Copy Number Variation in Congenital Heart Defects

Abstract

Congenital heart defects (CHDs) are the most common birth defect and a major contributor to mortality, morbidity, and healthcare costs throughout the world. Although improvements in surgical advances and cardiac care have increased the lifespan of individuals with CHDs,

Copy number variation as a genetic basis for heterotaxy and heterotaxy-spectrum congenital heart defects

“…Future studies will be important to determine whether specific subclasses of CHD, such as d-TGA, are less likely to have CNV abnormalities. In addition, the burden of common CNVs present in individuals with heterotaxy should be further evaluated since this has been a noted correlation in other diseases [15].…”

“…Studies of patients with CHD indicate that CNVs are a major genetic cause of cardiovascular disease, occurring in 3-25% of patients with extra-cardiac abnormalities and in 3-10% with isolated heart defects [15]. To date, two studies have employed genome-wide approaches to explicitly examine the role of CNVs in heterotaxy [16,17].…”

Genetics and Genetic Testing in Congenital Heart Disease

“…Known genetic causes are extremely heterogeneous, encompassing not only mutations in cardiac-relevant genes, but also more complex chromosomal abnormalities, submicroscopic duplications/deletions, and whole chromosome aneuploidies ( Table 3). As genetic testing technologies have evolved to offer higher resolutions and greater diagnostic yields than those provided by conventional chromosomal analyses, copy number variants (CNVs) have emerged as important causes of both syndromic and non-syndromic CHDs 9 . Moreover, an increasing recognition of contributing environmental 10,11 and epigenetic 12,13 factors has revealed a previously unanticipated breadth to CHD etiology.…”

“…These developments are significant: an ever-growing body of studies indicate that pathogenic CNVs are a major cause of CHDs, occurring in 3-25% of patients with extra-cardiac abnormalities and in 3-10% of patients with isolated heart defects (reviewed in Lander et al 9 ). In practice, the relatively limited resolutions of karyotyping and FISH have rendered them insufficient to detect a genetic cause in the majority of patients with CHDs of uncertain etiology 55 and in nearly half of all patients with syndromic CHD 61 .…”

Copy Number Variants, Aneuploidies, and Human Disease

“…These include neurodevelopmental disorders (such as autism, intellectual disability and epilepsy), congenital heart defects, and other congenital anomalies. 1-3 Not all CNVs, however, are disease-causing: some CNVs have been identified in apparently normal individuals. 4,5 Whether a CNV is disease-causing or not depends on many factors, such as gene content (e.g., a CNV that is gene-rich is more likely to cause a phenotype than one containing few or no genes).…”