diseases require homozygosity (i.e., two mutant genes at the same locus, one from each parent) for disease manifestation. Examples include cystic fibrosis, phenylketonuria, hemochromatosis, Bloom’s syndrome, and ataxia-telangietasia.
The X-linked recessive diseases are due to mutations in genes located on the X chromosome and include Duchenne’s muscular dystrophy, Fabry’s disease, steroid sulfatase deficiency, and ocular albinism. Some X-linked dominant diseases are known, but for most of them, no data on incidence estimates are currently available. Therefore, these diseases are not considered further in this report. The general point with respect to Mendelian diseases is that the relationship between mutation and disease is simple and predictable.
The major burden of naturally occurring genetic diseases in human populations, however, is not constituted by Mendelian diseases, which are rare, but by those that have a complex etiology. The term “multifactorial” is used to designate these diseases to emphasize the fact that there are multiple genetic and environmental determinants in their etiology. Their transmission patterns do not fit Mendelian expectations. Examples of multifactorial diseases include the common congenital abnormalities such as neural tube defects, cleft lip with or without cleft palate, and congenital heart defects that are present at birth, and chronic diseases of adults (i.e., with onset in middle and later years of life) such as coronary heart disease, essential hypertension, and diabetes mellitus.
Evidence for a genetic component in their etiology comes from family and twin studies. For example, first-degree relatives of patients affected with coronary heart disease have a two- to sixfold higher risk of the disease than those of matched controls, and the concordance rates of disease for monozygotic twins are higher (but never 100%) than those for dizygotic twins (Motulsky and Brunzell 1992; Sankaranarayanan and others 1999).
As mentioned earlier, multifactorial diseases are presumed to originate from the joint action of multiple genetic and environmental factors; consequently, the presence of a mutant allele is not equivalent to having the disease. For these diseases, the interrelated concepts of genetic susceptibility and risk factors are more appropriate. The genetic basis of a common multifactorial disease is the presence of a genetically susceptible individual, who may or may not develop the disease depending on the interaction with other genetic and environmental factors. These concepts are discussed further in Annex 4A. The important general point is that unlike the situation with Mendelian diseases, the relationships between mutations and disease are complex in the case of multifactorial diseases. For most of them, knowledge of the genes involved, the types of mutational alterations, and the nature of environmental factors remains limited. Among the models used to explain the inheritance patterns of multifactorial diseases and to estimate the recurrence risks in relatives is the multifactorial threshold model (MTM) of disease liability. The MTM, its properties, and its predictions are discussed in Annex 4A.
Historically, both UNSCEAR and the BEIR committees have always had an additional class of genetic diseases—“chromosomal diseases”—in their lists that included those that had long been known to arise as a result of gross (i.e., microscopically detectable), numerical (e.g., Down’s syndrome, which is due to trisomy of chromosome 21), or structural abnormalities of chromosomes (e.g., cri du chat syndrome, due to deletion of part or the whole short arm of chromosome 5 [5p-]). As discussed later, this is really not an etiological category, and deletions (microscopically detectable or not) are now known to contribute to a number of constitutional genetic diseases grouped under autosomal dominant, autosomal recessive, and X-linked diseases.
In the absence of data on radiation-induced germ cell mutations that can cause genetic disease in humans, all of the methods developed and used for predicting the risk of genetic disease from the mid-1950s to the present are indirect. Their strengths and weaknesses are reviewed in BEIR V (NRC 1990). One such indirect method is the doubling dose method, on which attention is focused in this section. It has been in use since the early 1970s (NRC 1972, 1990; UNSCEAR 1977, 1982, 1986, 1988) and is used in the recent UNSCEAR (2001) report.
The doubling dose method enables expressing of the expected increase in disease frequency per unit dose of radiation in terms of the baseline frequency of the disease class. The doubling dose (DD) is the amount of radiation required to produce in a generation as many mutations as those that arise spontaneously. Ideally, it is estimated as a ratio of the average rates of spontaneous and induced mutations in a given set of genes:
The reciprocal of the DD (i.e., 1/DD) is the relative mutation risk (RMR) per unit dose. Since RMR is the reciprocal of DD, the smaller the DD, the higher is the RMR and vice versa. With the doubling dose method, until recently, risk was estimated as a product of two quantities—namely, the baseline disease frequency, P, and 1/DD: