A systematic review of real-world applications of genome sequencing for newborn screening

Abstract

Aim: With the costs of genomic sequencing falling quickly and an ever-increasing number of clinical laboratories equipped with new-generation sequencing machines, healthcare systems around the world are getting ready to enter the era of genomic newborn screening (NBS). However, the adoption of Genomic Sequencing (GS), encompassing whole-exome sequencing (WES) and whole-genome sequencing (WGS), in NBS programs raises a number of clinical, ethical, and legal questions as well as organizational and economic challenges. This systematic review is part of a feasibility study to assess the introduction of WGS for NBS in Lombardy region with the specific aim of gathering evidence from existing pilots in the field whose results have been published.

Methods: Three different sources were identified for the selection of articles in order to obtain a various and unbiased set of publications. 33 articles were retained for analysis to answer the following questions:

1. Clinical: Does genomic sequencing demonstrate clinical utility in the context of NBS? What are the limitations of these kind of programs?

2. Societal: What are the social, ethical and psychological implications of using GS for NBS?

3. Governance: What are the legal, economic, and organizational challenges for GS-based NBS programs?

Results: There is a general consensus in the literature on the key principles that should guide the adoption of GS in NBS, such as the inclusion of actionable genes only, the need for informed consent from the parents, the right of the newborn to an open future, which means the exclusion of late-onset diseases even when those are considered treatable. However, there are still several differences in how these principles are detailed and applied.

Conclusion: Real-world evidence from a handful of pilot projects (namely BabySeq and NC-Nexus, both carried out in the USA) have been published recently; however, this evidence is not yet sufficient to put an end to the broad and animated debate on the use of GS for NBS. Ethical, legal, and social issues still constitute great challenges and major barriers to wide and uniform adoption of GS in NBS. On the clinical side, a number of issues remain unaddressed, such as the benefits and limitations of the different approaches (targeted sequencing, GS only versus GS+standard NBS), the genes/diseases to include and the frequency of incidental findings, identification of carrier status, and variants of uncertain significance (VUS). Further pilots and consultations with involved stakeholders will be necessary before GS-based NBS can be accepted and systematically implemented in national healthcare programs.

Keywords

Newborn screening / genome sequencing / whole exome sequencing / whole genome sequencing

References

[1] Loeber JG,Zetterström RH.Neonatal screening in europe revisited: An ISNS perspective on the current state and developments since 2010.Int J Neonatal Screen2021;7:15 PMCID:PMC8006225

[2] Berg JS,O'Daniel JM.A semiquantitative metric for evaluating clinical actionability of incidental or secondary findings from genome-scale sequencing.Genet Med2016;18:467-75 PMCID:PMC4752935

[3] Berg JS,Bailey DB Jr.Newborn sequencing in genomic medicine and public health.Pediatrics2017;139 PMCID:PMC5260149

[4] Burlina A,Chakrapani A.A new approach to objectively evaluate inherited metabolic diseases for inclusion on newborn screening programmes.Int J Neonatal Screen2022;8:25 PMCID:PMC9036245

[5] Milko LV,DeCristo DM.An age-based framework for evaluating genome-scale sequencing results in newborn screening.J Pediatr2019;209:68-76 PMCID:PMC6535354

[6] Ceyhan-Birsoy O,Lebo MS.A curated gene list for reporting results of newborn genomic sequencing.Genet Med2017;19:809-18 PMCID:PMC5507765

[7] Andermann A,Beauchamp S.Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years.Bull World Health Organ2008;86:317-9 PMCID:PMC2647421

[8] Pereira S,Gutierrez AM.BabySeq Project GroupPerceived benefits, risks, and utility of newborn genomic sequencing in the babyseq project.Pediatrics2019;143:S6-S13 PMCID:PMC6480393

[9] Zacharias RL,King JS.The legal dimensions of genomic sequencing in newborn screening.Hastings Cent Rep2018;48 Suppl 2:S39-41

[10] Tarini BA.Ethical issues with newborn screening in the genomics era.Annu Rev Genomics Hum Genet2012;13:381-93 PMCID:PMC3625041

[11] Lantos JD.Ethical and psychosocial issues in whole genome sequencing (WGS) for newborns.Pediatrics2019;143:S1-5

[12] Ross LF.Ethical issues in newborn sequencing research: the case study of babyseq.Pediatrics2019;144 PMCID:PMC6889970

[13] Pichini A,Patch C.Developing a national newborn genomes program: an approach driven by ethics, engagement and co-design.Front Genet2022;13:866168. PMCID:PMC9195613

[14] Holm IA,Ceyhan-Birsoy O.BabySeq project teamthe babyseq project: implementing genomic sequencing in newborns.BMC Pediatr2018;18:225 PMCID:PMC6038274

[15] Schuijff M.Practices of responsible research and innovation: a review.Sci Eng Ethics2020;26:533-74

[16] Loeber A,Nieminen M.Implementing responsible research and innovation: from new public management to new public governance. In: Blok V, editor. Putting Responsible Research and Innovation into Practice. Cham: Springer International Publishing; 2023. pp. 211-28.

[17] Responsible research and innovation: Europe’s ability to respond to societal challenges Available from: https://data.europa.eu/doi/10.2777/11739 [Last accessed on 24 Aug 2023]

[18] European commission. Open innovation, open science, open to the world. Available from: http://europa.eu/rapid/press-release_SPEECH-15-5243_en.htm [Last accessed on 24 Aug 2023]

[19] HTA core model^R version 3.0. Available from: https://www.eunethta.eu/hta-core-model/ [Last accessed on 29 Aug 2023]

[20] HTA core model version 3.0. Available from: https://www.eunethta.eu/wp-content/uploads/2018/03/HTACoreModel3.0-1.pdf [Last accessed on 29 Aug 2023]

[21] Downie L,Lewis S.Principles of genomic newborn screening programs: a systematic review.JAMA Netw Open2021;4:e2114336 PMCID:PMC8293022

[22] Souche E,Brosens E.Recommendations for whole genome sequencing in diagnostics for rare diseases.Eur J Hum Genet2022;30:1017-21 PMCID:PMC9437083

[23] Hendricks-Sturrup RM.When should genomic and exome sequencing be implemented in newborns?.Genet Med2020;22:809-10

[24] van El CG,Borry P.Whole-genome sequencing in health care: recommendations of the European society of human genetics.Eur J Hum Genet2013;21:580-4 PMCID:PMC3658192

[25] Morava E,Patterson M,Rahman S.Newborn screening: to WES or not to WES, that is the question.J Inherit Metab Dis2020;43:904-5

[26] Veldman A,Heiner-Fokkema MR.Towards next-generation sequencing (NGS)-based newborn screening: a technical study to prepare for the challenges ahead.Int J Neonatal Screen2022;8:17 PMCID:PMC8949100

[27] Roman TS,Roche MI.Genomic sequencing for newborn screening: results of the NC NEXUS project.Am J Hum Genet2020;107:596-611 PMCID:PMC7536575

[28] Ceyhan-Birsoy O,Machini K.BabySeq Project TeamInterpretation of genomic sequencing results in healthy and ill newborns: results from the BabySeq project.Am J Hum Genet2019;104:76-93 PMCID:PMC6323417

[29] Wojcik MH,Ceyhan-Birsoy O.BabySeq Project TeamDiscordant results between conventional newborn screening and genomic sequencing in the BabySeq Project.Genet Med2021;23:1372-5 PMCID:PMC826347

[30] Genetti CA,Robinson JO.BabySeq Project TeamParental interest in genomic sequencing of newborns: enrollment experience from the BabySeq project.Genet Med2019;21:622-30 PMCID:PMC6420384

[31] Lewis MA,Roche MI.Supporting parental decisions about genomic sequencing for newborn screening: the NC NEXUS decision Aid.Pediatrics2016;137 Suppl 1:S16-23 PMCID:PMC4922487

[32] Ulm E,Dineen R,Wicklund C.Genetics professionals' opinions of whole-genome sequencing in the newborn period.J Genet Couns2015;24:452-63

[33] Bombard Y,Hayeems RZ.Public views on participating in newborn screening using genome sequencing.Eur J Hum Genet2014;22:1248-54 PMCID:PMC4200434

[34] Johnston J,Goldenberg A,Parens E.members of the NSIGHT Ethics and Policy Advisory BoardSequencing newborns: a call for nuanced use of genomic technologies.Hastings Cent Rep2018;48 Suppl 2:S2-6 PMCID:PMC6901349

[35] Reinstein E.Challenges of using next generation sequencing in newborn screening.Genet Res2015;97:e21 PMCID:PMC6863625

[36] Grob R,Timmermans S.Families' experiences with newborn screening: a critical source of evidence.Hastings Cent Rep2018;48 Suppl 2:S29-31

[37] Joseph G,Harris-Wai J,Young C.Parental views on expanded newborn screening using whole-genome sequencing.Pediatrics2016;137 Suppl 1:S36-46 PMCID:PMC4939888

[38] King JS.Whole-genome screening of newborns?.Pediatrics2016;137 Suppl 1:S8-15 PMCID:PMC4939764

[39] Friedman JM,Goldenberg AJ,Sénécal K.Global Alliance for Genomics and Health Regulatory and Ethics Working Group Paediatric Task TeamGenomic newborn screening: public health policy considerations and recommendations.BMC Med Genomics2017;10:9 PMCID:PMC5320805

[40] Morrison A. Newborn screening for disorders and abnormalities in Canada. Available from: https://www.cadth.ca/sites/default/files/pdf/Newborn_Screening_es-26_e.pdf [Last accessed on 24 Aug 2023]

[41] Goldenberg AJ.The ethical hazards and programmatic challenges of genomic newborn screening.JAMA2012;307:461-2 PMCID:PMC3868436

[42] Timmermans S.Patients-in-waiting: living between sickness and health in the genomics era.J Health Soc Behav2010;51:408-23

[43] COMMITTEE ON BIOETHICS, COMMITTEE ON GENETICS, AND, AMERICAN COLLEGE OF MEDICAL GENETICS AND, GENOMICS SOCIAL, ETHICAL, LEGAL ISSUES COMMITTEEEthical and policy issues in genetic testing and screening of children.Pediatrics2013;131:620-2

[44] Alarcón Garavito GA,Déom N,Pichini A.The implementation of large-scale genomic screening or diagnostic programmes: a rapid evidence review.Eur J Hum Genet2023;31:282-95 PMCID:PMC9995480