Delayed mutation as a cause of retinoblastoma: application to genetic counseling

The genealogic and genetic data on retinoblastoma were reviewed and interpreted according to the model of delayed mutation; then applications of the model to specific situations in genetic counseling were considered. Patients with multiple congenital abnormalities and systemic chromosome aberrations are regarded as belonging to a different category of retinoblastoma cases than the more common patients without such abnormalities. The model of delayed mutation is considered for the latter group of patients. According to the model, mutation at the retinoblastoma locus can be delayed or complete and can occur during meiotic or mitotic cell division. Genotypically, three clases of individuals can be identified in retinoblastoma families: homozygous normal, heterozygous for the premutated allele, and heterozygous for the (fully) mutated allele; the other possible combinations of individuals have apparently not been observed. There is to date no evidence to suggest incomplete penetrance of the mutant allele, but 14% of individuals who have the mutant gene are "only" unilaterally affected. Carriers produce normal, affected and carrier offspring in the empiric proportion of, respectively, 54.5%, 36.4% and 9.1%. Most difficulties in genetic counseling arise because affected individuals may have inherited the premutated or the mutated allele and because unaffected individuals may have inherited the normal or the premutated allele. These aspects were considered for individuals presenting as sporadic-unilateral, sporadic-bilateral, familial-unilateral and familial-bilateral cases, and the empiric risk figures for various situations were quoted from the literature.