Genetic Basis of Congenital Heart Disease

CHD refers to structural or functional abnormalities that are present at birth even if discovered much later. CHD comprises many forms of cardiovascular disease in the young, including cardiac malformations, cardiomyopathies, vasculopathies, and cardiac arrhythmias. It has been estimated that 4 to 10/1000 liveborn infants have a cardiac malformation, 40% of which are diagnosed in the first year of life. However, bicuspid aortic valve (BAV), the most common cardiac malformation, is usually excluded from this estimate. BAV is associated with considerable morbidity and mortality in affected individuals and, by itself, occurs in 10 to 20/1000 of the population. When isolated aneurysms of the atrial septum and persistent left superior vena cava, each occurring in 5 to 10/1000 live births, are taken into account, the incidence of cardiac malformations approaches 50/1000 live births. The incidence of cardiomyopathy, vasculopathy, and arrhythmias, including channelopathies, is less well characterized, but in light of the just-mentioned considerations, an incidence of cardiac disease of 50/1000 live births is a conservative estimate.

Heart development is under genetic control. The genetic contribution to CHD is well recognized based on familial clustering, differing recurrence rates depending on the type of CHD, and well-recognized genetic syndromes associated with CHD. Mendelian inheritance of CHD includes autosomal dominant, autosomal recessive, X-linked, and mitochondrial inheritance. In many cases, rather than being inherited in a Mendelian fashion, CHD is inherited as a complex trait with multifactorial causation. Epidemiologic information demonstrates clustering of both concordant and discordant CHDs in families. The classes of CHD with the highest recurrence risk of the same defect phenotype were heterotaxy, with a relative risk of 79.1 (95% confidence interval [CI]: 32.9 to 190), right ventricular outflow tract defects, with a relative risk of 48.6 (CI: 27.5 to 85.6) and left ventricular outflow tract obstructive (LVOTO) defects, with a relative risk of 12.9 (95% CI: 7.48 to 22.2). In addition, families were found to have clustering of distinct phenotypes of different heart defects, with a relative risk of 3.02, suggesting that common genetic causes may underlie a broad variety of malformations. Epidemiologic studies also indicate that approximately 25% of CHD is syndromic, whereas 75% is nonsyndromic. With progressively sophisticated genetic testing available, the causes of CHD are increasingly identified at the molecular or cytogenetic level. Because of this, consensus guidelines recommend genetic testing in patients with particular classes of CHD (eg, testing infants with interrupted aortic arch for 22q11.2 deletion syndrome [DiGeorge or Velocardiofacial syndrome]). However, most ACHD patients were born prior to the ability to test for these disorders.

Genetics in the Adult Congenital Heart Disease Population

The rate of genetic cardiac disease in the ACHD population should be very similar to rates quoted for the adult population for heritable conditions such as cardiomyopathy, connective tissue disorders, vasculopathies, and inherited arrhythmias. Although some children with syndromic congenital heart defects die in infancy, one would still expect a significant prevalence in the ACHD population, but few dedicated studies have been performed. A recent study in the ACHD population indicates that there remain a relatively large number of patients who have a syndromic basis of their CHD and would benefit from diagnostic evaluation.

The landscape of genetic evaluation and genetic testing has changed substantially over the past two decades. For example, the standard of care with neonates is currently to provide genetic testing for 22q11.2 deletion syndrome for a variety of conotruncal lesions, including truncus arteriosus, tetralogy of Fallot with absent pulmonary valve, right aortic arch, and others. However, this was not standard practice until recently; thus the majority of ACHD patients have likely not been offered modern genetic testing. In a 2005 study of 103 consecutive adult patients with conotruncal malformations, Beauchesne et al. identified a prevalence of 22q11.2 deletion of 5.8%. Half of those patients reportedly did not have physical features of 22q11.2 deletion syndrome. In addition, in a study of 156 consecutive Chinese patients with conotruncal abnormalities but no genetic diagnosis, 11.5% were diagnosed by fluorescence-polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) with 22q11.2 deletion syndrome. In this study only two-thirds of those found to have 22q11.2 deletions were considered dysmorphic by their referring cardiologist. This study concluded that nearly 1 in 10 adults with conotruncal lesions have undiagnosed 22q11.2 disease, thus emphasizing the benefit of thorough phenotypic assessment by someone knowledgeable about genetic syndromes and cytogenetic testing in this population.

Assessment by the Adult Congenital Heart Disease Clinician

It is important for the ACHD clinician to be aware of genetic etiologies of disease for a variety of reasons. First, although many patients are appropriately diagnosed in childhood with genetic syndromes, it is not uncommon for less obvious cases to be lacking an appropriate diagnosis. Identifying patients who should undergo further assessment may require a high level of suspicion. Second, unfortunately there are large numbers of patients who are lost to follow-up for many years and may reestablish care with an adult provider who does not have access to old records. In addition, some patients may be diagnosed with CHD for the first time in adulthood. Third, extracardiac manifestations are common in genetic syndromes leading to cardiovascular malformations, and knowledge of underlying syndromes is essential for generating appropriate referrals for care and management. Fourth, having a genetic diagnosis can help provide the patient with appropriate social services, as needed, and can justify additional therapy or neuropsychiatric testing and evaluation. Finally, having knowledge of either a discrete syndrome or a specific genetic diagnosis can help further refine the risk of transmission of CHD to the offspring. This recurrence risk information is of primary importance to many ACHD patients who would like a family.

In evaluating the ACHD patient, medical history, family history, and the clinical examination are all important facets contributing to an assessment of the likelihood of identifying a genetic cause for CHD. Detailed assessment of the patient’s medical history, and in some cases the pregnancy history, can provide a starting point for classification of genetic disease. In some cases, clinical history will identify the presence of a characteristic trait that would not otherwise be found on clinical examination. One example is the individual who was born with polydactyly but had early surgical removal of extra fingers or toes. This type of information can be crucial for the classification of patients with syndromic versus nonsyndromic phenotypes. A developmental assessment is also part of the medical history. Evaluation of past gross and fine motor skills, as well as cognitive development will lead to the recognition of developmental delay, which is more likely to be associated with CHD as part of a syndrome. Because this assessment may not have been done since childhood, it is particularly important to explore this aspect of the past medical history with the adult patient. In general, any patient with evidence of other birth defects, in addition to CHD, should be referred for further evaluation by a geneticist. Likewise, consideration of referral should occur for patients with abnormalities of stature (tall stature or short stature), sensory deficits without obvious explanation, or intellectual disability. Table 4.1 summarizes possible findings that should trigger suspicion of a genetic syndromic condition and prompt further evaluation.

Family history can distinguish genetic conditions that are not usually inherited (eg, Down syndrome or trisomy 21) from genetic conditions that exhibit familial clustering (eg, BAV). The recognition of familial heart disease has been complicated by three genetic phenomena that obscure the familial nature: reduced penetrance, variable expressivity, and genetic heterogeneity. Furthermore, whereas most patients believe family history is important, many are unfamiliar with important clinical details. Too often, in the hustle and bustle of a busy clinic, family history is asked on the initial visit, recorded, and never revisited. This leads to a situation in which family history is an underused tool in the recognition of genetic etiology. A precise recording of family history may require revisiting the questions on more than one occasion and obtaining information from more than one family member. In addition, family history, like other elements of the medical history, is dynamic and subject to change with the passage of time. Based on family history and clinical examination, the likelihood of identifying a genetic etiology can be determined. If the condition appears to be inherited, a three-generation pedigree is imperative to further the differential. Some clinics are not structured to allow for collection of this information, and referral to a genetic counselor and/or geneticist is important in this instances. The family history is often the primary tool used to counsel patients about recurrence risk. Patterns of inheritance that may be identified include autosomal dominant, autosomal recessive, X-linked, and mitochondrial. However, physicians should use caution not to rely entirely on family history because some genetic conditions occur de novo rather than being inherited. However, these conditions can then be passed on to the patient’s offspring.

A genetic condition may be identified by recognizing signature cardiac and/or noncardiac findings during the clinical examination. For example, tetralogy of Fallot is a signature cardiac malformation for 22q11.2 deletion syndrome, but a physician evaluating a patient with right ventricular outflow tract malformation may overlook characteristic dysmorphic facial features. Table 4.2 outlines common genetic syndromes identified in the ACHD population. Even with what appears to be isolated CHD, typical features of the cardiac phenotype may suggest a genetic etiology with known inheritance. For example, electrocardiographic findings of prolonged QT interval or echocardiographic findings of unexplained cardiac hypertrophy would be recognized by most cardiologists as conditions with a strong likelihood of genetic etiology and family clustering.