Other Factors Affecting Risk and Risk Assessment

Classic and atypical modes of inheritance provide a framework for assessment of risk to close relatives of individuals affected by hereditary disorders. However, many factors influence the ability to clearly define patterns of inheritance in families. From a logistical perspective, family members may not know details about medical conditions in more distant relatives, or relatives may not wish to share those details by medical record request. For some,there may be stigma or guilt attached to discussion of hereditary conditions in themselves or their children. Mechanistically, there are a number of processes that may confound pedigree interpretation (Table 4-4). Variable expressivity and pleiotropy relate, respectively, to the presence of different degrees of severity of symptoms and the presence of varying phenotypic features in affected individuals. These could lead to misclassification of affected status, or failure to recognize the presence of a single clinical entity in affected family members. Further,variability in age of onset, particularly with adult-onset disease, may leave gaps in an otherwise classic pedigree, as can penetrance, or the likelihood that an individual who carries the gene(s) for a condition will show signs or symptoms of that condition. Some conditions show genetic heterogeneity, that is, can be caused by mutations in a number of different genes. While mutations in these genes may be rare, theoretically more than one type of gene mutation could lead to symptoms within a family. Phenocopies, similar conditions with different genetic or nongenetic etiologies or both, may also occur within a family and lead to misinterpretations of patterns of inheritance and, thus, of risk to family members. Small family size or relatively low frequency of the at-risk gender in gender-influenced disorders (sex-limited vs. sex-influenced expression) may result in failure to recognize a hereditary disorder and underestimation of risk.

Accurate reporting of relationships within a pedigree is critical. Nonpaternity, estimated at 10% in the United States,4 and consanguinity, or inbreeding (shared common ancestors), are particularly important when considering possible autosomal recessive traits. A recent review confirmed only modest contribution of consanguinity to overall risk,16 but it can be of critical importance when an autosomal recessive disorder is under consideration in a symptomatic individual due to potential presence of shared nonfunctional genes in related parents. Expression and risk assessment of X-linked disorders are influenced by lyonization, or the random inactivation of one X chromosome in each cell in a female. The percentages of the active and inactive nonfunctional X-chromosome gene could lead to full expression, intermediate symptomatology, or lack of symptoms altogether for an X-linked recessive condition in a female. The occurrence of spontaneous new mutations could lead to failure to recognize risk due to autosomal dominant or X-linked conditions, in particular. Similarly, mosaicism, or the presence of a mixture of at least two populations of cells with some containing a functional and others a nonfunctional gene, could lead to partial expression of a condition in an individual (somatic mosaicism). Mosaicism also could lead to unrecognized or indefinable risk to future offspring if only the germ cells (egg or sperm) are affected or only a percentage of germ cells are affected (germline mosaicism).

Finally, factors outside of the critical gene can influence the expression of that gene and thus the assessment of risk. Expression of some genes is influenced by variant forms of other, so-called modifying genes. Polymorphisms or mutations in these modifying genes can change gene-gene or protein-protein interactions to affect expression of the condition in question. Similarly, environmental factors such as shared environment, dietary practices, and specific exposures (medications, smoke, etc.) may positively or negatively affect gene function or expression of clinical symptoms.

Each of these factors must be carefully considered in the overall diagnostic and risk assessment, initially based on collection of a family pedigree and continued through clinical evaluation, including physical examination and indicated diagnostic testing.

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