View

12.

Bailey Jr D, Porter K, Andrews S, Raspa M, Gwaltney A, Peay H . Expert Evaluation of Strategies to Modernize Newborn Screening in the United States. JAMA Netw Open. 2021; 4(12):e2140998. PMC: 8717100. DOI: 10.1001/jamanetworkopen.2021.40998. View

13.

Peck D, Lacey J, White A, Pino G, Studinski A, Fisher R . Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I. Int J Neonatal Screen. 2020; 6(1):10. PMC: 7422968. DOI: 10.3390/ijns6010010. View

14.

Bick D, Jones M, Taylor S, Taft R, Belmont J . Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases. J Med Genet. 2019; 56(12):783-791. PMC: 6929710. DOI: 10.1136/jmedgenet-2019-106111. View

15.

Pejaver V, Byrne A, Feng B, Pagel K, Mooney S, Karchin R . Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria. Am J Hum Genet. 2022; 109(12):2163-2177. PMC: 9748256. DOI: 10.1016/j.ajhg.2022.10.013. View

16.

Jee H, Huang Z, Baxter S, Huang Y, Taylor M, Henderson L . Comprehensive analysis of ADA2 genetic variants and estimation of carrier frequency driven by a function-based approach. J Allergy Clin Immunol. 2021; 149(1):379-387. PMC: 8591146. DOI: 10.1016/j.jaci.2021.04.034. View

17.

Roman T, Crowley S, Roche M, Foreman A, ODaniel J, Seifert B . Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project. Am J Hum Genet. 2020; 107(4):596-611. PMC: 7536575. DOI: 10.1016/j.ajhg.2020.08.001. View