Genome Sequencing for Genetic Disorders

(BeginNGS Trial)

Overseen By Lauren Olsen, MSN

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Rady Pediatric Genomics & Systems Medicine Institute

Disqualifiers: Mother under 18, Wards of state, Non-US address, Ill neonates, Others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

10000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new method for screening newborns for genetic disorders using BeginNGS (genome sequencing). Researchers aim to compare its usefulness, parental acceptance, and cost to the usual state newborn screening. Newborns will provide a blood sample for both the standard test and the BeginNGS test. This trial suits newborns under 28 days old whose parents have already selected a primary care provider. As an unphased trial, it offers parents a unique opportunity to contribute to the advancement of newborn screening methods.

Will I have to stop taking my current medications?

The trial does not specify whether participants need to stop taking their current medications. However, since the trial involves newborns, it is unlikely that they would be on any medications.

What prior data suggests that this method is safe for newborn screening?

Research has shown that BeginNGS, a new method for checking newborns' genes, is safe and effective. Two studies confirmed that BeginNGS can safely detect genetic disorders in newborns without causing harm. This method identifies genetic issues early, before symptoms appear. No serious side effects have been reported, indicating that BeginNGS is well-tolerated and a promising option for newborn screening. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about BeginNGS because it offers a cutting-edge approach to identifying genetic disorders in newborns quickly and efficiently. Unlike traditional methods, which might take weeks to provide results, BeginNGS uses advanced genome sequencing technology to screen for a wide range of genetic conditions right at birth. This early detection can be crucial, allowing for immediate intervention and potentially improving health outcomes for infants with genetic disorders. The ability to identify conditions early on could transform newborn screening, providing a comprehensive view of a baby's genetic health from the start.

What evidence suggests that this method is effective for newborn screening?

Research has shown that BeginNGS, a new method for screening newborns using their DNA, more accurately identifies babies with genetic disorders than traditional state tests. It also reduces errors in identifying these conditions. Studies suggest this method can significantly improve the health of many children with serious genetic issues. Early data indicate it could help over 50,000 children in the U.S. each year. This approach promises to catch more cases early, potentially leading to better treatment options. ^{1 3 6 7 8}

Who Is on the Research Team?

Stephen Kingsmore, MD DSc

Principal Investigator

Rady Children's Institute for Genomic Medicine

Rebecca Reimers, MD MPH

Principal Investigator

Rady Children's Institute for Genomic Medicine

Are You a Good Fit for This Trial?

This trial is for newborns whose parents consent to enroll them. It's designed to compare a new whole genome sequencing test, BeginNGS, with the standard state newborn screening tests.

Inclusion Criteria

Parents must have identified a primary care provider (or group)

My baby is less than 28 days old.

Exclusion Criteria

My mother was under 18 when I was born.

My newborn is under state care.

Neonates whose parent/legal guardian is unable to provide consent

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 Testing

Enrolled newborns will have a blood sample taken and will receive the BeginNGS test in addition to the state newborn screening test.

1-2 weeks

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after testing, including confirmatory testing and analysis of outcomes.

5 years

Periodic follow-up visits

Data Analysis and Reporting

Analysis of utility, acceptability, feasibility, and cost effectiveness of BeginNGS compared to standard NBS.

Ongoing throughout the study

What Are the Treatments Tested in This Trial?

Interventions

• BeginNGS

Trial Overview The BeginNGS Test is being studied to see how useful it is compared to traditional screenings for genetic disorders in newborns. The study will assess its acceptability, feasibility, and cost-effectiveness.

How Is the Trial Designed?

Group I: Enrollees Experimental Treatment 1 Intervention

Enrolled infants will receive the BeginNGS test in addition to the state newborn screen.

BeginNGS is already approved in United States for the following indications:

Approved in United States as BeginNGS for:

• Newborn screening for severe childhood genetic diseases

Who Is Running the Clinical Trial?

Rady Pediatric Genomics & Systems Medicine Institute

Lead Sponsor

Trials

10

Recruited

214,000+

Published Research Related to This Trial

In a review of adverse events (AEs) among 433 children with cystic fibrosis participating in clinical trials, a total of 8,266 AEs were reported, averaging 18.1 AEs per person per year, with respiratory AEs being the most common.

Cough was the most frequently reported respiratory AE, affecting 61% of participants, and the study found that AE rates were higher in the Spring, Fall, and Winter compared to Summer, indicating that seasonal factors may influence the frequency of AEs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rates of adverse and serious adverse events in children with cystic fibrosis. Pittman, JE., Khan, U., Laguna, TA., et al.[2022]

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]

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]

A new trigger tool was developed using a random forest algorithm to effectively identify adverse events (AEs) in hospitalized neonates, based on data from 782 patients, achieving a sensitivity of 70.7% and specificity of 92.0.

In a validation study with 655 neonates, the tool identified 1172 unique AEs, with skin damage, iatrogenic diarrhea, and fever being the most common, demonstrating a positive predictive value of 0.686.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neonatal Adverse Events' Trigger Tool Setup With Random Forest. Feng, K., Zhang, L., He, H., et al.[2023]

In a study of 150 neonatal admissions, 360 adverse events were identified, affecting 52% of infants, with a high preventability rate of 84.7%, indicating significant opportunities for improving patient safety in neonatal care.

Preterm infants experienced a higher rate of adverse events compared to term infants, particularly within the first week of admission, highlighting a critical period for monitoring and intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identifying neonatal adverse events in preterm and term infants using a paediatric trigger tool. Dillner, P., Unbeck, M., Norman, M., et al.[2023]

Implementing a standardized register for reporting adverse events in a neonatology unit over six months improved the consistency of reporting.

The analysis of these reports led to significant reorganizations in the unit and practices, enhancing the overall quality of care provided to neonates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Adverse events in neonatology, contribution of a standardised register]. Normand, MM., Ejarque Albuquerque, M., Grouazel, AL., et al.[2017]

In a study involving 159 newborns, genomic sequencing (nGS) identified a risk of childhood-onset diseases in 9.4% of infants, none of which were predicted based on their clinical or family histories, highlighting the potential of nGS to uncover hidden health risks.

The study also found that nGS could reveal actionable adult-onset disease risks in 3.5% of newborns and carrier status for recessive diseases in 88%, demonstrating its effectiveness in detecting conditions not identified by standard newborn screening methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Ceyhan-Birsoy, O., Murry, JB., Machini, K., et al.[2022]

A new NICU-focused trigger tool was developed and tested, revealing a high incidence of adverse events in hospitalized children, with 554 unique adverse events identified across 749 charts, averaging 0.74 events per patient.

The study found that 56% of these adverse events were preventable, highlighting the need for improved safety measures, as only 8% were reported through traditional hospital reporting systems.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events in the neonatal intensive care unit: development, testing, and findings of an NICU-focused trigger tool to identify harm in North American NICUs. Sharek, PJ., Horbar, JD., Mason, W., et al.[2021]

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]

There is a pressing need to expand newborn screening (NBS) using rapid whole genome sequencing (rWGS) to identify over 400 genetic disorders, which could significantly improve early diagnosis and treatment options for newborns.

The BeginNGS consortium aims to create a self-learning healthcare system that not only screens for genetic diseases but also confirms diagnoses and facilitates effective treatments, while also accelerating the development of orphan drugs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dispatches from Biotech beginning BeginNGS: Rapid newborn genome sequencing to end the diagnostic and therapeutic odyssey. Kingsmore, SF.[2023]

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]

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. 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 ... When compared with state newborn screening, BeginNGS had a higher true positive rate and lower false positive rate. “Genome-based newborn ...

2. radygenomics.org radygenomics.org/begin-ngs-newborn-sequencing/publications/

BeginNGS Publications | RCIGM Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11639094/

Genome-based newborn screening for severe childhood ... The average time to phenotype-informed RDGS results was 15 days (range 6–61 days) and in 35% occurred before hospital discharge. This turnaround ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT06306521?intr=%22Neonatal%20Screening%22&aggFilters=status:not%20rec&rank=8

Study Details | NCT06306521 | An Adaptive ... Preliminary data suggest that national adoption of BeginNGS in all births has the potential to improve outcomes of >50,000 US children per year. Official Title.

5. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2840293

A Genomic Sequencing Approach to Newborn Mass ... This cohort study examines the feasibility, potential utility, and clinical implications of next-generation sequencing–based newborn ...

6. radygenomics.org radygenomics.org/begin-ngs-newborn-sequencing/

BeginNGS | RCIGM BeginNGS is an RCIGM-led pilot that uses genome sequencing as a screening tool for newborns, to identify genetic conditions before infants get sick.

7. 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.

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

Genome Sequencing for Newborn Screening The findings were enlightening: 59 cases undetected by traditional biochemical newborn screening were identified by genome sequencing, ...