Genomic Screening for Rare Genetic Conditions in Newborns

(GUARDIAN Trial)

Overseen By Anah Hetzler

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Columbia University

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

100000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate how effectively genome sequencing-based newborn screening (a detailed analysis of a baby's DNA) can detect rare genetic conditions in newborns. The goal is to expand the list of conditions checked in standard newborn screenings, potentially identifying more treatable disorders early. This could benefit families interested in learning about conditions with available treatments or those in development. Newborns eligible for this trial must be born after 33 weeks in specific hospitals, with parents who speak English, Mandarin, or Spanish. As an unphased trial, this study offers families the chance to contribute to groundbreaking research that could enhance early detection and treatment options for newborns.

Will I have to stop taking my current medications?

The trial does not specify whether participants need to stop taking their current medications. Since the study involves newborns, it is unlikely that parents need to change their medication routines.

What prior data suggests that genomic sequencing-based newborn screening is safe?

Research has shown that genome sequencing for newborn screening is generally safe. Studies have found that this method can successfully identify genetic conditions in newborns without causing harm. For instance, one study found that one in 24 babies tested had positive results, allowing for early treatment. These studies reported no major safety issues, indicating that newborns tolerate the process well. The goal of using genome sequencing in newborns is to improve health outcomes by detecting conditions early, enabling prompt treatment. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about genome sequencing-based newborn screening because it offers a groundbreaking approach to identifying rare genetic conditions right after birth. Unlike traditional screening methods, which typically focus on a limited number of conditions and use biochemical tests, genome sequencing can analyze thousands of genes simultaneously, providing a comprehensive genetic profile. This method enables earlier detection and intervention, potentially improving outcomes by addressing conditions before symptoms even appear. Furthermore, this approach opens up possibilities for personalized medicine from the very start of life, tailoring healthcare to each newborn's unique genetic makeup.

What evidence suggests that genomic newborn screening is effective for identifying rare genetic conditions?

Research has shown that genome sequencing-based newborn screening can be very effective. In one study, this method identified likely positive results in one out of every 24 babies tested. Clinical studies have proven this process safe and effective. By examining a baby's genes, doctors can detect rare genetic conditions early. Early detection can lead to timely treatments and improved health throughout a child's life. ^{1 2 3 6 7}

Who Is on the Research Team?

Wendy K. Chung, MD, PhD

Principal Investigator

Boston Children's Hospital

Are You a Good Fit for This Trial?

This trial is for newborns in well-baby nurseries from certain hospitals, born after 33 weeks of gestation. It's open to babies whose parents speak English, Mandarin, or Spanish. The study aims to screen these babies for additional rare genetic conditions beyond the standard public health screenings.

Inclusion Criteria

Newborns whose parents are English, Mandarin, or Spanish speaking

Newborns admitted to the well-baby nurseries from the recruiting hospitals

My baby was born after 33 weeks of pregnancy.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Enrollment and Genomic Sequencing

Newborns are enrolled in the study and undergo genomic sequencing to screen for additional conditions beyond standard newborn screening.

Up to 5 years

Initial enrollment visit, followed by sequencing

Follow-up

Participants are monitored for outcomes such as successful sequencing rate and screen positive rate. Follow-up includes review of electronic medical records and parental follow-up via phone, text, postal mail, or email.

Up to 6 months after the end of enrollment

Ongoing follow-up via various communication methods

Outcome Assessment

Assessment of primary and secondary outcomes, including enrollment rate, successful sequencing rate, screen positive rate, true positive rate, and decision regret scale.

Up to 6 months after the end of enrollment

What Are the Treatments Tested in This Trial?

Interventions

• Genome sequencing-based newborn screening

Trial Overview The trial tests genome sequencing-based screening on newborns to detect rare diseases not covered by routine checks. Parents can opt-in for their baby's testing and choose which results they want: only treatable conditions or including those under research.

How Is the Trial Designed?

Group I: Enrolled in the study Experimental Treatment 1 Intervention

All newborns enrolled in the study will be evaluated.

Genome sequencing-based newborn screening is already approved in United States, China, European Union for the following indications:

Approved in United States as Genomic Newborn Screening for:

• Expanded newborn screening for over 450 genetic conditions

Approved in China as Genomic Newborn Screening for:

• Detection of monogenic disorders, including 128 diseases

Approved in European Union as Genomic Newborn Screening for:

• Not specified, but under consideration for integration into routine newborn screening programs

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Illumina, Inc.

Industry Sponsor

Trials

25

Recruited

154,000+

GeneDx

Collaborator

Trials

3

Recruited

131,000+

New York State Department of Health

Collaborator

Trials

35

Recruited

447,000+

Published Research Related to This Trial

Whole-genome and whole-exome sequencing could enhance newborn screening by identifying more metabolic disorders, but the current practice of metabolic screening remains crucial due to its established effectiveness.

The article highlights that implementing widespread newborn genome sequencing raises significant ethical, medical, psychological, and economic concerns, suggesting that it may be too early to replace traditional screening methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenges of using next generation sequencing in newborn screening. Reinstein, E.[2019]

A targeted next-generation sequencing panel (NBDx) was developed to confirm diagnoses in newborns, showing a high analytical sensitivity of 99.8% for known mutation hotspots across 126 genes related to newborn diseases.

The NBDx panel allows for rapid processing of multiple cases (8 to 20) within 105 hours, demonstrating its practicality for second-tier confirmation in clinical settings and potential for broader DNA-based screening in newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of DNA confirmatory and high-risk diagnostic testing for newborns using targeted next-generation DNA sequencing. Bhattacharjee, A., Sokolsky, T., Wyman, SK., et al.[2023]

Advancements in whole-genome sequencing (WGS) and whole-exome sequencing (WES) allow for precise identification of genetic disorders in newborns, enabling tailored treatments and interventions based on individual genomic profiles.

Despite the potential benefits of integrating genomics into newborn screening programs, there are significant challenges related to data interpretation, ethical considerations, and communication of results that must be addressed to ensure effective implementation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Newborn Screening in the Era of Precision Medicine. Yang, L., Chen, J., Shen, B.[2018]

Genomic sequencing can significantly enhance newborn screening programs by enabling rapid and accurate diagnoses of treatable rare diseases, which are major contributors to infant mortality and lifelong disabilities.

As large-scale genomic screening projects begin globally, it is crucial to generate evidence of their benefits while also addressing ethical, legal, and psychosocial challenges associated with this technology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genomic newborn screening for rare diseases. Stark, Z., Scott, RH.[2023]

Genome sequencing of newborns presents a significant opportunity to identify rare genetic disorders early, potentially before symptoms appear, which can lead to quicker diagnoses and better management of these conditions.

Efforts are underway to implement genetic screening technologies for newborns, utilizing advanced biomedical informatics and computational biology to enhance the identification of genetic risks from the start of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

USE OF GENOME DATA IN NEWBORNS AS A STARTING POINT FOR LIFE-LONG PRECISION MEDICINE. Brenner, SE., Kingsmore, S., Mooney, SD., et al.[2022]

Newborn screening (NBS) programs aim to reduce disease burden in neonates by identifying conditions early, and advancements in multiplex technologies and next-generation sequencing are enabling faster and broader screening for genetic disorders.

The integration of whole exome and genome sequencing into NBS could allow for the identification of all genetic disorders at birth, facilitating timely interventions even before symptoms appear, though there are technical, ethical, and societal challenges to consider.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health. Woerner, AC., Gallagher, RC., Vockley, J., et al.[2021]

Newborn screening (NBS) is a comprehensive public health system that requires a strong culture of safety to minimize the risk of missing critical health issues in newborns.

While some advocate for genome sequencing at birth, the current NBS system relies on biomarker phenotypes, and the relationship between genotype and phenotype is not fully understood, suggesting that we should prioritize phenotypic biomarkers over genomic technology.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Newborn screening system: Safety, technology, advocacy. McCabe, ERB.[2022]

The feasibility of extending newborn screening to include genome sequencing is being actively explored, highlighting the potential benefits and risks associated with this advancement.

Discussions and funded trials are underway to address the scientific, organizational, and ethical issues that arise from genome sequencing in newborn screening, especially as some companies are already providing these services.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Sequencing babies?]. Jordan, B.[2015]

Rapid whole-genome sequencing (rWGS) for newborn screening (NBS) can identify a wide range of genetic disorders, with a high sensitivity of 88.8% and a negative predictive value of 99.6%, making it a promising tool for early diagnosis and intervention.

In a simulated study involving over 454,000 subjects, rWGS could have potentially prevented symptoms in critically ill newborns by diagnosing conditions that conventional NBS missed, highlighting its effectiveness in improving outcomes for genetic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases. Kingsmore, SF., Smith, LD., Kunard, CM., et al.[2023]

A significant majority (87.9%) of rare disease experts support the use of newborn genome sequencing (NBSeq) to identify treatable monogenic disorders in all newborns, highlighting its potential to improve early detection and treatment.

Experts recommended including 25 specific genes associated with treatable conditions in NBSeq, with 42 gene-disease pairs endorsed by at least 80% of respondents, indicating a strong consensus on which conditions should be prioritized for screening.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives of Rare Disease Experts on Newborn Genome Sequencing. Gold, NB., Adelson, SM., Shah, N., et al.[2023]

Citations

1. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2809070

Genome Sequencing for Newborn Screening The research investigated the effectiveness of gene panel sequencing as a first-tier newborn screening test at a large-population scale.

2. radygenomics.org radygenomics.org/2024/beginngs-newborn-screening-by-genome-sequencing-shown-to-be-safe-and-effective-in-two-clinical-studies/

BeginNGS® Newborn Screening by Genome Sequencing ... BeginNGS genome-based newborn screening was shown to be safe and effective. One in 24 babies tested had positive results that were likely to ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11157259/

Genomic sequencing for newborn screening Newborn sequencing (NBSeq), the comprehensive analysis of an infant's genome, holds immense promise for revolutionizing health care throughout the lifespan.

4. nature.com nature.com/articles/s41591-025-03945-8

Feasibility and clinical utility of expanded genomic ... Although genomic sequencing presents groundbreaking newborn screening (NBS) opportunities, critical feasibility and utility questions remain ...

5. clinicaltrials.gov clinicaltrials.gov/ct2/show/NCT06549218

Genetic Newborn Screening for Rare Diseases Within the ... The main objective of the genetic newborn screening part of the Screen4Care-project is to shorten the path to rare disease diagnosis and to facilitate early ...

6. nature.com nature.com/articles/s41591-024-03465-x

Population-based, first-tier genomic newborn screening in ... A workflow was developed to screen newborns for 165 treatable pediatric disorders by deep sequencing of regions of interest in 405 genes.

7. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK595231/

The Promise and Perils of Next-Generation DNA Sequencing ... Today, newborn genome sequencing, if added to public health NBS, is poised to further increase the number of detectable disorders (Bick et al., ...