Core Principles in Family History: Interpretation

Recognize Genetic Red Flags

In general, identifying “Genetic Red Flags” in a family medical history can help determine if a condition (or similar conditions) present in a family has a significant genetic contribution. These Genetic Red Flags include:

• Known or suspected genetic disorder in family members. A patient may know of a specific genetic disorder, or suspected diagnosis, that affects one or more relatives. The accuracy of the information is supported when the patient knows the name of a specific diagnosis, especially if it is unusual. Awareness of a specific diagnosis facilitates immediate assessment and appropriate management if the patient is at risk for this disorder.
• Multiple affected relatives with same or related disorders.  The presence of multiple affected relatives could indicate a single-gene disorder that follows a Mendelian inheritance pattern:
• If each affected individual in the family has a parent with related symptoms, the condition may be autosomal dominant. Be aware that some autosomal dominant conditions are expressed to varying degrees even within the same family. Some individuals may exhibit only minimal symptoms, or even appear unaffected unless closely examined. This means it is possible for a parent to be only mildly or minimally affected, but his or her child be severely affected.  
• If neither of an affected individual’s parents is affected, the condition could be recessive. If only males seem to be affected, the condition could be X-linked.
• Multiple affected relatives in a pedigree that does not show a clear pattern of inheritance are also characteristic of complex traits such as cancers, heart disease, and obesity, which result from a combination of shared genetic and environmental factors among relatives.
• Earlier age at onset of disease than expected.  Common, complex disorders that occur at an earlier age than expected are more likely to have a genetic etiology, for example, breast cancer in a pre-menopausal woman.
• Intellectual disability (formerly referred to as developmental delay or mental retardation).  Environmental exposures in the pre- or postnatal period can cause intellectual disability. However, intellectual disabilities can result from genetic conditions such as chromosomal disorders, untreated or poorly managed inborn errors of metabolism, and some single- gene disorders. As a result, the report of a relative (or several) with intellectual disability should alert the clinician to consider a genetic etiology. 
• Diagnosis in the less-often-affected sex.  Some disorders may occur more commonly in one sex. These differences reflect a variety of factors such as hormonal, developmental, and environmental variables. If a disorder occurs in the less-often-affected sex, however, it is possible that inherited genetic influences have superseded the other factors. For example, because male breast cancer is rare in the general population, when it occurs, an underlying genetic etiology should be ruled out.
• Multifocal or bilateral occurrence in paired organs.  Over time, people are exposed to environmental influences that may cause changes and damage to genes, organs, or body systems. When changes result from genetic influences, they are more likely to occur in multiple locations. For example, unilateral (only one eye) retinoblastoma (malignant tumor of the retina) occurs sporadically, but bilateral (in both eyes) retinoblastoma is seen in individuals who have an inherited form of this cancer.
• One or more major malformation(s).  Minor malformations are physical alterations that do not have substantial medical or cosmetic consequences, such as differently shaped ears or syndactyly of the second and third toes. These may be due to normal population variation or a familial trait; the clinician should examine the parents of the affected child before concluding that a minor malformation is significant. A slight physical change may be a familial trait. Major malformations, on the other hand, are birth defects of medical or cosmetic significance. These include heart defects, underdeveloped or absent organs, and cleft lip and/or palate, among others. Some malformations can be isolated single occurrences, arising because of a combination of environmental and genetic influences. However, a genetic syndrome is suspected when one (or more) major malformation is present, multiple minor malformations are present, or a combination of the two. (Bennett, 2010).
• Disease in the absence of risk factors or after preventive measures.  People can change their diets, intensity of exercise, level of stress, and other environmental factors to avoid or delay the onset of disease. They cannot, however, change their genetic make-up. A person who develops symptoms despite a low-risk lifestyle and/or radical preventative measures may have a genetic predisposition to the disease in question. 
• Abnormalities in growth (growth retardation, asymmetric growth, excessive growth).  Though not the only causes of abnormalities in growth, genetic conditions should be considered when evaluating an individual for prenatal or postnatal growth changes or deficiencies, especially in the absence of other risk factors such as malnutrition.  Many genetic disorders and syndromes cause growth retardation, asymmetric growth, and/or excessive growth. In fact, the specific pattern of abnormal growth may be crucial in making a diagnosis.
• Recurrent pregnancy losses (2 or 3+). Spontaneous miscarriages, especially in the first trimester, are common, and often due to an isolated chromosome abnormality. However, structural or numerical changes in the chromosomes of one parent, or other deleterious genetic changes in one parent, could lead to more frequent pregnancy losses. The presence of multiple spontaneous miscarriages in an individual, or several related individuals, indicates an underlying genetic modification. This situation can result in a spectrum of outcomes ranging from spontaneous miscarriage to genetic disorders in a child.
• Consanguinity (blood relationship of parents).  
• Ethnic predisposition to certain genetic disorders, or ethnicities associated with common, or founder, mutations for a particular condition (Jobling et al., 2004).  The incidence of some disorders varies depending on the ancestry of the family. For example, sickle cell disease is most common in African Americans, while cystic fibrosis is most common in Caucasians of Northern European descent. Knowledge of a patient’s ancestry should not be the only information used in making a diagnosis, but it should be included in a comprehensive evaluation of family history. Note that knowledge of the region of geographic origin is more helpful than ethnicity, because ethnicity (and race) is much more subjective.

Recognize basic inheritance patterns

• Multifactorial (complex) disorders
• Single-gene disorders:  
  • autosomal dominant
  • autosomal recessive
• X-linked
• Chromosomal disorders
  
  • extra or missing chromosomes
  • deletions or duplications
  • translocations
• Mitochondrial

Learn more about patterns of inheritance.

Recognize factors that may complicate interpretation of the family history

Genetic professionals can assist with family history interpretation and risk assessment.  Consultation with a genetic professional can help identify red flags in the family health history, possible patterns of disease segregation in the family, and also the more complex family relationships and sociocultural factors that influence interpretation. 

• Missing information vs. unaffected relatives.  Assessment of a patient’s risk must include consideration of affected relatives and unaffected relatives, making it essential to include both in the documentation of a patient’s family history. This documentation should differentiate clearly between individuals for whom specific information is missing and individuals who are unaffected or asymptomatic; the two have different effects on risk assessment. This can be as simple as writing “no contact, “no information,” or a question mark next to an individual about whom little information is known, and writing the abbreviation A&W, for “alive and well,” next to an individual with no reported medical concerns.
• Reliability of information.  It is important to consider the reliability or accuracy of the information when interpreting a medical family history. Patients may not be good historians, may not remember accurate or complete information, or may withhold information intentionally to maintain privacy. An asterisk (*) can be used on the pedigree to indicate that health information has been reviewed through examination of the medical chart or a death certificate (Bennett et al., 2008).
• Non-traditional families.  Healthcare providers collecting family histories should be prepared to document non-traditional families such as non-nuclear families, multiple marriages, offspring conceived through sperm or egg donors, and same-sex partners or parents. The representation of various family structures in the pedigree should be clear because the degree of relationship among different family members affects risk assessment (Bennett et al., 2008). Furthermore, a “social family” may not be genetically related, but its members may have common behaviors and environmental influences, all of which must be considered in a comprehensive evaluation of a patient’s risk for health complications.
• Unknown paternity. Limited information from the paternal side of the family limits the reliability of risk assessment for disease. It is important to keep in mind that a patient’s family history and the results of some genetic tests may reveal misattributed or unknown paternity; the clinician should share this information with the family carefully and sensitively. 
• Adoption.  Little may be known about the personal- or family-health histories of individuals adopted into or out of a family, thereby affecting risk assessment for disease. Also, this information can be sensitive if some family members have not been made aware that an adoption occurred.
• Cultural definitions of family.  Different cultures define “family” in different ways. Because an interpretation of a family history evaluates individuals who are related genetically, it is important to clarify the exact relationship of relatives, including half-siblings and adopted relatives.
• Cultural biases.  Patient or provider assumptions can affect the collection of data and ultimately influence interpretation, assessment, and patient management. Cultural awareness in healthcare is crucial for providing quality healthcare services and is particularly important when asking a patient for personal details about his or her family history.
• Consanguinity.  Consanguinity refers to a mating between biologically related individuals. Although marriage between cousins is a common practice in many parts of the world, it is uncommon in the United States. Children of consanguineous unions are at increased risk for autosomal recessive disorders or birth defects because close relatives are more likely than unrelated individuals to share the same genetic variants through a common ancestor. The size of risk depends on the degree of relatedness. The term incest usually is reserved for a relationship between first-degree relatives, such as a parent and child, or siblings.
• Confidentiality. Patients may view the collection of family history information as intrusive, and possibly unnecessary. Patients’ reluctance to share family information may be due to fear of stigmatization and discrimination by medical providers and insurance companies, concern about possible loss of privacy, or general distrust of the medical community. To encourage patients to be open and honest, it is important to ensure the confidentiality of the information they share and to explain the importance of this information in their overall healthcare. Additionally, the Genetic Information Nondiscrimination Act (GINA) and the Health Information Privacy Portability Act (HIPPA) provide some protections for family history information.  Learn more about GINA. 

Medical family history information is unique in that it applies to multiple individuals in addition to the patient. Despite its relevance for the patient’s relatives, the information recorded can be applied only to the medical management of the patient, and patient confidentiality must be maintained.