DISTINCT RB-1 GENE-MUTATIONS WITH LOW PENETRANCE IN HEREDITARY RETINOBLASTOMA

The interfamilial diversity in penetrance and expressivity of heredita ry retinoblastoma was investigated in 29 families. By using a simple: parameter for estimating the severity of the disease (diseased-eye-rat io), we were able to identify four families with a discrete low-penetr ance phenotype. The underlying genetic defect was identified in three families. One family has a 3-bp deletion in exon 16 that results in th e deletion of Asn(480). In two further unrelated families, the identic al missense mutation at codon 661 in exon 20 (CGG to TGG, Arg to Trp) was identified. These mutations are distinct from the majority of reti noblastoma gene alterations, as they do not result in the disruption o f the gene product. We propose that reduced penetrance of retinoblasto ma is the result of a residual function of these alleles in retinoblas toma precursor cells.