Detection of mosaicism in three families with retinoblastoma: relevance to genetic counseling
Practice Guidelines as Topic
Purpose. Germ-line mosaicism is important to consider when providing genetic counseling to families with retinoblastoma. We present here three families in which mosaicism of one member could be documented. In each case, detection of the mosaicism allowed more accurate genetic counseling. Methods. Segregation analysis of alleles at the retinoblastoma locus was performed using intragenic RFLPs. Single-strand conformation polymorphism analysis and direct sequencing were used to discover the responsible genetic defects. Results. In family 262, all three children inherited the same paternal allele. Two children developed retinoblastoma and carried the same germ-line mutation (Arg556Ter) on the paternally derived allele; the mutation could not be detected in paternal leukocyte DNA. In family 139, two children inherited the same paternal allele from an unaffected father. Only one child developed retinoblastoma and only he was found to carry a mutation (Arg467(l 1-bp ins)) on the paternally derived allele; the mutation was also found in the father's leukocyte DNA. In family 26, two children inherited different alleles from a bilaterally affected father. Neither child developed retinoblastoma and neither carried the mutation (Lys329( 1-bp del)) found in the father's leukocyte DNA. Conclusion. The most likely explanation for the observed constellation of genetic findings is that the fathers in all three families are mosaics. We are currently in the process of quantifying the proportion of mutant sperm from these fathers. These families demonstrate that the examination of sperm DNA may provide important information relevant to the prediction of recurrence risk of retinoblastoma. Note: Mutations in families 139 and 26 were identified in collaboration with D. W. Yandell.