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Background  Retinoblastoma is a malignant tumor of the retina in children <5 years of age and occurs after two mutations in the  RB1  gene. The first mutation (M1) is germinal and confers predisposition to the hereditary type, which is transmitted as an autosomal dominant highly penetrant trait, so 90 % of carriers develop retinoblastoma; however, 10 % of carriers either do not develop the tumor or develop it unilaterally. Most mutations are point mutations. Inactivation of the RB1 gene is usually caused by mutations affecting the coding region. Silencing by methylation of the  RB1  promoter has been observed in retinoblastoma tumors as a second mutation (M2) and is classified as somatic epimutation. Germline methylation of the  RB1  gene promoter was studied in a particular pedigree of six generations from the paternal side, with incomplete penetrance and bias towards healthy male carriers and those affected with unilateral retinoblastoma.    Results  The methylation status of the 27 CpGs dinucleotides that constitute the core of the RB1 gene promoter, analyzed by cloning and genomic sequencing after DNA sodium bisulfite conversion, demonstrated a monoallelic methylation pattern which coincides with a c. [−187T > G; −188T > G] sequence variant that is found in peripheral blood lymphocytes and tumor DNA. Unexpectedly, it was the mother who transmitted this variant to two more generations. Microsatellite markers of D chromosome showed a biparental contribution of both D13 chromosomes to the retinoblastoma phenotype, conferring double heterozygosity in the affected cases.    Conclusions  The monoallelic genetic-epigenetic finding, the sequence variant, and methylation suggest a constitutive epimutation and probably a genetic-epigenetic hereditary predisposition for retinoblastoma in this family.

clinical epigenetics

“Monoallelic germline methylation and sequence variant in the promoter of the RB1 gene: a possible constitutive epimutation in hereditary retinoblastoma”