Heart formation is a fantastic metamorphosis regulated by many sequences of genes. Given the remarkably complex orchestration of molecular and morphologic processes in formation of the heart, even small genetic and/or environmental changes in the control of these processes can have major, and variable, consequences. Truly, it is wonderful that development occurs and it does, as often as it does. Nevertheless, understandably, parents ask why their baby was born with a cardiac abnormality and whether it is likely to recur with a subsequent pregnancy.

Occasionally, children with isolated cardiac anomaly have a parent who has survived with cardiac anomaly, or another family member with a cardiac anomaly, but more often, there is no family history. However, an inheritable defect in a single gene (e.g., Marfan syndrome) or a chromosomal anomaly (e.g., trisomy) is identified in a significant minority of patients with cardiac malformations. More commonly there may be susceptibility from inherited or acquired mutations in two or more genes, perhaps with additional alterations in gene transcription or posttranscriptional processes from maternal-fetal folate metabolism, or fetal exposure to specific pharmacologic, biochemical, infectious and environmental factors that cumulatively surpass a threshold of liability (9). These result in pathogenetic changes in embryonic development, including defects in mesenchymal tissue migration (tetralogy of Fallot, truncus arteriosus, interrupted aortic arch, malalignment conal-septal ventricular septal defects, transposition of great arteries), extracellular matrix defects (endocardial cushion defects), abnormal cell death (muscular ventricular septal defect, Ebstein anomaly), targeted growth (anomalous pulmonary vein connection, single atrium), defective situs and cardiac looping (heterotaxy syndromes, L-transposition), and secondary effects from alterations in blood flow in the right heart (secundum atrial septal defect, pulmonary valve stenosis and atresia) or left heart (hypoplastic left heart syndrome, coarctation of aorta, aortic valve stenosis, patent ductus arteriosus) (9,10,11 and 12).

Approximately 13% of children with cardiac anomalies have chromosomal syndromes associated with cardiovascular malformation. Another approximately 8% to 13% of children have inheritable syndromes with associated cardiovascular abnormalities (11,12 and 13). The genes affected in many of these syndromes have been identified (9,14,15 and 16) (Table 33-3). The most common human mutations are in a critical 30 gene region of chromosome 22q11 involved in neural crest and cardiac development that cause DiGeorge
and velocardiofacial syndromes and associated conotruncal and aortic arch malformations (15). Other mutations in the genes encoding the extracellular matrix proteins fibrillin-1 and elastin are responsible, respectively, for Marfan and Williams syndrome. Genetic syndromes associated with abnormal cardiac development are generally associated with specific cardiac malformations, for instance Down syndrome and endocardial cushion defects, Williams syndrome and supravalvar aortic stenosis, DiGeorge syndrome and tetralogy of Fallot, truncus arteriosus, and interrupted aortic arch (Table 33-3). Recognition that a child has a syndrome associated with a cardiac anomaly, or vice versa, should prompt an investigation for possible associated anomalies (16,17,18,19 and 20).

Most children with cardiac malformations, even those with tetralogy of Fallot, have isolated cardiac anomalies, without generalized syndrome or other apparent abnormality. Many specific cardiac anomalies are rarely associated with a noncardiac syndrome, for example, transposition of the great arteries, and pulmonary atresia with intact ventricular septum (Table 33-4). Although the molecular biology of cardiovascular development is being unraveled, the specific genetic and/or environmental causes of isolated cardiac anomalies remain unknown in most individual cases (14,15,21). Mutations in 22q11 cause 20% to 30% of isolated conotruncal and aortic arch malformations. Other mutations are involved with at least some of the remainder (15). For example, alterations in cardiac specific transcription factor control genes, or their function (e.g., NKX2.5, TBX5), sometimes in combination with genes that they control, are being identified in children with isolated cardiac anomalies (15).

Although the occurrence of cardiac malformation has been mostly constant year by year, and by location, there are exceptions. Biochemical and chance events during fetal development may play roles in causation of new genetic mutations and in transcriptional and posttranscriptional processes (9,14,15,22). For instance, the risk for development of conotruncal anomalies is significantly influenced by maternal-fetal intake and metabolism of folic acid and homocysteine (24,25,26,27 and 28). Although fetal exposure to specific pharmacologic, biochemical, infectious and environmental factors may increase the risk for developing a cardiac abnormality (Table 33-5) (9,29,30 and 31), these factors alone do not appear to explain most cases. In individual cases, it is usually difficult or impossible to identify specific extrinsic factors that may have modified the baby’s genotype or genotypic expression.