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Congenital heart disease (CHD) is one of the most prevalent causes of mortality among US born infants and a significant source of global economic burden, affecting almost 1% of all live-born infants. The estimate of CHD in aborted fetuses is even higher, reaching up to 10%. The underlying causes of CHD are varied and can include cytogenetic abnormalities, single-gene disorders, epigenetic alterations, environmental etiologies, or most commonly, multifactorial etiologies. Large-scale epidemiologic studies suggest that a genetic or environmental cause for CHD is identifiable in approximately 20% to 30% of cases. Infants with CHD are considered to have syndromic conditions based on the findings of multiple congenital anomalies or neurodevelopmental delays. The distinction between syndromic and nonsyndromic, or isolated, CHD can be subtle, leading to lack of recognition of syndromic cases. In addition, as genetic diagnostic modalities have become more sophisticated, the spectrum of genetic syndromic conditions has expanded, and therefore, previous assessments of syndromic cases may represent an underestimate.

High heritability provides evidence for an important genetic role in isolated CHD. Specific types of CHD show strong familial clustering in first-degree relatives, ranging from 3-fold to 80-fold compared to the prevalence in the population. Not all families show evidence of similar types of CHD, and familial clustering of discordant CHD has also been documented. Because CHD is so common, the majority of cases occur in individuals without a family history of cardiovascular malformations despite a high heritability. The prevalence of familial CHD will likely increase as more patients with CHD survive into adulthood. Securing a genetic diagnosis is important, as a definitive diagnosis not only alerts the clinician to the likelihood of noncardiac concerns that require intervention, but could also alter management considerations of CHD if a syndrome with significantly reduced life expectancy is uncovered, as observed for trisomy 18 and 13.


Cardiac development is a complex, multistep process of morphogenesis that is under genetic regulation. Multiple developmental pathways act independently or in combination to affect proper cardiac lineage specification, differentiation, and subsequent patterning and organogenesis. Because of this complexity, there are multiple potential mechanisms by which genetic variations can impact both fetal cardiac development and latent cardiac disease. Systems biology approaches illustrate the functional convergence of causative CHD gene pathways and support the hypothesis that some CHD phenotypes may result from additive effects of multiple low-effect susceptibility alleles. The resulting web of developmental interactions is a highly complex milieu in which individual or multiple risk factors can act to disrupt normal heart morphogenesis. Clinical genetic testing is increasingly available for a number of genes important during cardiac development. Both monogenic and chromosomal abnormalities account for a substantial proportion of CHD, particularly when coupled with extracardiac defects.


In large studies, the frequency of chromosomal abnormality in infants with CHD is estimated to be about 12%, including aneuploidies ...

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