Risk of congenital heart disease in relatives of probands with conotruncal cardiac defects: An evaluation of 1,620 families

Current recurrence risk counseling for conotruncal cardiac defects (CTD) is based on empiric estimates from multiple studies. We examined the risk of congenital heart disease (CHD) in relatives of probands with CTDs to assist in counseling practices in the current era. One thousand six-twenty probands with CTDs and no reported chromosomal or genetic abnormalities were recruited sequentially. A three-generation pedigree was obtained for each proband by a genetic counselor detailing the presence and type of CHD in each family member. Risks and 95% confidence intervals (CI) were calculated for sub-groups of relatives based on degree of relationship for all probands and by individual lesion of the proband. For pairs of affected relatives, concordance rates were calculated. Severity of CHD in the affected relative was assessed. The risk of CHD was higher in siblings (4.4%, 95% CI 3.4-5.4) than in parents (1.5%, 95% CI 1.1-1.9). Risk varied by the cardiac lesion of the proband with the highest risk in first-degree relatives of probands with tetralogy of Fallot and the lowest in D-transposition of the great arteries. 39% of affected parents and 69% of affected siblings had a concordant lesion (i.e., CTD). Most affected siblings of probands with severe CTDs had complex defects (58%), whereas very few affected parents had complex defects (20%). These data suggest that recurrence risk varies by lesion and relationship, with substantial concordance observed by cardiac lesion and complexity of disease, particularly among siblings. These findings contribute to risk counseling in the current era

22q11.2 Deletions in Patients with Conotruncal Defects: Data from 1,610 Consecutive Cases

The 22q11.2 deletion syndrome is characterized by multiple congenital anomalies including conotruncal cardiac defects. Identifying the patient with a 22q11.2 deletion (22q11del) can be challenging because many extracardiac features become apparent later in life. We sought to better define the cardiac phenotype associated with a 22q11del to help direct genetic testing. 1,610 patients with conotruncal defects were sequentially tested for a 22q11del. The counts and frequencies of primary lesions and cardiac features were tabulated for those with and those without a 22q11del. Logistic regression models investigated cardiac features that predicted deletion status in tetralogy of Fallot (TOF). Deletion frequency varied by primary anatomic phenotype. Regardless of the cardiac diagnosis, a concurrent aortic arch anomaly (AAA) was strongly associated with deletion status [odds ratio (OR), 5.07; 95 % confidence interval (CI), 3.66-7.04]. In the TOF subset, the strongest predictor of deletion status was an AAA (OR, 3.14; 95 % CI 1.87-5.27; p < 0.001), followed by pulmonary valve atresia (OR, 2.03; 95 % CI 1.02-4.02; p = 0.04). Among those with double-outlet right ventricle and transposition of the great arteries, only those with an AAA had a 22q11del. However, 5 % of the patients with an isolated conoventricular ventricular septal defect and normal aortic arch anatomy had a 22q11del, whereas no one with an interrupted aortic arch type A had a 22q11del. A subset of patients with conotruncal defects are at risk for a 22q11del. A concurrent AAA increases the risk regardless of the intracardiac anatomy. These findings help to direct genetic screening for the 22q11.2 deletion syndrome in the cardiac patient

The Congenital Heart Disease Genetic Network Study: Cohort description.

The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC

Diagnostic types of congenital heart defect in the Pediatric Cardiac Genetic Consortium Cohort.

<p>Diagnostic types of congenital heart defect in the Pediatric Cardiac Genetic Consortium Cohort.</p

Demographic, pregnancy, and birth history comparisons of nonsyndromic^a cases across major types of congenital heart defect in the Pediatric Cardiac Genetic Consortium Cohort.

<p>Demographic, pregnancy, and birth history comparisons of nonsyndromic<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191319#t004fn002" target="_blank">^a</a> cases across major types of congenital heart defect in the Pediatric Cardiac Genetic Consortium Cohort.</p

Syndromic diagnoses in the Pediatric Cardiac Genetic Consortium Cohort.

<p>Syndromic diagnoses in the Pediatric Cardiac Genetic Consortium Cohort.</p

Description of nonsyndromic^a cases in the Pediatric Cardiac Genetic Consortium Cohort.

<p>Description of nonsyndromic<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0191319#t003fn002" target="_blank">^a</a> cases in the Pediatric Cardiac Genetic Consortium Cohort.</p

22q11.2 Deletions in Patients with Conotruncal Defects: Data from 1,610 Consecutive Cases

BACKGROUND: The 22q11.2 deletion syndrome is characterized by multiple congenital anomalies including conotruncal cardiac defects. Identifying the patient with a 22q11.2 deletion (22q11del) can be challenging because many extracardiac features become apparent later in life. We sought to better define the cardiac phenotype associated with a 22q11del to help direct genetic testing. METHODS: 1,610 patients with conotruncal defects were sequentially tested for a 22q11del. Counts and frequencies for primary lesions and cardiac features were tabulated for those with and without a 22q11del. Logistic regression models investigated cardiac features that predicted deletion status in tetralogy of Fallot (TOF). RESULTS: Deletion frequency varied by primary anatomic phenotype. Regardless of the cardiac diagnosis, a concurrent aortic arch anomaly (AAA) was strongly associated with deletion status (OR 5.07, 95% CI: 3.66–7.04). In the TOF subset, the strongest predictor of deletion status was an AAA (OR 3.14, 95% CI: 1.87–5.27, p <0.001), followed by pulmonary valve atresia (OR 2.03, 95% CI: 1.02–4.02, p= 0.04). Among those with double outlet right ventricle and transposition of the great arteries, only those with an AAA had a 22q11del. However, five percent of patients with an isolated conoventricular ventricular septal defect and normal aortic arch anatomy had a 22q11del, while no one with an IAA-A had a 22q11del. CONCLUSION: A subset of patients with conotruncal defects are at risk for a 22q11del. A concurrent AAA increases the risk regardless of the intracardiac anatomy. These findings help direct genetic screening for the 22q11.2 deletion syndrome in the cardiac patient

Results of the Fontan Udenafil Exercise Longitudinal (FUEL) Trial.

Background: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. Methods: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. Results: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. Conclusions: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold