The medical family history is a comprehensive and dynamic record of illnesses and other pertinent health information among family members. Family history is used to facilitate diagnosis, to identify family members at risk for developing a particular disease, and increasingly to manage disease. This article reviews the application of family history to pediatric cardiovascular disease. As more is learned about the genetic basis of cardiovascular disease, the family history will play an increasingly central role in management. Improved understanding of the causes of pediatric cardiovascular disease promises the opportunity to develop new diagnostic and therapeutic strategies.
Key points
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Complete detailed family histories are critical for the optimal management of children and families.
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Awareness of family history is important for individual health.
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Evaluation of family history may provide reassurance regarding disease risk and allow patients to avoid unnecessary testing.
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Family history evaluation may allow early diagnosis and improved outcomes.
Introduction
The medical family history is a record of illnesses and other pertinent health information among family members. Applications of the family history include confirming medical diagnoses, identifying family members at risk for various conditions, and calculating risk for developing a particular disease. A detailed family history provides the first genetic screen for an individual and contains substantial medical information. As genetic testing becomes more available, and clinicians embrace primary prevention and early intervention, the family history will become increasingly important in clinical decision making, especially in pediatrics, where universal screening approaches are already engrained in the culture. Further, because clinicians are learning that many of the supposedly acquired diseases of adulthood have developmental causes, the genetic basis of these conditions need to be understood and proactively acted on even though the clinical conditions may not typically manifest in the pediatric age range. At present, many efforts are being directed toward increasing awareness of the value of the family history and identifying efficient and practical ways to use the family history information. In summary, family history has a central usefulness for all health care providers and a significant impact on clinical management in the emerging genetic era.
A pedigree, also known as a family tree, is a graphic representation of a family history using symbols. The pedigree is used for many clinical and research purposes including: making a diagnosis, establishing a pattern of inheritance, identifying family members at risk, calculating risk, making decisions regarding tests and surveillance strategies, and patient education. Given the universal use of this tool, the National Society of Genetic Counselors (NSGC) formed a Pedigree Standardization Task Force and developed standard nomenclature for pedigrees. Because the family history affects all areas of medicine, it is important that all health care professionals have a working knowledge of pedigree structure. Practical suggestions for recording a medical pedigree are included in Box 1 . The family history is dynamic and needs to be revisited and updated periodically. Once the detailed family history is obtained, time and effort needs to be invested to maintain the accuracy and value of the information. There are significant barriers to the optimal use of family history information, primarily a lack of awareness on the family’s part and considerable time restrictions on the health care professional’s part. In an effort to increase family history awareness, tools have been developed and are available to the general public to generate and maintain a detailed family history ( Table 1 ). For example, the Health and Human Services Family History Initiative has designed a publicly available, Web-based program providing a means to generate and maintain a detailed family history, as well as keeping track of prenatal genetic and environmental risk factors. Further, as electronic medical records become increasingly sophisticated and personalized medicine initiatives are implemented, there will be a need to combine this information in a way that the patient can access and use.
Start with the patient or proband and work backwards
Indicate the proband with an arrow
Confirm whether the proband has siblings and clarify whether they share 1 (half siblings) or both parents (full siblings)
Ask about the mother, followed by her siblings and their children, and maternal grandparents
Repeat with father’s side of the family
Ask specifically about each individual:
- •
For affected individuals, document the age at diagnosis and the diagnosis
- •
For unaffected individuals, document specific cardiovascular symptoms and any completed cardiac screening
- •
For all individuals, document current age or age and cause of death
- •
Be consistent when documenting:
- •
Include the father/male partner on the left hand side and the mother/female partner on the right hand side
- •
Keep generations (ie, proband, siblings, maternal and paternal first cousins) on the same horizontal level
- •
Place siblings in birth order (oldest on left, youngest on right)
- •
| Health and Human Services Family History Initiative | www.hhs.gov/familyhistory |
| Online Mendelian Inheritance of Man | www.ncbi.nlm.nih.sov/Omim |
| US Centers for Disease Control and Prevention | www.cdc.gov/genomics |
| March of Dimes | www.marchofdimes.com |
| National Coalition for Health Professional Education in Genetics | www.nchpeg.org |
| NSGC | www.nscg.org |
| American Academy of Pediatrics | www.aap.org |
| American Medical Association | www.ama-assn.ore |
| American Society of Human Genetics | www.ashg.ore |
| Gene Tests | www.genetests.org |
The family history is widely used in pediatrics, and this article describes specific approaches to family history in the context of pediatric cardiovascular disease. The various approaches to family history in cardiovascular malformation (CVM) are reviewed, along with known cardiovascular diseases with a genetic basis, including cardiomyopathy, arrhythmia, thoracic aortic aneurysm, and sudden cardiac death, and the practical applications of family history information, including diagnosis, risk stratification, and management, are also discussed.
Introduction
The medical family history is a record of illnesses and other pertinent health information among family members. Applications of the family history include confirming medical diagnoses, identifying family members at risk for various conditions, and calculating risk for developing a particular disease. A detailed family history provides the first genetic screen for an individual and contains substantial medical information. As genetic testing becomes more available, and clinicians embrace primary prevention and early intervention, the family history will become increasingly important in clinical decision making, especially in pediatrics, where universal screening approaches are already engrained in the culture. Further, because clinicians are learning that many of the supposedly acquired diseases of adulthood have developmental causes, the genetic basis of these conditions need to be understood and proactively acted on even though the clinical conditions may not typically manifest in the pediatric age range. At present, many efforts are being directed toward increasing awareness of the value of the family history and identifying efficient and practical ways to use the family history information. In summary, family history has a central usefulness for all health care providers and a significant impact on clinical management in the emerging genetic era.
A pedigree, also known as a family tree, is a graphic representation of a family history using symbols. The pedigree is used for many clinical and research purposes including: making a diagnosis, establishing a pattern of inheritance, identifying family members at risk, calculating risk, making decisions regarding tests and surveillance strategies, and patient education. Given the universal use of this tool, the National Society of Genetic Counselors (NSGC) formed a Pedigree Standardization Task Force and developed standard nomenclature for pedigrees. Because the family history affects all areas of medicine, it is important that all health care professionals have a working knowledge of pedigree structure. Practical suggestions for recording a medical pedigree are included in Box 1 . The family history is dynamic and needs to be revisited and updated periodically. Once the detailed family history is obtained, time and effort needs to be invested to maintain the accuracy and value of the information. There are significant barriers to the optimal use of family history information, primarily a lack of awareness on the family’s part and considerable time restrictions on the health care professional’s part. In an effort to increase family history awareness, tools have been developed and are available to the general public to generate and maintain a detailed family history ( Table 1 ). For example, the Health and Human Services Family History Initiative has designed a publicly available, Web-based program providing a means to generate and maintain a detailed family history, as well as keeping track of prenatal genetic and environmental risk factors. Further, as electronic medical records become increasingly sophisticated and personalized medicine initiatives are implemented, there will be a need to combine this information in a way that the patient can access and use.
Start with the patient or proband and work backwards
Indicate the proband with an arrow
Confirm whether the proband has siblings and clarify whether they share 1 (half siblings) or both parents (full siblings)
Ask about the mother, followed by her siblings and their children, and maternal grandparents
Repeat with father’s side of the family
Ask specifically about each individual:
- •
For affected individuals, document the age at diagnosis and the diagnosis
- •
For unaffected individuals, document specific cardiovascular symptoms and any completed cardiac screening
- •
For all individuals, document current age or age and cause of death
- •
Be consistent when documenting:
- •
Include the father/male partner on the left hand side and the mother/female partner on the right hand side
- •
Keep generations (ie, proband, siblings, maternal and paternal first cousins) on the same horizontal level
- •
Place siblings in birth order (oldest on left, youngest on right)
- •
| Health and Human Services Family History Initiative | www.hhs.gov/familyhistory |
| Online Mendelian Inheritance of Man | www.ncbi.nlm.nih.sov/Omim |
| US Centers for Disease Control and Prevention | www.cdc.gov/genomics |
| March of Dimes | www.marchofdimes.com |
| National Coalition for Health Professional Education in Genetics | www.nchpeg.org |
| NSGC | www.nscg.org |
| American Academy of Pediatrics | www.aap.org |
| American Medical Association | www.ama-assn.ore |
| American Society of Human Genetics | www.ashg.ore |
| Gene Tests | www.genetests.org |
The family history is widely used in pediatrics, and this article describes specific approaches to family history in the context of pediatric cardiovascular disease. The various approaches to family history in cardiovascular malformation (CVM) are reviewed, along with known cardiovascular diseases with a genetic basis, including cardiomyopathy, arrhythmia, thoracic aortic aneurysm, and sudden cardiac death, and the practical applications of family history information, including diagnosis, risk stratification, and management, are also discussed.
Family history of CVM
Pediatric heart disease includes CVM, also known as congenital heart disease (CHD), cardiomyopathy, channelopathy, and aortopathy. CVM refers to malformation of the cardiovascular system that is present at birth. These cardiovascular anomalies are the most common birth defects and a leading cause of infant mortality. Despite advances in the diagnosis and treatment of CVM, there continues to be significant associated mortality, morbidity, and economic burden. The incidence of CVM is classically cited as 8 per 1000 live births, or approximately 1%, but the true incidence of all CVM is estimated to be 5 per 100, or 5% of live births. A substantial number of spontaneous abortuses have CVM, with an estimated incidence of 20 per 100, suggesting that the true incidence of CVM is even higher.
Because the detection of cardiovascular disease, especially CVM, is increasingly occurring during gestation, the role of prenatal counseling is rapidly evolving and is necessary for optimal care. The primary goals of genetic counseling for CVM in the prenatal period are to determine whether the specific CVM suggests an underlying genetic syndrome and whether genetic testing is indicated. Parents receive comprehensive information about the diagnosis for anticipatory care. A prenatal confirmation of the cause prepares both the family and health care providers before delivery and often affects medical management and family decision making. With the advent of noninvasive prenatal diagnosis, certain chromosomal abnormalities can be identified without the risk of miscarriage associated with amniocentesis and chorionic villus sampling. Genetic counselors are positioned to help the family understand the diagnosis and possible associated genetic conditions, to discuss the risks and benefits of genetic testing if indicated, and to provide psychosocial support to the family. Genetic counseling during the preconception or prenatal period may also be indicated for individuals affected with CVM. The goals of prenatal genetic counseling may include discussion of recurrence risks for CVM and recommendations for fetal echocardiography.
The Baltimore-Washington Infant Study, the largest and most comprehensive epidemiologic study of CVM, recognized diabetes and environmental teratogens such as retinoic acid as risk factors for CVM, but more importantly identified a positive family history as the most common risk factor for CVM. Classification schemes have evolved substantially since Maude Abbott generated The Atlas of Congenital Cardiac Disease more than 100 years ago, which is widely regarded as the first classification system for CVM. An exquisite clinical taxonomy was established based on anatomy and physiology, but classification paradigms have been developed recently that attempt to account for the underlying causes of CVM by using the developmental relationships of lesions. For example, the National Birth Defects Prevention Study developed a comprehensive taxonomy that organizes CVM in several ways, including the most specific definition of a single defect, such as hypoplastic left heart syndrome (the splitting approach), the most broad groupings, such as left-sided outflow tract obstruction lesions (the clumping approach), and an intermediate level that allows flexibility with the analysis of common associations, such as aortic stenosis and coarctation of the aorta. Overall, a classification system that incorporates causal factors as well as deep phenotyping is necessary for informed counseling and optimal risk assessment.
Given the high incidence of CVM, a positive family history is likely to be encountered by any health care provider obtaining family histories routinely. As with any reported family history, confirming the specific defect is necessary to guide appropriate counseling and recommendations. In addition, it is important to consider possible causes, which are broad and include chromosomal imbalances and single-gene sequence variants, with most arising through various combinations of genetic and environmental factors. This information should be used to determine whether genetic evaluation and/or cardiac screening may be indicated for the patient. Understanding the family history of CVM may allow the identification of important genetic reproductive risks for the patient and family.
Approximately 7% to 12% of individuals with CVM have an underlying chromosome abnormality including trisomy 21, trisomy 18, 22q11 deletion, and trisomy 13. Of these diagnoses, 22q11 deletion syndrome is most frequently transmitted from parent to child. In addition, features of 22q11.2 deletion syndrome are variable and, in some families, diagnosis may be missed or delayed. CVMs that should prompt further questioning and consideration of 22q11.2 deletion syndrome include interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, ventricular septal defect (VSD) with aortic arch anomaly, and isolated aortic arch anomalies, including a right-sided aortic arch that can be associated with vascular rings. There are also well-described genetic syndromes caused by DNA sequence variants in known genes including Noonan syndrome, Holt Oram syndrome, and Alagille syndrome. A summary of CVMs with commonly associated genetic syndromes is given in Table 2 . If the CVM is associated with a known underlying genetic syndrome, caused by either a chromosomal or single-gene abnormality, the inheritance pattern is readily known and the presence or absence of extracardiac features in the patient and relatives is often easy to assess, thus allowing the provision of risk assessment.
| CVM | Genetic Syndrome | Frequency (%) |
|---|---|---|
| Supravalvar aortic stenosis | Williams syndrome | 75 |
| Pulmonary stenosis (peripheral and branch) | Alagille syndrome | 67 |
| Conotruncal defects (IAA, VSD with AA, TA, TOF, AAA) | Deletion 22q syndrome | >50 |
| Pulmonary valve stenosis | Noonan syndrome | 20–50 |
Most CVM is not associated with a well-described chromosome abnormality or genetic syndrome. The emergence of chromosome microarray technology has identified chromosomal imbalances not previously detected by traditional karyotype in approximately 18% to 20% of cases of CVM when additional features, such as other congenital anomalies or intellectual impairment, are present. The yield of chromosome microarray testing in isolated CVM is not known and likely depends on the age of the affected individual, with a potentially higher yield in infants, given the inability to evaluate for developmental delay and other late-onset features. If a family history of CVM is reported and the affected individual has additional congenital anomalies or intellectual impairment, genetic evaluation is typically indicated. For example, a patient with pulmonary valve stenosis and short stature should be referred for genetic evaluation with specific consideration of Noonan syndrome. In addition, a patient with tetralogy of Fallot and mental illness should be referred for consideration of 22q11.2 deletion syndrome. Even if the cardiac and noncardiac features do not suggest a specific syndrome, the presence of CVM in the context of other medical or developmental concerns warrants genetic evaluation.
More than 30 genes have been associated with nonsyndromic forms of CVM. The contribution both in terms of risk for malformation and number of cases remains uncertain but has been reported to be between 3% and 5%. Studies regarding heritability of isolated CVM suggest that genetic factors play an important role and the contribution of single genes may be greater than currently reported. Single-gene testing is not typically indicated in cases of isolated CVM unless there are multiple affected individuals in the family. One example of this is the association of mutations in the NKX2.5 gene with familial CVM, specifically atrial septal defects and atrioventricular block. Mutations in this gene are inherited in an autosomal dominant manner with reduced penetrance and variable expressivity, underscoring the common observation that what seems to be mendelian inheritance is complex inheritance (ie, a single gene does not fully explain inheritance). The findings of genetic heterogeneity, reduced penetrance, and variable expressivity are typical in nonsyndromic CVM and suggest that most of these defects are polygenic.
Despite the well-known genetic basis of CVM, less than 20% have a known genetic cause. Environmental factors have been shown to be associated with increased risk for CVM, including maternal health, maternal exposures, and pregnancy complications. Diabetes is known to be associated with an increased risk for CVM in addition to other congenital anomalies. Fertility medications and maternal smoking during pregnancy were recently associated with an increased risk of CVM. Although these risk factors are considered nongenetic, they may still be shared within the family and result in an increased risk of CVM for future pregnancies or other relatives. Given what is known regarding genetic and environmental risk factors for CVM, it is likely that most defects are the result of multifactorial inheritance. In light of the currently limited knowledge and understanding about the multifactorial traits, the family history tool remains the most reliable in establishing risk.
The overall recurrence risk of nonsyndromic CVM generally ranges from 2% to 10%. The risk of recurrence is based on the specific CVM, the relationship to the affected individual, and the gender of the affected individual. For example, the likelihood of a couple having a child with a CVM is higher if the mother has a personal history of CVM as opposed to the father, and the risk is greater if the affected first-degree relative is a parent as opposed to a sibling. A severe left ventricular outflow tract obstruction lesion (LVOTO), hypoplastic left heart syndrome (HLHS), has been shown to have a high degree of heritability with an empiric recurrence risk for CVM being approximately 20%. In addition, HLHS and bicuspid aortic valve (BAV) are genetically related, with an increased risk of BAV among relatives. Thus, cardiac screening may be indicated for individuals with a family history of an LVOTO lesion. This finding again shows the importance of confirming the family history and specific lesion in order to provide the most accurate risk assessment and cardiac screening recommendations.
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Positive family history is a common risk factor for CVM
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Confirmation of a specific CVM may help guide appropriate counseling, risk assessment, and testing
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Individuals with CVM and an additional congenital anomaly or intellectual impairment may benefit from genetic evaluation
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Single-gene mutations are not known to be a common cause of isolated familial CVM; however, they may be underreported
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Most CVMs are attributed to multifactorial inheritance
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