Copy number variation in congenital heart defectsThe aim of this thesis was to advance our insight on copy number variation in the genesis of congenital heart defects. The body of current knowledge on the genetics of CHD is scattered across publications, text books and genomic databases. To enhance the identification of chromosomal regions and genes recurrently linked to congenital heart defects, we developed a Wiki-based portal for standardized and curated integration of clinical and molecular data on CHD, termed CHDWiki, which is described in Part I of this thesis. In the first chapter we elaborate on the developmental process underlying CHDWiki, and we discuss on how this Wiki knowledge and analysis portal can serve the broad community that is studying CHDs, ranging from the pediatric cardiologist and clinical geneticist to the basic investigator of cardiogenesis (Part I, Chapter 1). Subsequently, all submicroscopic imbalances recurrently related to CHDs, compiled in CHDWiki, were evaluated in a systemic way to delineate overlapping imbalanced regions critical for heart development. We aimed to identify novel candidate genes for CHD within these regions, using computational gene prioritization tools. We provide an overview of these results in chapter 2 (Part I, Chapter 2), and we elaborate on the delineation of 3 novel chromosomal CHD-related syndromes in chapter 3: the 16p13.3 microduplication syndrome, a novel recurrent 22q11 deletion and deletions on 10q22q23 (Part I, Chapter 3). Array comparative genomic hybridization is already widely used in a clinical setting for the diagnosis of individuals with congenital malformations. The interpretation of CNVs is challenging as infrequent disease-causing copy number changes should be distinguished from the abundant copy number variations without obvious major clinical significance. In Part II of this thesis, we discuss some of the challenges that arise upon the introduction of aCGH as a diagnostic tool in a clinical cardiogenetic setting, and introduce an algorithm for CNV interpretation (Part II, Chapter 1). We applied aCGH studies in large cohorts with syndromic CHD (Part II, Chapter 2) and sporadic non-syndromic CHD (Part II, Chapter 3). Based on our experience as well as those of others described in the literature, we outline the state-of-the-art and attempt to answer a number of outstanding questions, such as the yield of aCGH in different patient populations, the added value of higher resolution arrays, and the existence of predictive factors in syndromic cases. Studies addressing the role of somatic copy number variation (CNV) in the genesis of congenital heart defects are scarce. In Part III of this thesis, we explore the occurrence of CNV differences in monozygotic twins discordant for the presenece of a congenital heart defect, as an illustrative model for chromosomal mosaicism in CHD.