Association Between Genotype and Phenotype in Consecutive Un
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.

Among 1404 patients with RB, 866 cases were unilateral and 538 cases were bilateral. Loss of function variants was found throughout the coding sequence, with 259 of 272 somatic pathogenic variants and 537 of 606 germline pathogenic variants 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, more frequent bilateral involvement, and more advanced International Intraocular Retinoblastoma Classification group. Among the 765 nongermline carriers of an RB1 pathogenic variant, most were female (419 females [54.8%] vs 346 males [45.2%] ), and males were more likely to have bilateral RB (23 males [71.4%] vs 12 females [34.3%] ).

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