A splicing mutation in RB1 in low penetrance retinoblastoma.

The pediatric eye-tumor retinoblastoma is widely held as a paradigm of human cancer genetics and has been a model system for both the two-hit hypothesis of dominantly inherited cancer as well as for the concept of tumor-specific loss of constitutional heterozygosity to achieve expression of the tumorigenic phenotype. Familial retinoblastoma is usually inherited as an autosomal dominant disease with high penetrance and expressivity. In a small but significant number of families, however, retinoblastoma is inherited with greatly reduced penetrance and expressivity. In these families, retinoblastoma tumors occur relatively late, are often unilateral, and unaffected carriers may exist. We have identified a mutation in such a family that exhibited extremely low penetrance and expressivity. This mutation appeared to affect splicing of the mutant allele such that both a normal length RB1 mRNA and a truncated RB1 mRNA were expressed from the same allele.