The genetic basis for the variabilityof hereditable diseases

Summary It has been shown that certain hereditarysyndromes can be produced by a variety of genetic determinants. Certain of the clinical conditions demonstrating genetic heterogeneity cited in this presentation were previously believed to be caused by a single abnormal gene. Although within a single family the same disease in several of its members is likely to be the result of the same altered gene, caution must be exercised when a similar inherited syndrome in other families is attributed to the same genetic aberration. Illustrations are cited of inherited disorders that are caused not only by heterogeneity of the same gene, but also by genes located on different chromosomes. Laboratory methods can be important in establishing genetic heterogeneity for some clinical conditions, but the role of family analysis is still critical in defining genetic variations of both normal and pathological traits. When the expression of a genetic disease is similar in affected members of the same family, but is different in affected individuals of another family, heterogeneity becomes a distinct possibility. When the pedigree distribution of a disease varies between families with a similar clinical disorder, heterogeneity is a certainty. This situation exists in the mucopolysaccharidoses, which are caused by both autosomal and X-linked genes. The pediatrician has long been accustomedto studying his patient in the context of the family and is naturally sympathetic to the needs of the genetic investigator. The geneticist will often search out more distant relatives than those the pediatrician usually includes in his family analysis. We have cited instances in which the diagnosis of genetic heterogeneity has hinged on an extensive evaluation of the specific intrafamilial manifestations of a clinical condition. Two areas of development that have accounted for much of the recent progress in human genetics have been mentioned only briefly. These are the recognition of normal genetic variants in the human population and the description of both normal and pathological variations in the microscopic appearance of human chromosomes. The methods used to analyze normal variants of genes are the same as those applied in establishing heterogeneity of traits that lead to disease. The significance of clinical studies in human cytogenetics has been mentioned in the discussion of the oral-facial-digital syndrome. The fragmentary nature of the data and the technical limitations in current studies of human chromosomes have been mainly responsible for existing confusion as to the role of chromosome analysis in clinical investigation. The type of interpretation presented here in regard to disorders caused by alterations of individual genes, in contrast to gross abnormalities of chromosome morphology, is the result of the critical analysis of considerable clinical and laboratory data over a period of many years. Heterogeneity of genetic diseases based on different transmission patterns, as well as on basic differences in etiological biochemical factors, should be a subject of continuing and growing interest to the clinician. Information pertaining to heterogeneity should help explain apparent differences in the expression of seemingly similar clinical conditions. An improved understanding of how genetic heterogeneity is related to a patient's hereditary disorder may be valuable to the clinician in estimating prognosis and in planning therapy, as well as in genetic counseling.