Cardiogenetics

The molecular basis of congenital heart defects (CHD)

Congenital heart defects (CHD) affect about 1% of all newborn children with lifelong emotional socioeconomic and medical impact. Surgery greatly improved the prognosis and over 75% of children with CHD now survive into adulthood. Parallel with this evolution, the recurrence risk in offspring and hence the genetic basis of CHD becomes of utmost clinical importance. Furthermore, dissection of the molecular basis of CHD will add to the understanding of the genetic complexity and the biological processes underlying cardiac organogenesis.

CHD may occur as part of a syndromic constellation or, more frequently, as an isolated feature. Identification of causal genes and copy number variants (CNVs) has been relatively successful in syndromic forms of CHD (SCHD). In contrast, the genetic background of isolated CHD (ICHD) remains largely obscure. Causative genes were identified following fine-mapping of microdeletion syndromes presenting with cardiopathies (e.g. TBX1 within the 22q11.2 region), or, more recently, using exome sequencing. In addition, some studies have shown an increased prevalence of de novo CNVs in patients with ICHD compared to the general population.

ICHD is regarded as multifactorial disorders based on the overall recurrence of about 3%¹ in sibs. However, many ICHD that become manifest in adulthood (including thoracic aortic aneurysms and cardiomyopathies) bypass reduced productive fitness and are often determined by Mendelian inheritance. In addition, families with multiple affected individuals harbor incomplete penetrant defects in a select number of pathways in cardiac development.

In this project we evaluate germline and somatic mosaicism in ICHD combined in one experimental setup. In addition, we will evaluate the frequency of de novo CNVs in a large cohort of CHD patients compared to the reference population and use bioinformatics tools to identify the candidate genes included in the CNV. Strong candidate genes identified through both arms of the study will be validated in a zebrafish model. In addition, we evaluate syndromic forms of congenital heart defects.