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Observational Study
. 2025 Jan 21;333(3):232-240.
doi: 10.1001/jama.2024.19662.

Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions

Alban Ziegler  1 , Carrie Koval-Burt  1 , Denise M Kay  2 , Sharon F Suchy  3 , Amber Begtrup  3 , Katherine G Langley  3 , Rebecca Hernan  1 , Laura M Amendola  4 , Brenna M Boyd  1 , Jennifer Bradley  2 , Tracy Brandt  3 , Lilian L Cohen  5 , Alison J Coffey  4 , Joseph M Devaney  3 , Beata Dygulska  6 , Bethany Friedman  3 , Ramsay L Fuleihan  7 , Awura Gyimah  1 , Sihoun Hahn  8 , Sean Hofherr  3 , Kathleen S Hruska  3 , Zhanzhi Hu  9 , Médéric Jeanne  10 , Guanjun Jin  1 , D Aaron Johnson  3 , Haluk Kavus  1 , Rudolph L Leibel  1 , Steven J Lobritto  1 , Stephen McGee  3 , Joshua D Milner  7 , Kirsty McWalter  3 , Kristin G Monaghan  3 , Jordan S Orange  1 , Nicole Pimentel Soler  1 , Yeyson Quevedo  1 , Samantha Ratner  1 , Kyle Retterer  3 , Ankur Shah  11 , Natasha Shapiro  12 , Robert J Sicko  2 , Eric S Silver  13 , Samuel Strom  4 , Rebecca I Torene  3 , Olatundun Williams  14 , Vincent D Ustach  3 , Julia Wynn  1 , Ryan J Taft  4 , Paul Kruszka  3 , Michele Caggana  2 , Wendy K Chung  1   10   15
Affiliations
Observational Study

Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions

Alban Ziegler et al. JAMA. .

Abstract

Importance: The 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.

Objective: To 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 participants: The 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.

Exposure: Sequencing 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 measures: The primary outcome was screen-positive rate. Additional outcomes included enrollment rate and successful completion of sequencing.

Results: Over 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 relevance: These 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 registration: ClinicalTrials.gov Identifier: NCT05990179.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Kay reported receiving grants from Illumina and GeneDx during the conduct of the study. Dr Suchy reported receiving grants from Illumina to GeneDx during the conduct of the study; and being an employee and shareholder of GeneDx. Mrs Langley reported being an employee of GeneDx during the conduct of the study. Ms Amendola reported being an employee and shareholder of Illumina outside the submitted work. Ms Bradley reported receiving grants from Illumina and GeneDx during the conduct of the study. Dr Cohen reported receiving grants from Illumina and GeneDx during the conduct of the study. Dr Coffey reported being an employee and shareholder of Illumina. Ms Friedman reported being an employee of GeneDx during the conduct of the study. Dr Fuleihan reported receiving grants from Illumina and GeneDx to institution during the conduct of the study. Dr Hahn reported receiving grants from the National Institutes of Health during the conduct of the study; equity as a founder of Key Proteo outside the submitted work; and having a patent pending for Key Proteo. Dr Hofherr reported receiving personal fees from Fabric Genomics and Broad Institute outside the submitted work. Dr Hruska reported that Illumina provided reagents for testing during the conduct of the study; and being an employee and shareholder of GeneDx. Dr Hu reported receiving grants from Illumina and GeneDx during the conduct of the study. Dr Jeanne reported receiving grants from Illumina and GeneDx during the conduct of the study. Dr Lobritto reported receiving personal fees from Mirum (advisory board), Ipsen (advisory board and speaker's bureau), and IPRO (professional reviewer); and grants from Orphalan outside the submitted work. Dr McGee reported being an employee of GeneDx during the conduct of the study. Dr Milner reported receiving personal fees from Blueprint Medicines; and grants from Pharming outside the submitted work. Ms McWalter reported being an employee of GeneDx during the conduct of the study and outside the submitted work. Prof Orange reported receiving grants from GeneDx and Illumina during the conduct of the study. Mr Retterer reported receiving personal fees from Juno Genetics outside the submitted work. Mr Sicko reported receiving grants from Illumina and GeneDx during the conduct of the study. Dr Williams reported receiving grants from Illumina and GeneDx during the conduct of the study. Dr Ustach reported being an employee of GeneDx during the conduct of the study. Mrs Wynn reported being an employee of and owning options in BillionToOne (not an employee at the time of the study). Dr Kruszka reported being an employee of GeneDx outside the submitted work. Dr Caggana reported receiving grants from Illumina and GeneDx during the conduct of the study. Dr Chung reported in-kind support from Illumina and GeneDx; a grant from Sanofi during the conduct of the study; and being on the board of directors of Prime Medicine outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flow of Interim Analysis of the First 4000 Enrolled Newborns
GUARDIAN indicates Genomic Uniform-screening Against Rare Disease in All Newborns.
Figure 2.
Figure 2.. Genomic Uniform-Screening Against Rare Disease in All Newborns (GUARDIAN) Flow of Participants
A total of 8617 newborns were eligible for inclusion from study launch in September 2022 to July 2023. At least 1 parent was approached in person or by phone for 5555 of these newborns (approach rate, 64.5%). Parents were approached in person only on weekdays. Of those approached, 4000 consented to the study (consent rate, 72.0%), with 3624 (90.6%) consenting for the disorders with established interventions group and neurodevelopmental disorders associated with seizures group. Sequencing was successful for 3982 participants (99.6%). A total of 147 newborns (3.7%) received a positive screen result, including 4 newborns with positive screen results for G6PD deficiency and for a second condition (cystic fibrosis, sickle cell disease, mucopolysaccharidosis type VII, and TRIO-related neurodevelopmental disorder). Among the 151 positive results reported, 120 (79.5%) were confirmed as true positives, including 110 not previously identified by traditional NBS. NBS indicates newborn screening. aSee eTable 5 in Supplement 1.
Figure 3.
Figure 3.. Schematic of Variant Interpretation Workflow
A total of 3654 probands (91.8%) did not meet the study gene reporting requirements (ie, single rare variant identified in a recessive disease gene) and were automatically reported as having negative screen results. GUARDIAN indicates Genomic Uniform-screening Against Rare Disease in All Newborns. aDragen whole-genome sequencing. bVariant analysis in the Xome Analyzer platform with the study gene list filtering results in a mean of 11 variants displayed for each proband.
See this image and copyright information in PMC

Comment in

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