As detailed in Chapter 6, two classes of genes, protooncogenes and tumor suppressor genes, regulate normal cell growth. Mutations affecting these genes, most often in somatic cells, are involved in the pathogenesis of tumors. In approximately 5% to 10% of all cancers, however, mutations affecting certain tumor suppressor genes are present in all cells of the body, including germ cells, and hence can be transmitted to the offspring. These mutant genes predispose the offspring to hereditary tumors, a topic discussed in greater detail in Chapter 6. A few salient examples of familial neoplasms arising in children are discussed later in this chapter.
Complex multigenic disorders—so-called “multifactorial or polygenic disorders”—are caused by interactions between genetic variants and environmental factors. A genetic variant that occurs in at least 1% of the population is called a polymorphism. According to the common disease–common variant hypothesis, complex multigenic disorders occur when many polymorphisms, each with a modest effect and low penetrance, are coinherited. Two additional important facts have emerged from studies of common complex disorders such as type 1 diabetes: • Although complex disorders result from the collective inheritance of many polymorphisms, different polymorphisms vary in significance. For example, of the 20 to 30 genes implicated in type 1 diabetes, 6 or 7 are most important, and a few HLA alleles contribute more than 50% of the risk (Chapter 20).
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Fig. 7.12 (Top) Asimplifiedschemeofnormalglycogenmetabolismintheliverandskeletalmuscles.(Middle) Theeffectsofaninheriteddeficiencyofhepaticenzymesinvolvedinglycogenmetabolism.(Bottom) Theconsequencesofageneticdeficiencyintheenzymesthatmetabolizeglycogeninskeletalmuscles.
Some polymorphisms are common to multiple diseases of the same type, whereas others are disease-specific. This observation is well illustrated in immune-mediated inflammatory diseases (Chapter 5).
Many of the disease-associated polymorphisms are in noncoding regions so they likely affect epigenetic regulation of gene expression.
Several normal phenotypic characteristics are governed by multigenic inheritance, such as hair color, eye color, skin color, height, and intelligence. These characteristics (also known as quantitative trait loci [QTLs]) show a continuous variation within, as well as across, all population groups. Environmental influences, however, significantly modify the phenotypic expression of complex traits. For example, type 2 diabetes mellitus has many of the features of a complex multigenic disorder. It is well recognized clinically that affected persons often first exhibit clinical manifestations of this disease after weight gain. Thus, obesity, as well as other environmental influences, unmasks the diabetic genetic trait. Assigning a disease to this mode of inheritance must be done with caution. Such attribution depends on many factors but first on familial clustering and the exclusion of mendelian and chromosomal modes of transmission. A range of levels of severity of a disease is suggestive of a complex multigenic disorder, but, as pointed out earlier, variable expressivity and reduced penetrance of single mutant genes also may account for this phenomenon. Because of these issues, it is sometimes difficult to distinguish between mendelian and multifactorial disorders.
Chromosomal abnormalities occur much more frequently than is generally appreciated. It is estimated that approximately 1 in 200 newborn infants has some form of chromosomal abnormality. The figure is much higher in fetuses that do not survive to term; in as many as 50% of first-trimester spontaneous abortions, the fetus may have a chromosomal abnormality. Cytogenetic disorders result from alterations in the number or structure of chromosomes and may affect autosomes or sex chromosomes.