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Step 2: Identification of Risk—Assessment of Red Flags
After completing the data collection process and reviewing the personal and family history, including pertinent tests and findings from the physical examination, all data should be synthesized and reviewed for red flags that are suspect for disease risk. The review may indicate frequent family members with chronic disease, which indicates a familial propensity or disease risk for the individual; alternatively, the reviewed data may be suspect for an inherited disease or genetic predisposition. The significance of risk assessment is risk identification so that appropriate measures can be implemented to reduce risk, establish the need for genetic testing if applicable, enable diagnosis, or institute prophylactic or treatment regimens to improve outcomes.
Objectives
1. Discuss red flags in the family history that may be suspect for a genetic predisposition to disease
2. Describe limitations in the family history regarding some genetic disorders
66All data—personal and family history, physical examination as well as ancillary/radiology tests, and laboratory data, if applicable, obtained from the genomic risk assessment—should be carefully scrutinized to determine if there are elements for disease risk. Personal history issues that may be suspect for genetic disease include developmental delays, mental retardation, congenital anomalies, infertility, specific medical condition(s) or significant physical characteristics, and dysmorphology associated with inherited syndromes. Medical conditions associated with early-onset (e.g., colon cancer at age 35), atypical diseases based on gender or disease occurring in the less-often-affected gender (e.g., male breast cancer), rare cancers, and reproductive abnormalities such as recurrent pregnancy loss or infertility may raise suspicion for a genetic condition. Abnormal laboratory findings such as serum iron overload with elevated ferritin and transferrin saturation level or extreme lipid levels might suggest inherited hemochromatosis (autosomal recessive [AR] disorder) or familial hypercholesterolemia (autosomal dominant [AD] disorder), respectively. Physical examination findings, as previously stated, are also an important part of the genomic risk assessment as certain physical characteristics may be strongly suggestive of an inherited disorder. For example, sebaceous adenomas, epitheliomas, and carcinomas (Figure 6.1), as well as keratocanthomas, are all skin conditions that, if present and confirmed via clinical examination, may be suspect for an inherited colon cancer syndrome known as Muir–Torre syndrome, a form of Lynch syndrome (John & Schwartz, 2016; Mintsoulis & Beecker, 2016). Congenital hypertrophy of the retinal epithelium, a pigmented fundal lesion observed via ophthalmoscopic exam (Figure 6.2), may be observed in some individuals with familial adenomatous polyposis (FAP), an inherited colon cancer (Chen et al., 2006), and multiple café au lait spots on the skin or ophthalmic findings of Lisch nodules could be clinical signs of neurofibromatosis type 1 (NF1), an AD disorder (see Figures 6.1 to 6.3).
Family history is considered by some as the first genetic test. When complete and accurate, it can provide essential information that may denote patterns of inheritance indicating AD, AR, X-linked, or mitochondrial conditions. For example, a family history with unusual presentations like that of early age onset of sudden cardiac death may be suspect for an inherited cardiac disorder like familial dilated cardiomyopathy (80%–90% AD; rare AR and X-linked; U.S. National Library of Medicine [U.S. NLM], 2016), familial hypertrophic cardiomyopathy (AD), long QT syndrome, or other hereditary cardiac conditions (Figure 6.4). It can also play an important role in determining above-average risk for disease based on familial risk, due to shared genetics and environmental factors. For instance, risk increases if more than one family member has the same illness, particularly regarding common chronic disorders such as diabetes, coronary heart disease, stroke, and some cancers (Acheson et al., 2010).
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FIGURE 6.1 Sebaceous carcinoma of eyelid found during routine screening of a patient with Muir–Torre syndrome.
Source: Lynch and Anderson (2010).
FIGURE 6.2 Congenital hypertrophy of the retinal pigment epithelium (CHRPE) that may be found in some patients with familial adenomatous polyposis (FAP), an inherited colon cancer disorder; it is not diagnostic of FAP.
Source: Half, Bercovich, and Rozen (2009).
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FIGURE 6.3 Multiple small, oval, yellow-brown papules (Lisch nodules) in the right iris.
An early published mnemonic that can be used to identify red flags for genetic disorders is Family GENES, with the letter F and each letter in G-E-N-E-S representing elements that could be suspect for an inherited disease (Whelan et al., 2004). The F represents family history, denoting multiple family members with a specific disease or condition associated with a genetic syndrome that could indicate the need for further evaluation or genetic testing. A family history of multiple members in the family with colon cancer or colon and endometrial cancer, for example, might indicate a suspicion for Lynch syndrome. Table 6.1 shows some elements that denote red flags, including a brief description of the mnemonic Family GENES.
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FIGURE 6.4 A three-generation pedigree with a family history suspect for early sudden cardiac death on the paternal lineage with the proband diagnosed at the time of hospitalization for left ventricular hypertrophy (LVH) attributed to a genetic cardiac disorder.
ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor.
Limitations and Pitfalls of the History in Risk Identification
Although the personal and family history and physical examination play a critical role in determining genetic/genomic risk for disease, implementation of it does not guarantee identification of genetic red flags. Some examples of limitations from history data include inaccurate or unknown family history; adoption status; and AR pattern of inheritance that may not show disease occurrence in many generations due to the horizontal rather than vertical pattern of inheritance. In addition, genetics conditions impacted by penetrance and de novo mutations also influence the family history and may not result in identifiable red flags. De novo mutation is defined as a “new mutation” that is present for the first time in a family member as a consequence of a germline mutation in a germ cell or a mutation that arose during early embryogenesis (National Cancer Institute [NCI], n.d.). Penetrance refers to the likelihood that a clinical condition will occur based on the genotype (Cooper, Krawczak, Polychronakos, Tyler-Smith, & Kehrer-Sawatzki, 2013; NCI, n.d.). This means that the occurrence or signs and symptoms of disease is dependent on the genotype, with some genotypes having a high penetrance while others may have a reduced penetrance or probability of disease occurrence. For instance, gene mutations for FAP, an inherited colon cancer syndrome; multiple endocrine neoplasia; and retinoblastoma are complete (100%) penetrant disorders (Shawky, 2014), leading to disease certainty unless the individual dies of other causes. Although most inherited breast cancer syndromes are highly, but not 100%, penetrant, the risk for breast cancer is particularly high among those with a BRCA mutation, with an increased lifetime probability of breast cancer risk for women estimated at 50% to 87% (Antoniou et al., 2003; Ford et al., 1998). In addition, variable expressivity may lead to diagnosis failure, particularly with mild disease expressivity. Variable expressivity refers to the range of signs and symptoms that may occur from an inherited condition, which may vary from mild to severe and occur among individuals with the same genetic condition (NCI, n.d.). An example is the inherited condition of NF1 that can manifest as café au lait spots only or severe disease with numerous neurofibromas and brain tumors (NCI, n.d.). Further, pleiotropy, a single gene affecting multiple traits (Paaby & Rockman, 2013), may also result in different characteristics or clinical manifestations (phenotype) observed in the family history, making recognition and diagnosis of a genetic condition challenging if APRNs are not knowledgeable regarding this phenomenon. An example of pleiotropy is the multiple traits observed in mutations due to the cystic fibrosis transmembrane conductance regulator (CTFR) gene that leads to AR cystic fibrosis disease (Cutting, 2015). Cystic fibrosis (CF) can have varied symptoms that can affect multiple organs (e.g., liver, sweat glands, pancreas, intestines), from life-threatening obstructive lung disease to atypical CF that is a milder form of the disease manifesting as chronic sinusitis and occurring later in adulthood (Schram, 2012) to other forms of CF such as male infertility due to bilateral absence of the vas deferens (Sokol, 2001).
