Importance  Retinoblastoma (RB) is the most common pediatric intraocular neoplasm. RB is a complex model in which atypical pathogenic variants, modifier genes, imprinting, and mosaicism are known to be associated with the phenotype. In-depth understanding of RB therefore requires large genotype-phenotype studies.

Objective  To assess the association between genotype and phenotype in patients with RB.

Design, Setting, and Participants  This single-center, retrospective cohort study, conducted from January 1, 2000, to September 30, 2017, enrolled 1404 consecutive ascertained patients with RB who consulted an oncogeneticist. All patients had their genotype and phenotype recorded. Statistical analysis was performed from July 1, 2018, to December 31, 2018.

Main Outcomes and Measures  RB1 germline and somatic pathogenic variant types, family history, and disease presentation characteristics (ie, age at diagnosis, sex, laterality, and International Intraocular Retinoblastoma Classification group).

Results  Among 1404 patients with RB (734 [52.3%] female; mean [SD] age, 20.2 [21.2] months), 866 cases (61.7%) were unilateral and 538 cases (38.3%) were bilateral. Loss of function variants were found throughout the coding sequence, with 259 of 272 (95.2%) somatic pathogenic variants and 537 of 606 (88.6%) germline pathogenic variants (difference, 6.6%; 95% CI, 4.0%-9.2%; P < .001) after excluding tumor-specific pathogenic variants (ie, promoter methylation and loss of heterozygosity); a novel low-penetrance region was identified in exon 24. Compared with germline pathogenic variants estimated to retain RB protein expression, germline pathogenic variants estimated to abrogate RB protein expression were associated with an earlier mean (SD) age at diagnosis (12.3 [11.3] months among 457 patients vs 16.3 [13.2] months among 55 patients; difference, 4 months; 95% CI, 1.9-6.1 months; P = .01), more frequent bilateral involvement (84.2% among 452 patients vs 65.2% among 45 patients; difference, 18.9%; 95% CI, 14.5%-23.3%; P < .001), and more advanced International Intraocular Retinoblastoma Classification group (85.3% among 339 patients vs 73.9% among 34 patients; difference: 11.4%; 95% CI, 6.5%-16.3%; P = .047). Among the 765 nongermline carriers of an RB1 pathogenic variant, most were female (419 females [54.8%] vs 346 males [45.2%]; P = .008), and males were more likely to have bilateral RB (23 males [71.4%] vs 12 females [34.3%]; P = .01).

Conclusions and Relevance  These results suggest that RB risk is associated with the germline pathogenic variant and with maintenance of RB protein and that there is a sex-linked mechanism for nongermline carriers.

https://jamanetwork.com/journals/jamaophthalmology/article-abstract/2766938