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

RB1

Germline loss-of-function RB1 variants, screened by whole genome sequencing in clinically unselected adults

About half of retinoblastomas are heritable and linked to a germline pathogenic RB1 variant, which also predisposes to extraocular cancers. The authors screened predicted loss-of-function variants and ClinVar pathogenic or likely pathogenic RB1 variants among whole-genome-sequenced participants of the UK Biobank (n = 490,413) and All of Us (n = 317,964), then reviewed electronic health records and questionnaires. Twenty-one pathogenic loss-of-function variants were detected, in 12 UK Biobank and 13 All of Us participants. In the UK Biobank, 25.0% of carriers (3 of 12) reported retinoblastoma by age 60, rising to 50.0% when ocular and extraocular cancers were included; in All of Us, 30.8% (4 of 13) had developed retinoblastoma and/or ocular cancer, giving a combined penetrance estimate of 28.0% (7 of 25). The 21 and 28 retinoblastoma cases identified in the two cohorts respectively are consistent with published prevalence estimates, suggesting these cohorts are not depleted of cases.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

A figure of 28% against a penetrance believed to be near complete is exactly the kind of result that changes what is said to a family after a positive genomic newborn screen, just as these programmes are being rolled out. The main reservation is sample size: 25 carriers in total, hence a very imprecise estimate, and two adult volunteer biobanks that by construction contain neither children who died of retinoblastoma nor the most severe forms — a survival bias that mechanically pushes penetrance downward. The authors counter with a solid argument, the expected number of retinoblastoma cases found in both cohorts, but the estimate needs confirmation in prospective newborn cohorts before being quoted in clinic.

Analysis by Dr Thibaut Benquey