Newborn Sequencing: Approaches taken by programs around the globe
Ethical Legal Social Issues (ELSI) Public Health and Policy
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
Methods:
Over 20 programs were surveyed or studied based on published reports to understand analytic practices, data handling, and reporting. Of the more than 20 programs surveyed, 15 responded by June 2024, and 14 of these allowed their data to be used. Responses were combined with published data to highlight similarities and differences, and to broaden and advance the conversation on newborn sequencing.
Results:
Survey respondents represented 14 distinct programs, most of which (n=11) focused on genomic sequencing of asymptomatic newborns. Most programs collaborate with others, for example via International Consortium on Newborn Sequencing (ICoNS). Most aim to supplement existing newborn bloodspot screening. All programs responding to the survey use short-read sequencing; >60% of programs sequence the genome, but no program reports all variants from the genome. A minority of programs use or plan to use orthogonal testing to confirm results and/or assess variants not consistently identified by short-read sequencing.
Conclusion:
Newborn screening (NBS) initiated in the US in the 1960s and quickly became one of the most impactful public health endeavors ever implemented. NBS continues to expand globally. Newborn genetic sequencing appeared on the horizon only recently and offers a paradigm shift whereby molecular screening occurs at birth as a supplement to, or instead of biochemical NBS. Over 30 newborn sequencing pilots or programmatic offerings exist or have been run globally, with many others in preparation or nearing launch. Differences in genes targeted by programs were recently reviewed (Gold et al., JAMA Netw Open, 2023; Minten et al., medRxiv preprint, 2024; Ziegler et al., JAMA, 2024). Gene-disease pairs range from 100 to over 1000, with 1,750 distinct genes targeted across all programs.
Methods:
Over 20 programs were surveyed or studied based on published reports to understand analytic practices, data handling, and reporting. Of the more than 20 programs surveyed, 15 responded by June 2024, and 14 of these allowed their data to be used. Responses were combined with published data to highlight similarities and differences, and to broaden and advance the conversation on newborn sequencing.
Results:
Survey respondents represented 14 distinct programs, most of which (n=11) focused on genomic sequencing of asymptomatic newborns. Most programs collaborate with others, for example via International Consortium on Newborn Sequencing (ICoNS). Most aim to supplement existing newborn bloodspot screening. All programs responding to the survey use short-read sequencing; >60% of programs sequence the genome, but no program reports all variants from the genome. A minority of programs use or plan to use orthogonal testing to confirm results and/or assess variants not consistently identified by short-read sequencing.
Criteria used to select conditions, as reported from survey respondents, include: 1) adapted Wilson-Jungner criteria, 2) Automated Semiquantitative Metric (ASQM) criteria for actionability, 3) a Delphi panel, or 4) other criteria. Programs also reported using multiple databases/resources to identify gene-condition pairs including: ClinGen, GTRx, Mastermind,PanelApp (UK or Australia), rx-genes, or other. An analysis of gene content of various programs (including those surveyed and those with publicly accessed data) revealed variability in gene content, even when restricting to gene-conditions with existing treatment guidelines and orthogonal test availability.
Programs from the survey vary in variant of uncertain significance (VUS) reporting. All programs report results consistent with disease, with a minority reporting potentially positive results for autosomal recessive disorders (1 pathogenic or likely pathogenic with a VUS) and a minority reporting VUS for dominant disorders. A minority also report carrier results. Most programs are contributing or will contribute to variant databases such as ClinVar (70%).
Conclusion:
Newborn genomic sequencing is rapidly becoming faster, cheaper, and more widely available in screening pilots around the world. As a screening program, newborn sequencing is not a diagnostic test; confirmatory testing is warranted to confirm clinical diagnosis and improve screening accuracy. Gene panels used for newborn genomic sequencing vary widely, making it difficult to compare detection rates and outcomes. Further, there is a need for the medical and public health community to align on benefit-risk for the diseases screened.
Programs are divided on whether to return VUS to families, making it difficult to compare detection rates and to evaluate the impact of false positives and false negatives, highlighting an opportunity for standard reporting of VUS. Data storage and use of data by programs varies, and external access is limited. Developing cross-program data federation practices and broadening access to patient results will facilitate research on impact of newborn genomic sequencing, which can spur wider adoption and improve variant classification. Long-term sustainable federation models continue to emerge and present an opportunity to harmonize and improve actionability.