The Sequencing for Detection in Congenital Heart Disease (SD-CHD) Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 200
- 试验地点
- 2
- 主要终点
- Diagnostic yield of WGS in fetal congenital heart disease
研究概览
简要总结
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.
详细描述
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:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Pregnant individual with ongoing pregnancy with prenatally detected fetal CHD
- •Desire for genetic diagnosis and clinical plan for amniocentesis or chorionic villus sampling
排除标准
- •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
结局指标
主要结局
Diagnostic yield of WGS in fetal congenital heart disease
时间窗: Anticipated 200 trios in 2 years
Trios with pathogenic or likely pathogenic sequencing results/ total number of trios.
次要结局
- Patient depression and anxiety measures over time: EPDS(Final survey 18 months after birth)
- Provider utility of WGS: Clinician-reported Genetic testing Utility InDEx (C-Guide)(Final survey 18 months after birth)
- Patient utility of WGS as measured by: The Feelings About genomiC Testing Results (FACToR) Questionnaire(Final survey 18 months after birth)
- Patient depression and anxiety measures over time: GAD7(Final survey 18 months after birth)
- Diagnostic yield by type of CHD lesion(Anticipated 200 trios in 2 years)
- Patient utility of WGS as measured by: The Genome Empowerment Scale (GEmS)(Final survey 18 months after birth)
- Demographics of the cohort.(Duration of enrollment.)
研究者
Rebecca Reimers
Principal Investigator
Scripps Translational Science Institute