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

Description

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.