Clinical genetics / edited by Arnold Sorsby.

Date:
1953
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Clinical genetics / edited by Arnold Sorsby. Source: Wellcome Collection.

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    PENETRANCE AND EXPRESSION In laboratory animals, it is obviously rather easy to determ'ne whether variant forms of an hereditary abnormaHty are attributable to modifiers affecting the expressivity of a single gene, or to the existence of more than one main gene. In human material the problem is also simple if the patterns of hereditary trans¬ mission are clearly different. Thus, marked differences in age of onset and in rate of progress are seen in cases of progressive muscular dystrophy, depending on whether they are found in pedigrees which indicate dominant, autosomal recessive or sex-linked recessive transmission ; the same is true for retinitis pigmentosa, peroneal atrophy, and a number of other diseases. When differences in cHnical type, age of onset, or severity are not associated with obvious differences in pattern of heredity, the problem of determining whether modifiers of a single principal gene or different main genes are responsible is likely to be more difl&cult. In general, if the variability in expression is conspicuously less among affected sibs than it is among affected members of different sibships, we have strong evidence that different main genes are involved. In amaurotic idiocy, for example, the familial incidence and the frequency of parental consanguinity are both consistent with dependence on a fully penetrant, single recessive gene. The onset of some cases is during the first year of life ; in others, it ranges from age 4 to 11 years. But when several cases occur in a sibship, it is invariably found either that they all have had their onset before age 1 year, or that the onset had been after age 3 years in all cases. In this instance, there could be little doubt of the existence of different principal genes for the infantile and juvenile forms of the disease, even if no clinical differentiation were possible. Not all situations in which different major genes exhibit similar pathological expression can be expected to permit as clear-cut a differentiation as this, of course. Nevertheless, when different principal genes rather than modifiers of a single main gene are responsible for an appreciable part of the variability in some quantitative characteristic of a disease that appears to constitute a clinical entity, their existence may be demonstrable by quantitative methods. As Haldane (1941) has pointed out, the segregation of modifiers can result in a correlation between sibs in respect to age of onset, or other quantitative features of the disease of as much as 0-5, but cannot yield a coefficient of correlation significantly above this value. Hence, if the correlation between sibs is found to be significantly in excess of 0-5, there is strong presumptive evidence for the implication of different major genes in different families. The same principle holds, in the case of dominant genes, for parent-child correlations. On this basis Haldane tentatively infers that dominantly transmitted peroneal atrophy is genetically heterogeneous, that is, that there are at least two different major genes behaving as dominants, either of which can produce peroneal atrophy; whether they are mutually allelic, or occupy different loci, cannot be stated. Haldane finds similar evidence of genetic heterogeneity in recessive peroneal atrophy, dominant glaucoma, and for both dominant and recessive types of Friedreich's ataxia, spastic ataxia, and spastic paraplegia. Data which yield correlations between sibs, for age of onset, in the neighbourhood of 0-5 or below (Huntington's chorea, optic atrophy) are less readily interpreted. Such low correlations would be obtained if the same major gene is responsible for all cases of the disease under consideration. But even if several different major genes are operative, the relatively high correlations they would be expected to produce in the absence of disturbing factors may be obscured by the effects of intra- familial environmental variability. Consequently, while high correlations in age of onset 20