Association Between Genotype and Phenotype in Consecutive Unrelated Individuals With Retinoblastoma

Abstract

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.

Introduction of a Variant Classification System for Analysis of Genotype-Phenotype Relationships in Heritable Retinoblastoma

“…Identification of genotype-phenotype relations for heritable retinoblastoma has been addressed by others and our own group before, but many questions remain unanswered [ 3 , 49 , 50 ]. The classification approach presented here summarizes the diverse types and consequences of pathogenic variants of the RB1 gene and may serve as a conceptual framework for the identification of genotype-phenotype relationships.…”

“…In the Dutch national cohort including 126 nonfamilial patients with heterozygous RB1 variants, children with frameshift and nonsense variants (most of these correspond to REC-I variants) developed more bilateral retinoblastoma than children with missense variants (REC-III) or large chromosomal deletions (REC-II) [ 49 ]. Recently, data of a large French national cohort of 512 children with constitutional RB1 variants were analyzed for associations between genotype and phenotype [ 3 ]. The authors compared variants associated with presence to those associated with the absence of pRB and, for analysis of laterality, further subcategorized variants by the type of DNA alteration.…”

“…The authors compared variants associated with presence to those associated with the absence of pRB and, for analysis of laterality, further subcategorized variants by the type of DNA alteration. Patients with variants associated with absent pRB (most correspond to REC-I and REC-II variants) showed a higher proportion of bilateral disease (absent pRB 84.2%, altered pRB 65.2%, respectively) and younger age at diagnosis (absent pRB mean age 12.3, altered pRB 16.3 months, respectively) than children with variants associated with an altered but present pRB (most correspond to REC-III variants) [ 3 ]. Moreover, the subcategory of large deletions or duplications associated with the absence of pRB showed a significantly lower proportion of patients with bilateral disease (73.8%) compared to 89.2% in patients with nonsense variants which is in accordance with the findings of the Dutch national cohort [ 3 , 49 ].…”

“…Patients with variants associated with absent pRB (most correspond to REC-I and REC-II variants) showed a higher proportion of bilateral disease (absent pRB 84.2%, altered pRB 65.2%, respectively) and younger age at diagnosis (absent pRB mean age 12.3, altered pRB 16.3 months, respectively) than children with variants associated with an altered but present pRB (most correspond to REC-III variants) [ 3 ]. Moreover, the subcategory of large deletions or duplications associated with the absence of pRB showed a significantly lower proportion of patients with bilateral disease (73.8%) compared to 89.2% in patients with nonsense variants which is in accordance with the findings of the Dutch national cohort [ 3 , 49 ]. These subcategories, large deletions and nonsense variants, correspond to REC-II and REC-I in our classification system, and data from patients in our study group confirm this genotype-phenotype relationship (proportions of bilateral disease: REC-II: 76.9% and REC-I: 93.5%).…”

“…Patients with heritable retinoblastoma also have a predisposition to develop extraocular cancers, mainly sarcoma, which most often develop later in life. RB1 may be regarded as the prototype tumor-suppressor gene with high penetrance in a specific age range, but genotype-phenotype correlations are very complex, as shown in previous studies [ 2 , 3 , 4 , 5 , 6 ].…”