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

Trial Summary

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 data supports the effectiveness of the treatment Genome sequencing-based newborn screening?

Research shows that rapid whole-genome sequencing (rWGS) can identify genetic disorders in newborns with high accuracy, detecting 87% of diagnoses previously made by traditional methods and finding additional cases not caught by conventional screening. This approach could potentially prevent symptoms in critically ill children if interventions are started early. ^{1 2 3 4 5}

Is genomic screening for newborns safe?

Genomic screening for newborns, such as whole genome sequencing, is being explored in several trials and has shown promise in accurately diagnosing genetic conditions early. However, there are ongoing discussions about its safety, ethical, and legal implications, and more evidence is needed to fully understand its benefits and risks. ^{1 2 6 7 8}

How does genomic newborn screening differ from other treatments for rare genetic conditions in newborns?

Genomic newborn screening is unique because it uses whole genome sequencing to identify almost all genetic disorders in newborns before symptoms appear, allowing for early intervention. This approach is more comprehensive than traditional newborn screening, which typically tests for a limited number of conditions by measuring blood metabolites. ^{1 7 8 9 10}

What is the purpose of this trial?

The goal of this study is to learn how genomic sequencing technology can be used to effectively expand the conditions screened on newborn screening. Newborn screening ensures equity and allows all babies to have the same chance at the healthiest life. Families will be invited to have their newborn baby screened for additional conditions beyond what all babies are screened for as part of the newborn screening public health program. Families can choose to be part of the study or choose not to be part of the study and just have the routine newborn screening test. Families will also be able to choose to learn about their baby's risk for conditions that have effective treatments available but are not on the routine newborn screening panel or also learn about conditions for which there is not currently FDA approved medications but for which medications are under development or for which early intervention services or treatment of seizures may improve the child's outcome. Families will be invited to the study shortly after the baby is born and will learn the decision not to participate, and we will interview a subset of parents who agree to be interviewed. Newborns who screen positive will be referred to appropriate providers for care and will be followed through review of electronic medical records and parental follow up via phone, text, postal mail or email.

Research Team

Wendy K. Chung, MD, PhD

Principal Investigator

Boston Children's Hospital

Eligibility Criteria

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 admitted to the well-baby nurseries from the recruiting hospitals

Newborns whose parents are English, Mandarin, or Spanish speaking

My baby was born after 33 weeks of pregnancy.

Timeline

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Genomic newborn screening for rare diseases. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

Perspectives of Rare Disease Experts on Newborn Genome Sequencing. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Development of DNA confirmatory and high-risk diagnostic testing for newborns using targeted next-generation DNA sequencing. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Newborn Screening in the Era of Precision Medicine. [2018]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. France pubmed.ncbi.nlm.nih.gov

[Sequencing babies?]. [2015]

8. Switzerland pubmed.ncbi.nlm.nih.gov

The Use of Whole Genome and Exome Sequencing for Newborn Screening: Challenges and Opportunities for Population Health. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

USE OF GENOME DATA IN NEWBORNS AS A STARTING POINT FOR LIFE-LONG PRECISION MEDICINE. [2022]

10. England pubmed.ncbi.nlm.nih.gov

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