The Sequencing for Detection in Congenital Heart Disease (SD-CHD) Study

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.

Many genetic causes of CHD are missed by standard microarray and karyotype. Whole genome sequencing (WGS) and other specialized technologies for genetic and epigenetic diagnosis such as long-read sequencing, digital droplet PCR, RNA sequencing, and methylation analysis will identify additional causes of CHD but these technologies have not been systematically offered to patients prenatally.

Precision fetal diagnosis has expanded from diagnosis of aneuploidy on karyotype to copy number variants detected on microarray (such as 22q11 deletion syndrome) to gene sequencing through gene panels and exome sequencing (ES). Overall, prenatal ES in the setting of an ultrasound anomaly has had diagnostic yields of 8.5% and 10% in fetuses with normal microarray and karyotype. Anomaly-specific cohorts have noted diagnostic rates of up to 29% in nonimmune hydrops, an etiology with genetic heterogeneity and overlap with CHD. Uptake in ES in prenatal diagnosis has been limited by patient access due to cost, the time needed for testing, provider comfort with the broad nature of ES, and potential variants of uncertain significance and secondary findings.

The quality and accuracy of the data from genomic sequencing is directly related to quality and accuracy of information that goes into the bioinformatic analysis. One small study noted that when prenatal ES cases were reanalyzed postnatal or after autopsy results were available, an additional 20% of cases reached a diagnostic result due to the increased phenotypic information. The influence of phenotype on diagnostic yield of genomic sequencing for specific anomalies is unclear.

The importance of viewing the fetal and neonatal period as a continuum of care is increasingly recognized. Prenatal detection of critical CHD has the opportunity to help a family to optimize neonatal survival and learning of the other health challenges, or lack thereof, may have a large influence on parental preparedness. This may influence their levels of stress, and clinical management decisions such as what consultants to meet with prenatally, which center to choose for delivery, and potentially even what therapeutics to consider in the first months and years of life. A prior pediatric cohort of patients with hypertrophic cardiomyopathy (HCM) noted that among those with a new molecular diagnosis, 73% of individuals had a pathogenic variant identified in a gene with established clinical management recommendations, 36% were in syndromic HCM genes, and 2.9% were in genes with an eligible clinical trial.

Specific aims:

1. Perform whole genome sequencing (WGS) on fetuses with prenatally detected congenital heart disease (CHD) who meet inclusion criteria. Assess diagnostic yield of WGS in CHD and effect of prenatal versus postnatal phenotype on diagnostic yield.
2. Improve bioinformatic filtering and prenatal phenotyping for phenotype-causing gene identification through the use of detailed ultrasonographic examinations, magnetic resonance imaging, autopsy or pathology findings, and biochemical or proteomic profiling results when available.
3. Evaluate WGS utility on pregnancy and neonatal care including choice of delivery location, antenatal consultation with subspecialist providers, and postnatal interventions and consultation with subspecialist providers.

Through these aims, the study team will expand scientific understanding of genetic diagnosis in fetuses with CHD and will evaluate the impact on families anxiety, depression, and assess the clinical utility of this information. This information will allow for patient-centered approaches to implementing new technologies while improving the health outcomes and allowing for future disease-specific tailored care in the most common structural malformation identified on prenatal ultrasound.

Eligibility Criteria:
Inclusion Criteria:

* Pregnant individual with ongoing pregnancy with prenatally detected fetal CHD
* Desire for genetic diagnosis and clinical plan for amniocentesis or chorionic villus sampling

Exclusion Criteria:

* Gestational age of 38 weeks or greater
* Clinical course entirely explained by known chromosomal abnormality or confirmed genetic diagnosis that explains the clinical condition
* Pregnant persons under 18 years of age