Neonate WGS Testing for Genetic Disorders

(PISCES Trial)

Age: < 18

Sex: Any

Trial Phase: Academic

Sponsor: Jerry Vockley, MD, PhD

Disqualifiers: Known diagnosis, Major anomaly, Infection, others

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

Compensation: Varies

Number of Visits: 1

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if whole genome sequencing (WGS) can diagnose genetic disorders more quickly in newborns in intensive care. Rather than focusing on new technology, the trial compares WGS to standard testing to see if it can more effectively identify health issues and improve patient care. Newborns in intensive care at certain hospitals, who might have genetic disorders, are suitable candidates for this study. As an unphased trial, it offers a unique opportunity to advance diagnostic methods for newborns.

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

What prior data suggests that whole genome sequencing is safe for neonates?

Research has shown that whole genome sequencing (WGS) for newborns offers a promising way to quickly identify genetic disorders. Studies have found that WGS is generally easy for babies to handle, as it primarily requires a simple blood test, similar to other routine tests.

Previous research indicates that the process itself does not pose direct health risks to newborns. Instead, it can help identify serious genetic conditions early, leading to faster treatment and better health outcomes. Although WGS is not a new technology, its use for newborn screening is still under study to enhance the speed and accuracy of diagnoses.

Overall, its safety is supported by use in many clinical settings. WGS focuses on analyzing genes that might cause problems early in life, helping doctors identify issues more quickly than standard tests. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about Neonate WGS Testing because it offers a comprehensive way to detect genetic disorders early in life. Unlike traditional methods that focus on specific symptoms or smaller gene panels, this approach uses whole genome sequencing to analyze a wide array of genes. This means it can potentially identify disorders that might be missed by current tests. Additionally, by filtering through a targeted panel of 1722 genes and then using a whole exome filter, it increases the chances of making a precise diagnosis, which can lead to more tailored and effective treatments for newborns.

What evidence suggests that Neonate WGS Testing is effective for increasing the speed of diagnosis in genetic disorders?

Research has shown that whole genome sequencing (WGS) is a powerful tool for diagnosing genetic disorders in newborns. In very sick infants, WGS successfully identified the genetic condition in about 42% of cases, effectively working in nearly half of the cases tested. This method is much quicker than traditional ones, usually taking about 8 days to complete. Studies have also found that WGS can detect conditions that standard newborn screening tests might miss. This suggests that WGS could help diagnose conditions faster and potentially improve outcomes for newborns in intensive care.

In this trial, eligible neonate subjects whose parents consent will undergo blood sampling for whole genome sequencing and bioinformatics analysis. ^{6 7 8 9 10}

Who Is on the Research Team?

Gerard Vockley, MD, PhD

Principal Investigator

University of Pittsburgh

Are You a Good Fit for This Trial?

This trial is for neonates in intensive care with suspected genetic disorders, over 24 weeks gestational age and weighing more than 600 grams. It's also open to their parents and necessary siblings. Neonates already diagnosed prenatally or with major congenital anomalies linked to chromosomal issues are excluded.

Inclusion Criteria

My parent or guardian has given formal consent for me to participate.

Neonates: Admitted to the intensive care unit at UPMC Children's Hospital (CHP) and/or Magee Women's Hospital

My newborn may have a genetic disorder, as suggested by their symptoms and tests, leading to a genetics consultation.

Exclusion Criteria

My newborn has a diagnosed condition from prenatal testing.

Neonates: Presence of documented significant congenital infection (e.g. congenital cytomegalovirus)

Siblings: Is not required for accurate interpretation of neonate results

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Sample Collection and Analysis

Neonate subjects undergo blood sampling for whole genome sequencing and bioinformatics analysis

Up to 4 years

1 visit (in-person) for sample collection

Genetic Counseling and Results Return

Pathogenic and likely-pathogenic variants are returned to the care team and parents in the setting of genetic counseling

Up to 4 years

Follow-up

Participants are monitored for changes in clinical management and outcomes after receiving WGS results

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Neonate WGS Testing

Trial Overview The study tests the effectiveness of whole genome sequencing (WGS) in diagnosing genetic conditions faster compared to standard testing in critically ill newborns. It will evaluate how WGS affects diagnosis time, patient outcomes, and healthcare costs.

How Is the Trial Designed?

Group I: Neonate WGS Testing Experimental Treatment 1 Intervention

Neonate subjects who are eligible and whose parents consent to study will undergo blood sampling which will be sent for whole genome sequencing and bioinformatics analysis, filtering first a targeted panel of 1722 genes most likely to cause genetic disorders in the first year of life, and then with a whole exome filter if no obvious diagnosis is determined using the 1722 gene panel filter.

Who Is Running the Clinical Trial?

Jerry Vockley, MD, PhD

Lead Sponsor

Trials

6

Recruited

460+

Published Research Related to This Trial

Implementing continuous incident reporting and prevention strategies led to a significant reduction in severe iatrogenic events in neonates, decreasing from 7.6 to 4.8 per 1000 patient-days over a two-year period.

Specific improvements included a notable drop in central catheter-related infections from 13.9 to 8.2 per 1000 catheter-days and a reduction in tenfold drug-dosing errors, although there was an increase in unplanned extubations from 5.6 to 15.5 per 1000 ventilation-days.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Iatrogenic events in neonates: beneficial effects of prevention strategies and continuous monitoring. Ligi, I., Millet, V., Sartor, C., et al.[2022]

Rapid whole-genome sequencing (WGS) can sequence an infant's genome in just 26 hours, enabling quick diagnosis and tailored management of genetic diseases.

This technology has the potential to reduce costs and minimize the time to diagnosis, which can alleviate pain and suffering for infants in the NICU, but it also raises important ethical considerations that need to be addressed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ethical Implications of Rapid Whole-Genome Sequencing in Neonates. Bell, SG.[2018]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5260149/

Newborn Sequencing in Genomic Medicine and Public Health The ability to analyze many or all genes in the genome simultaneously provides new opportunities for genomic medicine. The capacity of genome-scale sequencing ...

2. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2807782

At-Risk Genomic Findings for Pediatric-Onset Disorders ... This study suggests that, when compared with a gene panel, genome sequencing uncovered more potential pediatric-onset diagnoses among apparently healthy ...

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

BeginNGS | RCIGM BeginNGS is pilot project that uses whole genome sequencing (WGS) as a screening tool for newborns to identify genetic conditions before infants get sick.

4. sciencedirect.com sciencedirect.com/science/article/pii/S1098360021043136

Utility of whole-genome sequencing for detection ... WGS may help rule in and rule out NBS disorders, pinpoint molecular diagnoses, and detect conditions not amenable to current NBS assays.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12025730/

Rapid Whole-Genome Sequencing in Critically Ill Infants ... Rapid WGS clinical analysis in the U.K. with a median TAT of 8 days showed a 42% diagnostic rate in the pediatric ICU (PICU) [92], while a standard WGS study ...

6. reporter.nih.gov reporter.nih.gov/project-details/9451647&icde=42469782

Project Details Precision Medicine in the Diagnosis of Genetic Disorders in Neonates. Project ... sequencing methodology such as exome and whole genome sequencing (WGS).

7. 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). However, ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4795188/

Whole-genome sequencing in newborn screening? A ... The primary objective of genome sequencing in NBS should be the identification of gene variants conferring a high risk of preventable or ...

9. 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.

10. mdpi.com mdpi.com/2227-9067/12/4/429

Rapid Whole-Genome Sequencing in Critically Ill Infants ... This work aims to chronologically review significant clinical studies worldwide in pediatric genomic sequencing that have led to the development of rapid WGS ( ...