The Congenital Heart Disease Genetic Network Study: Cohort description

Abstract

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.

Development and evolution of the metazoan heart

“…The complexity of interactions leading to CHD may be inferred from large cohort studies in which mutations of many genes and parts of epigenetic pathways are involved. The diverse outcomes prevent pinpointing major gene regulatory networks, as is strengthened by the survey of a large cohort description showing that a mere 11% out of more than 9700 patients with CHD (69% of which had “conotruncal” or ventricular OFT defects) had a genetic diagnosis . These encompass often complex syndromes, such as 22q11, Kabuki, Alagille, Holt‐Oram, but also de novo mutations affecting multiple organs.…”

“…Tissue‐specific deletion of Smoothened resulted in compromised DMP formation, AVDs, reduced proliferation, and diminished Wnt/β‐catenin signaling . In humans, ASDs account for about 9% of more 9700 patients, which is far less than the 69% of children with OFT malformations . This difference may be a reflection of the difference in complexity in evolution and development of the venous and arterial poles of the heart.…”

“…6 It is evident that the myriad phenotypes of congenital human malformations must not be considered as interrupted or persisting steps in the evolution of the heart, but rather as results of mutations, imbalance in dosage, or "mismanagement" in the available (genetic) tool kits, including epigenetic regulation, 211 hemodynamics, 67,212 and external factors such as vitamin A/retinoic acid. 56,213 The complexity of interactions leading to CHD may be inferred from large cohort studies in which mutations of many genes 214 and parts of epigenetic pathways 66 are involved. The diverse outcomes prevent pinpointing major gene regulatory networks, as is strengthened by the survey of a large cohort description showing that a mere 11% out of more than 9700 patients with CHD (69% of which had "conotruncal" or ventricular OFT defects) had a genetic diagnosis.…”

The genetic workup for structural congenital heart disease

“…In 70–90% of CHD cases, the underlying etiology is undetermined, thus only 10–30% of cases are attributed to genetic or environmental factors (Cowan & Ware, ; Hoang et al, ; Russell, Chung, Kaltman, & Miller, ). Disruption of embryonic differentiation and cardiogenesis results in CHD (Zaidi & Brueckner, ), and these complex processes are highly influenced and regulated by genes and their products (Pierpont et al, ).…”

“…Disruption of embryonic differentiation and cardiogenesis results in CHD (Zaidi & Brueckner, ), and these complex processes are highly influenced and regulated by genes and their products (Pierpont et al, ). In a study of 9,727 CHD cases, from the 1,034 cases with genetic diagnoses, Down syndrome was most frequent genetic diagnosis (38%), followed by 22q11.2 deletion syndrome (24%), and Noonan syndrome (4.5%) (Hoang et al, ). Fortunately, animal studies in mouse, frog, and zebrafish models have increased our understanding of these processes and of normal heart development.…”