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

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 more effectively identify genetic causes of congenital heart disease (CHD) in unborn babies compared to standard tests. CHD, a common birth defect affecting the heart's structure, is a leading cause of infant death related to birth defects. Identifying a genetic issue before birth can help parents and doctors plan better care and treatments. The trial seeks pregnant individuals whose unborn baby has been diagnosed with CHD and who are interested in genetic testing through procedures like amniocentesis. As an unphased trial, it offers participants the chance to contribute to groundbreaking research that may enhance future diagnostic methods.

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 prior data suggests that whole genome sequencing is safe for prenatal diagnosis of congenital heart disease?

Research has shown that whole genome sequencing (WGS) is generally safe for patients. In studies with children who have congenital heart disease (CHD), WGS helped doctors find important genetic information in about 27-46% of cases. This test often provides useful insights without causing harm. Although some uncertainty or difficult decisions may arise, genome sequencing involves no risky procedures. It mainly involves analyzing DNA from samples like blood, a common practice in many medical settings. Thus, WGS is well-tolerated and considered low-risk in terms of safety. ^{1 2 3 4}

Why are researchers excited about this trial?

Researchers are excited about using whole genome sequencing (WGS) for congenital heart disease because it offers a new way to understand the genetic factors behind the condition. Unlike traditional diagnostic methods, which might focus on physical exams and imaging, WGS examines the entire genetic makeup of an individual. This comprehensive analysis can identify specific genetic mutations that might contribute to heart defects, potentially leading to more personalized and effective interventions. By uncovering these genetic insights, WGS could pave the way for earlier diagnosis and tailored treatments, improving outcomes for patients with congenital heart disease.

What evidence suggests that whole genome sequencing is effective for detecting genetic disorders in congenital heart disease?

Research has shown that whole genome sequencing (WGS), which participants in this trial will undergo, effectively diagnoses congenital heart disease (CHD). Studies have found that WGS identifies genetic causes in about 17.8% of CHD cases, increasing to 22.4% for cases with additional symptoms. When CHD is the only issue, the detection rate is around 9.8%. Importantly, WGS diagnoses genetic diseases at a rate up to four times higher than other tests. This advanced testing helps doctors understand the genetic reasons for CHD, guiding treatment and care planning. ^{5 6 7 8 9}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. obgyn.onlinelibrary.wiley.com obgyn.onlinelibrary.wiley.com/doi/10.1002/pd.6878

Yield of Whole Genome Sequencing for Pathogenic Single ... The pooled diagnostic yield of WGS in CHD is 17.8%, increasing to 22.4% in syndromic cases. ◦. In isolated CHD, the WGS yield drops to 9.8%.

2. nature.com nature.com/articles/s41525-021-00192-x

Rapid whole genome sequencing impacts care and ... In a prospective study, WGS increased the rate of childhood genetic disease diagnosis fourfold compared with CMA alone and twofold compared with ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10855915/

The New Challenge in Congenital Heart Disease Whole-genome sequencing facilitates the investigation of the oligogenic causes of CHD, including both uncommon and common variants, by providing a more ...

4. cell.com cell.com/hgg-advances/fulltext/S2666-2477(24)00025-3

Diagnostic yield after next-generation sequencing in ... We found a significant increase in the frequency of positive findings for patients who underwent genome sequencing compared to exome sequencing ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S2667164622000574

Review Article Genetic detection of congenital heart disease In this review, we present past and recent genetic testing in CHD based on our increased understanding of the pathogenesis of CHD along with current challenges.

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38339013/

The New Challenge in Congenital Heart Disease The use of next-generation sequencing has provided new insights into the causes and mechanisms of congenital heart disease (CHD).

7. gocm.bmj.com gocm.bmj.com/content/2/3/109

Genetic detection of congenital heart disease WES has been utilized in the testing of fetuses with CHD, typically after karyotype and/or CMA have yielded negative results and has demonstrated incremental ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11084871/

Clinical Genetic and Genomic Testing in Congenital Heart ... In these studies, rapid genome sequencing in select cohorts of CHD patients identified clinically actionable results, in 27–46% of patients, and ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S1098360021026101

Anticipating uncertainty and irrevocable decisions: provider ... We examined how clinicians caring for critically ill children with congenital heart disease (CHD) anticipate and perceive the impact of WGS on their decision- ...