Newborn screening research sponsored by the <scp>NIH</scp>: From diagnostic paradigms to precision therapeutics

Minear, Mollie A.; Phillips, Megan N; Kau, Alice; Parisi, Melissa A.

doi:10.1002/ajmg.c.31997

Cited by 6 publications

(2 citation statements)

References 54 publications

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“…There are several recent reports concerning new genomic research and NBS: review of the involvement of the USA National Institutes of Health (NIH) in support of NBS-oriented research and its future in supporting genomic research [ 173 ]; lessons learned from early NBS studies examining the use of whole genome and exome sequencing as screening tools and the technical, ethical, and societal challenges to broad implementation [ 174 ]; the role of exome sequencing in NBS for IEM [ 175 ]; the need for innovative trial designs in genomic NBS research and the necessity for partnerships with health authorities, patients, researchers, and drug developers to match pace with the development of targeted therapeutics [ 176 ]; discussions from a June 2021, 3-day NIH-sponsored workshop entitled, “Gene-Targeted Therapies: Early Diagnosis and Equitable Delivery” [ 177 ]; discussion of the knowledge gaps in genetic NBS globally, the opportunities for innovative research, and the need for attention to equitable implementation of research findings [ 178 ]; a survey study of 238 rare disease experts showing broad endorsement of the availability of genomic sequencing for monogenic treatable conditions for all newborns [ 179 ]; and a review of the challenges and opportunities of genomic NBS for rare diseases and the need to generate evidence of benefit and answers to ethical, legal and psychosocial questions [ 180 ].…”

Section: Resultsmentioning

confidence: 99%

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Therrell,

Padilla,

Borrajo

et al. 2024

IJNS

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Newborn bloodspot screening (NBS) began in the early 1960s based on the work of Dr. Robert “Bob” Guthrie in Buffalo, NY, USA. His development of a screening test for phenylketonuria on blood absorbed onto a special filter paper and transported to a remote testing laboratory began it all. Expansion of NBS to large numbers of asymptomatic congenital conditions flourishes in many settings while it has not yet been realized in others. The need for NBS as an efficient and effective public health prevention strategy that contributes to lowered morbidity and mortality wherever it is sustained is well known in the medical field but not necessarily by political policy makers. Acknowledging the value of national NBS reports published in 2007, the authors collaborated to create a worldwide NBS update in 2015. In a continuing attempt to review the progress of NBS globally, and to move towards a more harmonized and equitable screening system, we have updated our 2015 report with information available at the beginning of 2024. Reports on sub-Saharan Africa and the Caribbean, missing in 2015, have been included. Tables popular in the previous report have been updated with an eye towards harmonized comparisons. To emphasize areas needing attention globally, we have used regional tables containing similar listings of conditions screened, numbers of screening laboratories, and time at which specimen collection is recommended. Discussions are limited to bloodspot screening.

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Section: Resultsmentioning

confidence: 99%

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Therrell,

Padilla,

Borrajo

et al. 2024

IJNS

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“…Technological advances are enabling the integration of genome sequencing into routine healthcare, including proposals and large pilot programs to study the impact of including DNA sequence-based diagnostics in newborn screening. 42 While many human genes are clinically actionable, i.e. the presence of a pathogenic variant changes medical management, currently only ~2% of germline missense variants have clinical interpretations.…”

Section: Discussionmentioning

confidence: 99%

The functional impact of 1,570 SNP-accessible missense variants in humanOTC

Cromie

Tang

et al. 2022

Preprint

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Deleterious mutations in the X-linked gene encoding ornithine transcarbamylase (OTC) cause the most common urea cycle disorder, OTC deficiency. This rare, but highly actionable disease can present with severe neonatal onset in males or with later onset in either sex. Neonatal onset patients appear normal at birth but rapidly develop hyperammonemia, which can progress to cerebral edema, coma and death, outcomes ameliorated by rapid diagnosis and treatment. Existing biochemical assays have limitations, including the sensitivity of the citrulline assays used in newborn screening panels. With prior knowledge of variant pathogenicity, DNA sequence-based diagnostics would provide an alternative screening method. Here, we develop a high throughput functional assay for human OTC and measure the impact of 1,570 variants, 84% of all SNP-accessible missense mutations. Our assay scores agree well with existing clinical significance calls, distinguishing known benign from pathogenic variants and variants with neonatal onset from late-onset disease presentation. Further, use of an intronless expression construct allows us to measure the impact of amino acid changes at splice sites independent of their effect on splicing, thereby separating the contribution of splicing and protein coding changes to aid the analysis of molecular mechanisms underlying pathogenicity. Finally, we assess the utility of our functional data on OTC variant curation by using the current ACMG/AMP guidelines to reclassify variants. Inclusion of our data as PS3/BS3 substantially improves variant interpretation. Thus, our dataset is of high clinical utility and illustrates the power of functional assays to inform interpretation of existing and novel genetic variation.

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Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions

Ziegler,

Koval-Burt,

Kay

et al. 2024

JAMA

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ImportanceThe feasibility of implementing genome sequencing as an adjunct to traditional newborn screening (NBS) in newborns of different racial and ethnic groups is not well understood.ObjectiveTo report interim results of acceptability, feasibility, and outcomes of an ongoing genomic NBS study in a diverse population in New York City within the context of the New York State Department of Health Newborn Screening Program.Design, Setting, and ParticipantsThe Genomic Uniform-screening Against Rare Disease in All Newborns (GUARDIAN) study was a multisite, single-group, prospective, observational investigation of supplemental newborn genome screening with a planned enrollment of 100 000 participants. Parent-reported race and ethnicity were recorded at the time of recruitment. Results of the first 4000 newborns enrolled in 6 New York City hospitals between September 2022 and July 2023 are reported here as part of a prespecified interim analysis.ExposureSequencing of 156 early-onset genetic conditions with established interventions selected by the investigators were screened in all participants and 99 neurodevelopmental disorders associated with seizures were optional.Main Outcomes and MeasuresThe primary outcome was screen-positive rate. Additional outcomes included enrollment rate and successful completion of sequencing.ResultsOver 11 months, 5555 families were approached and 4000 (72.0%) consented to participate. Enrolled participants reflected a diverse group by parent-reported race (American Indian or Alaska Native, 0.5%; Asian, 16.5%; Black, 25.1%; Native Hawaiian or Other Pacific Islander, 0.1%; White, 44.7%; 2 or more races, 13.0%) and ethnicity (Hispanic, 44.0%; not Hispanic, 56.0%). The majority of families consented to screening of both groups of conditions (both groups, 90.6%; disorders with established interventions only, 9.4%). Testing was successfully completed for 99.6% of cases. The screen-positive rate was 3.7%, including treatable conditions that are not currently included in NBS.Conclusions and RelevanceThese interim findings demonstrate the feasibility of targeted interpretation of a predefined set of genes from genome sequencing in a population of different racial and ethnic groups. DNA sequencing offers an additional method to improve screening for conditions already included in NBS and to add those that cannot be readily screened because there is no biomarker currently detectable in dried blood spots. Additional studies are required to understand if these findings are generalizable to populations of different racial and ethnic groups and whether introduction of sequencing leads to changes in management and improved health outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT05990179

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Newborn screening research sponsored by the NIH: From diagnostic paradigms to precision therapeutics

Cited by 6 publications

References 54 publications

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

Current Status of Newborn Bloodspot Screening Worldwide 2024: A Comprehensive Review of Recent Activities (2020–2023)

The functional impact of 1,570 SNP-accessible missense variants in humanOTC

Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions

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