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Most congenital heart defects (CHDs) are due to the interaction of genetic predisposition with environmental influences. Historically, evidence for a genetic contribution to CHD came from studies of familial recurrence and the association of certain types of CHD with specific chromosomal abnormalities, whereas epidemiologic data supported a role for environmental factors as well.1 More recently, our understanding of the genetic contribution to CHD has advanced significantly, and it is clear that genetics plays a more important role than previously understood. Molecular genetic analysis of families with documented Mendelian transmission of CHD has led to the identification of disease-causing mutations in several cardiac transcription factors and signaling molecules. Studies of cardiac development in model organisms have led to the discovery of a number of genes required for heart formation. Searching for mutations in these “candidate” genes in patients with familial or isolated forms of CHD has yielded insight into the genetic basis of certain defects.

Clinical testing is increasingly available for many of the genetic alterations that underlie CHD, and information derived from these tests is affecting management of CHD patients and their families. Determining whether there is an underlying genetic defect in the patient with CHD is important for several reasons. Twenty to 30% of infants with CHD will have at least one other developmental anomaly.2,3 Diagnosis of a specific genetic syndrome facilitates early identification and treatment of other organ system involvement. Defining causative mutations may also provide prognostic information in defects for which there are genotype-phenotype correlations. In addition, identifying specific genetic defects allows for screening of family members who may be at risk for CHD, and also provides crucial information on reproductive risks for the family of the patient with CHD. As treatment of CHD improves and more CHD patients survive into adulthood, genetic diagnoses will aid these patients in their own reproductive decisions. For updated information on genetic testing availability, the reader is referred to online resources such as GeneTests (

This section contains a review of what is currently known about the contribution of genetics to both syndromic and isolated cardiovascular malformations. The genetic basis of cardiomyopathies and arrhythmias is discussed in other sections. For more extensive clinical descriptions of the syndromes discussed in this chapter, the reader is referred to text4 and online resources (see the Online Mendelian Inheritance in Man [OMIM] Web site at

Congenital Heart Defect Associated with Chromosomal Abnormalities

In population-based studies, approximately 13% of infants5 and up to 36% of stillborn and spontaneously aborted fetuses5,6 with cardiac defects had chromosomal abnormalities. Conversely, at least 30% of children with chromosomal anomalies have some form of congenital heart defect (CHD).7 Thus, when evaluating the patient with known or suspected chromosomal disorders, it is important to look for CHD, just as it is crucial to consider cytogenetic testing for certain CHD patients, especially ...

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