Prevalence and penetrance of heritable retinoblastoma in two adult population cohorts: implications for genomic newborn screening

Abstract Retinoblastoma (Rb) is a rare childhood eye cancer. Almost half of cases are heritable, associated with germline RB1 pathogenic variants that pre-dispose to Rb and extraocular cancers. This study aimed to investigate the prevalence and penetrance of RB1 -heritable Rb in two adult population cohorts. We screened participants with whole genome sequencing in the UK Biobank (UKB) ( n  = 490,413) and All of Us (AoU) ( n  = 317,964) cohorts for predicted loss-of-function (pLoF) and/or ClinVar pathogenic/likely pathogenic RB1 variants. Electronic health records and questionnaires were used to screen participants for Rb-associated features. In the UKB we generated a stringent and permissive phenotype category, ranging from Rb to Rb-associated extraocular cancers; in AoU we included participants with Rb or ocular cancer. A total of 21 pathogenic pLoF RB1 variants were detected in the UKB ( n  = 12) and AoU ( n  = 13) participants. In the UKB, only 25.0% (3/12) of variant carriers reported developing Rb by the age of 60, increasing to 50.0% when including ocular/extraocular cancers. Similarly, 30.8% (4/13) AoU participants developed Rb and/or ocular cancer by the age of 60. Overall, this results in a combined penetrance estimate of 28.0% (7/25). We found 21 and 28 individuals with Rb in the UKB and AoU, respectively, which is consistent with published prevalence estimates, suggesting these cohorts are not depleted of Rb cases. Notably, the penetrance of pathogenic RB1 variants in >800,000 clinically unselected adults was substantially lower than the near complete penetrance reported in clinical cohorts. This has important implications for counselling families following a positive newborn screening result.