Genome Sequencing for Congenital Heart Disease

Overseen By Rebecca Reimers, MD

Age: 18+

Sex: Female

Trial Phase: Academic

Sponsor: Scripps Translational Science Institute

Disqualifiers: Gestational age 38 weeks, Chromosomal abnormality, Under 18, 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: Unknown

200 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is enrolling pregnant persons treated at Rady Children's Hospital fetal cardiology program with a prenatal diagnosis of congenital heart disease to look for genetic disorders in the fetus or unborn baby. Congenital heart disease (CHD) is a group of structural differences to the heart that represent the most common birth defect among liveborn infants world-wide. CHD is the leading cause of birth-defect associated infant death. Prenatal detection allows for delivery planning, postnatal repair, specialized medications, and detailed counseling for parents. Up to one in three fetuses with CHD may have a genetic cause. In babies, knowing about genetic diseases helps patients and doctors provide the best care for their babies. If identified prenatally, this same knowledge may help participants prepare for their location of delivery, meet with specialists, and consider specialized treatments and medications that may be appropriate. The diagnostic yield and clinical utility of whole genome sequencing (WGS) in fetuses with prenatally detected congenital heart disease (CHD) will be compared to routine clinical testing in patients choosing amniocentesis or chorionic villus sampling. DNA will be obtained from fetal samples and biological parent blood samples and analyzed according to standard clinical interpretation guidelines. Results will be reported to healthcare providers and patients and measures of clinical utility will be collected. Additionally, measures of stress, anxiety, depression, and perceived utility of information will be assessed by validated survey tools. A historical cohort of patients electing for diagnostic procedures will be used as a comparison population.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment Whole Genome Sequencing for Congenital Heart Disease?

Rapid whole genome sequencing (rWGS) has been shown to increase the rate of diagnosis and reduce the cost of care in newborns with suspected genetic diseases, including those with congenital heart disease. This suggests that using rWGS can help identify genetic causes of heart defects more quickly, potentially leading to better management and outcomes for affected infants. ^{1 2 3 4 5}

Is genome sequencing safe for humans?

Genome sequencing, including whole genome sequencing (WGS) and next-generation sequencing (NGS), has been used in various studies and is generally considered safe for humans. These technologies have been applied in different medical conditions, including congenital heart disease, without specific safety concerns reported in the research. ^{1 2 3 5 6}

How is whole genome sequencing different from other treatments for congenital heart disease?

Whole genome sequencing (WGS) is unique because it analyzes the entire genetic makeup to identify potential genetic causes of congenital heart disease, which can lead to more accurate diagnoses and personalized treatment plans. Unlike traditional methods, WGS can uncover rare genetic variants that might not be detected otherwise, potentially reducing the cost of care and improving outcomes for patients. ^{1 2 3 7 8}

Eligibility Criteria

This trial is for pregnant individuals with a prenatal diagnosis of congenital heart disease in their fetus, who want genetic testing and are planning to undergo amniocentesis or chorionic villus sampling.

Inclusion Criteria

I am pregnant and my unborn baby has been diagnosed with a heart defect.

I want genetic testing and plan to have amniocentesis or CVS.

Exclusion Criteria

Gestational age of 38 weeks or greater

My condition is fully explained by a genetic diagnosis.

I am pregnant and under 18.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Whole Genome Sequencing

Whole genome sequencing (WGS) is performed on fetuses with prenatally detected congenital heart disease (CHD) to assess diagnostic yield and effect of prenatal versus postnatal phenotype on diagnostic yield.

Duration of enrollment

Consultation and Planning

Participants receive consultation with subspecialist providers to plan delivery location and postnatal interventions based on WGS results.

Throughout pregnancy

Follow-up

Participants are monitored for psychological impact and clinical utility of WGS results, including measures of stress, anxiety, and depression.

18 months after birth

Treatment Details

Interventions

• Whole Genome Sequencing

Trial Overview The study tests whole genome sequencing on fetal samples from pregnancies affected by congenital heart disease. It aims to compare the effectiveness of this method with routine clinical testing for detecting genetic disorders.

Participant Groups

Group I: Whole Genome Sequencing (WGC) from subject samples Experimental Treatment 1 Intervention

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

Approved in United States as Whole Genome Sequencing for:

• Genetic disorders
• Congenital heart disease
• Prenatal diagnosis

Approved in European Union as Whole Genome Sequencing for:

• Genetic disorders
• Congenital heart disease
• Rare genetic conditions

Approved in Canada as Whole Genome Sequencing for:

• Genetic disorders
• Congenital heart disease
• Prenatal diagnosis

Who Is Running the Clinical Trial?

Scripps Translational Science Institute

Lead Sponsor

Trials

53

Recruited

572,000+

Findings from Research

Rapid whole genome sequencing (rWGS) diagnosed genetic diseases in 46% of critically ill infants with structural congenital heart disease (CHD), significantly outperforming traditional testing methods like microarray and gene panels, which identified only 10%.

The implementation of rWGS not only provided timely and actionable genetic information that influenced patient care but also resulted in a reduction in average daily hospital costs after its use, indicating both clinical and economic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid whole genome sequencing impacts care and resource utilization in infants with congenital heart disease. Sweeney, NM., Nahas, SA., Chowdhury, S., et al.[2023]

Targeted next-generation sequencing (NGS) successfully identified pathogenic and likely pathogenic genetic variations in 15.9% of 44 fetuses with congenital heart defects (CHD), providing valuable insights into the genetic causes of these conditions.

The test had a turnaround time of 3 weeks, making it a timely option for prenatal diagnosis, which can significantly aid in clinical management and genetic counseling for affected families.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical application of targeted next-generation sequencing in fetuses with congenital heart defect. Hu, P., Qiao, F., Wang, Y., et al.[2018]

High-throughput sequencing technologies are crucial for uncovering the genetic causes of congenital heart diseases (CHD), which are the most common birth defects, as many cases still lack a clear genetic origin.

This review outlines a comprehensive approach for designing and analyzing sequencing studies in CHD, highlighting the advantages of different next-generation sequencing platforms and strategies for identifying disease-related genetic variations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Application of high-throughput sequencing for studying genomic variations in congenital heart disease. Dorn, C., Grunert, M., Sperling, SR.[2014]

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]

In a pilot study involving 50 adult patients with acute cardiovascular events, rapid whole-genome sequencing (rWGS) identified pathogenic variants in 20% of participants, highlighting its potential to uncover significant genetic information relevant to patient care.

The study also found that while 64% of participants had pharmacogenetic variants related to cardiovascular treatment, only 14% of these variants were actionable, indicating that integrating rWGS into clinical practice could enhance personalized treatment strategies over time.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Moving Genomics to Routine Care: An Initial Pilot in Acute Cardiovascular Disease. Aryan, Z., Szanto, A., Pantazi, A., et al.[2021]

Whole-exome sequencing (WES) of a custom congenital heart disease (CHD) geneset in 47 aborted fetuses with conotruncal defects (CTDs) revealed a 10.6% incremental diagnostic yield, identifying five pathogenic or likely pathogenic variants.

Incorporating postnatal phenotypic data significantly enhanced the diagnostic process, allowing for the reclassification of variants and improving the overall utility of WES in diagnosing genetic causes of CTDs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Diagnostic yield of whole exome data in fetuses aborted for conotruncal malformations. Shi, JW., Cao, H., Hong, L., et al.[2022]

Targeted next-generation sequencing (NGS) was successfully used to identify damaging missense variants in 9 genes related to congenital heart disease (CHD) in a study of 68 non-syndromic CHD patients, highlighting its efficacy in genetic diagnosis.

The study discovered both known and novel mutations, including four previously linked to CHD, demonstrating that targeted NGS can uncover rare genetic variants that may contribute to the disease, with 5.8% of patients carrying multiple potentially harmful variants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeted Next-Generation Sequencing in Patients with Non-syndromic Congenital Heart Disease. Pulignani, S., Vecoli, C., Borghini, A., et al.[2018]

In a study of 97 families with children born with congenital heart disease (CHD), genome sequencing identified clinically relevant genetic variants in 31% of cases, demonstrating the potential of genetic testing in improving diagnosis and treatment.

The two-tiered approach used in the study, which included a high-confidence gene screen and comprehensive analysis, successfully found actionable variants in 22% and an additional 9% of families, highlighting the importance of advanced genetic analysis in understanding CHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. Alankarage, D., Ip, E., Szot, JO., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Rapid whole genome sequencing impacts care and resource utilization in infants with congenital heart disease. [2023]

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

Clinical application of targeted next-generation sequencing in fetuses with congenital heart defect. [2018]

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

Application of high-throughput sequencing for studying genomic variations in congenital heart disease. [2014]

4. 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]

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

Moving Genomics to Routine Care: An Initial Pilot in Acute Cardiovascular Disease. [2021]

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

Diagnostic yield of whole exome data in fetuses aborted for conotruncal malformations. [2022]

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

Targeted Next-Generation Sequencing in Patients with Non-syndromic Congenital Heart Disease. [2018]

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

Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. [2022]