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.

    40/626 page 21
    PENETRANCE AND EXPRESSION IN RELATION TO DIAGNOSIS and SO on speak strongly for an hypothesis that more than one principal gene is involved, moderate or negligible correlations do not necessarily exclude this hypothesis. Genetic and non-genetic factors The detection of genotypic heterogeneity through simultaneous attention to clinical variability and familial distribution is well illustrated by Fogh-Andersen (1943), in his study of hare-lip and cleft palate. As is well known, either of these anomalies may occur separately, or, about as frequently, both may be found in the same individual. Formerly, it was usual to regard isolated hare-lip and isolated cleft palate, respectively, as partial manifestations of a developmental arrest which, when more severely effective, produced both defects together ; and most genetic studies have proceeded on the assumption of a common genetic basis for hare-lip, cleft palate, and for the combination of the two. Fogh-Andersen's analysis shows, however, that among sibs and other relatives of persons with either hare-Hp or hare-lip and cleft palate, both of these phenotypes occur with frequencies sig¬ nificantly in excess of their incidence in the general population ; on the other hand, isolated cleft palate is found among these relatives no more frequently than in the population at large. Conversely, there is an excessive incidence of isolated cleft palate among relatives of individuals with isolated cleft palate ; but in this group, neither hare-lip alone nor hare-hp in combination with cleft palate occurs more often than would be expected on the basis of their respective population frequencies. It appears, therefore, that hare-lip alone and hare-hp with cleft palate in many or most cases may be referable to the same main gene, but that isolated cleft palate is genetically distinct. The distinction is further reflected in the fact that familial incidence (that is, frequency of the defect among sibs of affected persons) is higher for hare-Hp, with or without cleft palate, than for isolated cleft palate. It is quite possible that not even all cases of hare-Hp with or without cleft palate are contingent upon the same principal gene. Indeed, it is plausible to assume that some may be phenocopies, produced through developmental accident without regard to genotype. Nevertheless, data on familial distribution, population frequency, and twin concordance are all reasonably consistent with an hypothesis that a single main gene is a predisposing cause in a preponderant majority of the cases ; and that both penetrance (which may be in the neighbourhood of 10 per cent) and expressivity are at least in part influenced by non-genetic factors. It is clear, too, that penetrance is conspicuously influenced by the sex of the developing foetus, and it is of interest to note that the effects of sex on penetrance in the case of hare-Hp with or without cleft palate and of isolated cleft palate, respectively, are in opposite directions ; hare-Hp, and hare-Hp with cleft palate, are manifested about twice as frequently in males as in females, while the converse is true for isolated cleft palate, an observation which affords additional basis for their differentiation. In neither case do we have any evidence to indicate whether the effect of sex on penetrance is intermediated through hormones or is in some other way a consequence of the different sex-chromosome : autosome ratio in the two sexes. PENETRANCE AND EXPRESSION IN RELATION TO DIAGNOSIS Establishment (or disproof) of the significant implication of genetic factors in the aetiology of a disease, identification of hereditary mechanisms (patterns of 21
    No text description is available for this image
    No text description is available for this image
    No text description is available for this image