Revisiting low penetrance retinoblastoma: an integrated clinical, genetic, and bioinformatic analysis

Retinoblastoma (RB) is typically associated with highly penetrant pathogenic sequence variants (PSVs) in the RB1 gene; however, some families exhibit low penetrance RB (LPRB). We aimed to determine the penetrance rate and identify genetic and clinical characteristics of LPRB. To that end two cohorts were analyzed: 250 genetically confirmed LPRB cases identified through systematic literature review and 78 classical germline RB (CGRB) from three international centers- Thailand, Korea, and Israel. Penetrance rate was estimated as the proportion of affected individuals among RB1 PSV carriers. Multivariate models assessed parent-of-origin effects and predictors of penetrance. PSVs were annotated with Combined Annotation Dependent Depletion (CADD) scores and mapped to pRB structural domains. LPRB penetrance ranged from 50% (125/250, non-age-adjusted, CI [43.8%-56.2%]) to 64% (125/196, age-adjusted, CI [56.8%-70.2%]). Paternal inheritance of RB1 PSV was associated with a significantly increased risk of LPRB in offspring (OR = 6.24; P < 0.0001). Clinically, LPRB were significantly more likely than CGRB to present with unilateral disease (OR = 9.3, P < 0.0001), diagnosed at an older age (13 Vs 6.5 months, P = 0.01), and affect males (OR = 2.4, P = 0.03). LPRB-associated PSVs showed lower CADD scores (OR = 1.5; P = 0.0008), indicating lower predicted pathogenicity, and were enriched in pRB's N- or C-terminal domains (OR = 3.2; P = 0.007), consistent with hypomorphic effects. In conclusion, LPRB shows a 50-64% penetrance rate, more likely to be paternally inherited, have unilateral presentation, and associated with hypomorphic RB1 PSVs in the terminal pRB regions. These findings support retitling 'low penetrance RB' to 'medium penetrance RB'.