Genome Sequencing for Newborn Screening

Recruiting at 3 trial locations

Overseen By Sheyenne Walmsley, MS, GC

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Brigham and Women's Hospital

Disqualifiers: Unwilling to share genomic reports, others

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: 5

500 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.

What data supports the effectiveness of the treatment Genome Sequencing for Newborn Screening?

Research shows that whole-genome sequencing (WGS) can help diagnose diseases in newborns that are hard to identify with regular tests, potentially improving their care. Next-generation sequencing (NGS) has also been useful in confirming genetic conditions in newborns, helping to rule out false positives and confirm diagnoses. ^{1 2 3 4 5}

Is genome sequencing safe for newborns?

Genome sequencing for newborns is generally considered safe, but there are important ethical and social considerations to keep in mind. The technology is still being studied to understand its full impact, and experts recommend careful use to avoid unnecessary risks. ^{5 6 7 8 9}

How is genome sequencing different from other newborn screening treatments?

Genome sequencing is unique because it can analyze the entire genetic makeup of a newborn in one test, identifying a wide range of genetic disorders early on, unlike traditional methods that target specific conditions. This comprehensive approach allows for the detection of single-nucleotide variants, copy number variants, and other genetic changes that might not be captured by conventional screening. ^{5 6 10 11 12}

What is the purpose of this trial?

This research study is exploring the use of genomic sequencing in the newborn period to screen healthy babies for current and future health risks. The study will enroll a diverse cohort of 500 healthy infants and their parents from Boston, MA; New York City, NY; and Birmingham, AL. A small blood sample will be collected from each infant, and whole genome sequencing will be performed in 1/2 of the cohort following a randomized controlled trial design. 3 months later, the randomization status and sequencing results will be shared with parents and pediatricians. Investigators will study the medical, behavioral, and economic outcomes of genomic sequencing to better understand how this technology can be implemented in outpatient primary care settings.

Research Team

Ingrid A. Holm, MD, MPH

Principal Investigator

Boston Children's Hospital

Robert C. Green, MD, MPH

Principal Investigator

Brigham and Women's Hospital

Eligibility Criteria

This trial is for healthy infants up to 12 months old and their parents in select U.S. cities. Parents must be over 18, speak English or Spanish, willing to have genetic counseling, and agree to place genomic reports in medical records. Infants should not show signs of genetic conditions or illness.

Inclusion Criteria

I am under 1 year old.

I can attend genetic counseling and agree to have my baby tested.

I am a parent.

Exclusion Criteria

My parents do not want my genetic test results shared with doctors.

Any infant in which clinical considerations preclude collecting blood via heel stick

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Enrollment and Sample Collection

Enrollment of 500 healthy infants and collection of a small blood sample for genomic sequencing

4 weeks

1 visit (in-person)

Randomization and Genomic Sequencing

Infants are randomized to receive either a family history report or a family history report plus whole genome sequencing

3 months

1 visit (in-person) for results disclosure

Follow-up

Participants are monitored for medical, behavioral, and economic outcomes of genomic sequencing

12 months

Surveys at baseline, 3 months, and 9 months post-disclosure

Treatment Details

Interventions

• Genome Sequencing

Trial Overview The study tests whole genome sequencing as a screening tool for future health risks in babies. It involves taking a blood sample from each infant and randomly selecting half for immediate genome sequencing, with results shared after three months.

Participant Groups

Group I: Sequencing cohort Experimental Treatment 1 Intervention

Infants receive genome sequencing with analysis of approximately 1000 genes associated with childhood-onset and highly actionable adult-onset disease risks. Pathogenic and likely pathogenic variants are reported to the child's parents and pediatrician. Participants also receive a detailed family history report and standard well-child care.

Group II: Control cohort Active Control 1 Intervention

Infants receive a detailed family history report plus standard well-child care.

Genome Sequencing is already approved in United States, European Union, China for the following indications:

Approved in United States as Genome Sequencing for:

• Newborn screening for genetic disorders
• Rare disease diagnosis

Approved in European Union as Genome Sequencing for:

• Rare genetic disorders
• Inherited diseases

Approved in China as Genome Sequencing for:

• Newborn screening for monogenic disorders
• Rare disease diagnosis

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

National Center for Advancing Translational Science (NCATS)

Collaborator

Trials

100

Recruited

32,100+

HudsonAlpha Institute for Biotechnology

Collaborator

Trials

3

Recruited

1,000+

Broad Institute of MIT and Harvard

Collaborator

Trials

21

Recruited

16,300+

Massachusetts General Hospital

Collaborator

Trials

3,066

Recruited

13,430,000+

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Collaborator

Trials

2,103

Recruited

2,760,000+

Harvard Pilgrim Health Care

Collaborator

Trials

61

Recruited

27,990,000+

Howard University

Collaborator

Trials

44

Recruited

15,200+

Icahn School of Medicine at Mount Sinai

Collaborator

Trials

933

Recruited

579,000+

HudsonAlpha Institute for Biotechnology

Collaborator

Trials

3

Recruited

1,000+

Findings from Research

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]

Whole-genome sequencing (WGS) significantly improved clinical management for acutely ill infants, with 21.1% of those receiving early results experiencing a change in management compared to only 10.3% in the delayed group, indicating a strong effect on treatment decisions.

The study involved 354 infants and showed that WGS not only provided a molecular diagnosis for more patients (31.0% in the early group vs 15.0% in the delayed group) but also has the potential to reduce healthcare disparities by offering equitable diagnostic access.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial. Krantz, ID., Medne, L., Weatherly, JM., et al.[2022]

Human genomic sequencing can provide valuable insights for diagnosis, prognosis, and treatment across various medical fields, but its widespread use is limited by a lack of evidence showing improved patient outcomes in those without specific testing indications.

The paper reviews clinical outcome studies in genomic medicine, highlighting the challenges of generating robust evidence to support the integration of next-generation sequencing into standard patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Building evidence and measuring clinical outcomes for genomic medicine. Peterson, JF., Roden, DM., Orlando, LA., et al.[2020]

Next-generation gene sequencing can sequence an individual's entire genome in under a week for $5000 to $10,000, making it a promising tool for diagnosing complex diseases that are hard to identify through traditional methods.

While there have been successful applications in diagnosing diseases and improving tumor management, significant challenges remain, including data interpretation, physician training, and the need for rigorous studies to validate its effectiveness in larger patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The promise and challenges of next-generation genome sequencing for clinical care. Johansen Taber, KA., Dickinson, BD., Wilson, M.[2022]

In a study of 1087 children, 201 were found to carry 1-4 genetic variants related to 63 genes, indicating that next-generation sequencing (NGS) can effectively identify carrier status for multiple monogenic disorders beyond initial screening methods.

The study validated 91.1% of identified variants through Sanger sequencing, demonstrating the reliability of amplicon sequencing-based carrier screening in clarifying abnormal results from liquid chromatography-tandem mass spectrometry (LC-MS/MS) tests.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amplicon sequencing-based carrier screening for 170 monogenic disorders among children with abnormal LC-MS/MS results. Chen, X., Xu, Z., Lei, X., et al.[2023]

Advancements in sequencing technologies have significantly reduced the cost and time required for whole-genome and whole-exome sequencing, making these methods more accessible for both research and clinical use.

The primary goal of newborn screening programs should be to identify gene variants that indicate a high risk for preventable or treatable conditions, allowing for early intervention and treatment during infancy or early childhood.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes. Howard, HC., Knoppers, BM., Cornel, MC., et al.[2022]

The BabySeq Project is a randomized trial involving newborns from Boston Children's Hospital and Brigham and Women's Hospital, aiming to assess the medical, behavioral, and economic impacts of genomic sequencing in newborn care.

This study will provide valuable data on the risks, benefits, and costs of integrating genomic sequencing into newborn care, which could influence future policies on universal genomic screening for newborns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The BabySeq project: implementing genomic sequencing in newborns. Holm, IA., Agrawal, PB., Ceyhan-Birsoy, O., et al.[2023]

The paper discusses the potential of next-generation sequencing technologies to revolutionize newborn screening programs by providing valuable genomic information for managing disease risks and medication responses throughout a person's life.

It highlights the significant practical, ethical, and social challenges associated with genomic data management, emphasizing the need for careful implementation to ensure that genome sequencing is used responsibly and effectively in promoting health and preventing genetic diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Genomic newborn screening. Perspective from the Ethics commission of the Spanish Society for Human Genetics. Part I. Next generation sequencing technologies applied to newborn screening. Challenges and opportunities.] Pàmpols Ros, T., Pérez Aytés, A., García Sagredo, JM., et al.[2022]

Genomic sequencing technologies are improving the accuracy and efficiency of diagnosing conditions in newborns, but there is still limited understanding of how to best implement this information in newborn screening programs.

Clinicians must navigate the complexities of presenting genomic information to families, weighing the potential benefits against the burdens and costs associated with genome sequencing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Burden and Benefits of Knowledge: Ethical Considerations Surrounding Population-Based Newborn Genome Screening for Hearing. Mitchell, CO., Rivera-Cruz, G., Chau, MHK., et al.[2022]

Genome sequencing (GS) has a diagnostic yield of 28% in a study of 2100 clinical cases, making it a valuable tool for identifying genetic conditions, especially as a first-tier test with a yield of 26%.

GS outperformed previous non-diagnostic genetic tests, providing diagnoses in 27% of cases that had previously been unresolved, highlighting its potential to significantly reduce the time taken to reach a genetic diagnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence from 2100 index cases supports genome sequencing as a first-tier genetic test. Guo, F., Liu, R., Pan, Y., et al.[2023]

A survey of 120 pediatricians and geneticists in Bulgaria revealed that while half of the pediatricians support the idea of using whole-genome sequencing (WGS) for all newborns, a significant majority of geneticists (65.2%) have concerns about its implementation, particularly regarding ethical issues and data protection.

Both groups agree that while non-selective WGS is not currently feasible, selective WGS could enhance existing newborn screening programs, highlighting the need for genetic counseling and psychological support for families.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Whole-Genome Sequencing in Newborn Screening-Attitudes and Opinions of Bulgarian Pediatricians and Geneticists. Iskrov, G., Ivanov, S., Wrenn, S., et al.[2022]

Whole-genome sequencing (WGS) effectively identifies genetic variants related to disorders included in newborn screening (NBS), showing high concordance with NBS results (88.6% true positives and 98.9% true negatives) in a study of 1,696 infants.

WGS has a lower false positive rate compared to traditional NBS (0.037% vs. 0.17%), but it also produces more uncertain results, indicating its potential to enhance NBS while also presenting challenges in interpretation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. Bodian, DL., Klein, E., Iyer, RK., et al.[2022]

References

1. 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]

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

Effect of Whole-Genome Sequencing on the Clinical Management of Acutely Ill Infants With Suspected Genetic Disease: A Randomized Clinical Trial. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Building evidence and measuring clinical outcomes for genomic medicine. [2020]

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

The promise and challenges of next-generation genome sequencing for clinical care. [2022]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Amplicon sequencing-based carrier screening for 170 monogenic disorders among children with abnormal LC-MS/MS results. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes. [2022]

7. England pubmed.ncbi.nlm.nih.gov

The BabySeq project: implementing genomic sequencing in newborns. [2023]

8. Spain pubmed.ncbi.nlm.nih.gov

[Genomic newborn screening. Perspective from the Ethics commission of the Spanish Society for Human Genetics. Part I. Next generation sequencing technologies applied to newborn screening. Challenges and opportunities.] [2022]

9. Switzerland pubmed.ncbi.nlm.nih.gov

The Burden and Benefits of Knowledge: Ethical Considerations Surrounding Population-Based Newborn Genome Screening for Hearing. [2022]

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

Evidence from 2100 index cases supports genome sequencing as a first-tier genetic test. [2023]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Whole-Genome Sequencing in Newborn Screening-Attitudes and Opinions of Bulgarian Pediatricians and Geneticists. [2022]

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

Utility of whole-genome sequencing for detection of newborn screening disorders in a population cohort of 1,696 neonates. [2022]