Genotype–phenotype correlations in hereditary familial retinoblastoma

Abstract

We studied 50 unrelated pedigrees with a family history of retinoblastoma (Rb) (165 carriers of a RB1 mutation) to delineate the spectrum of RB1 germline mutations in familial Rb and to identify genotype-phenotype correlations as well as putative modifiers. Patients were followed at Institut Curie and they were examined by an ophthalmologist, a pediatrician, and a geneticist. All cases of familial Rb were determined via genetic counseling. Clinical features included disease status, laterality, age at diagnosis, mutation type, follow-up, and disease-eye ratio (DER). To eliminate mosaic cases, first-generation carriers displaying low-penetrance (LP) Rb were excluded from the analysis. Complete penetrance was the rule for nonsense and frameshift mutations (25 families) and high penetrance was observed for large rearrangements (eight families). Promoter (two families) and missense (two families) mutations displayed heterogeneous phenotypes and LP. Variable penetrance was observed for splice abnormalities (13 families) and was explained by in/out of frame mutations or respect of functional domains. Surprisingly, two families with the LP g.45867G>T/IVS6+1G>T mutation presented data that conflicted with the data reported in previous publications, as unaffected carriers had paternally inherited mutant alleles. Moreover, RNA analyses suggested that the lack of penetrance in unaffected carriers could be explained by an increase in expression levels of the wild-type allele. This observation prompted us to define a new class "3" of LP alleles. We believe this is the first large-scale study of familial Rb with a high level of homogeneity in the clinical and genetic analysis of patients and their relatives, thereby allowing for reliable intrafamilial genotype-phenotype correlations. Our analysis suggests in some cases the influence of modifier factors probably involved in mRNA level regulation and/or pRB pathway regulation.

Retinoblastoma and Neuroblastoma Predisposition and Surveillance

“…The majority of germline mutations lead to 90% to 95% penetrance, and germline carriers usually develop bilateral or multifocal tumors (6). Nonsense and frameshift mutations in exons 2 to 25 almost always lead to highly penetrant bilateral RB, and they are the most frequent types of mutations found among familial cases (31)(32)(33). The high penetrance is likely due to posttranscriptional nonsensemediated decay, leading to degradation of truncated mRNA transcripts (32).…”

“…Lower penetrant mutations with variable expressivity have also been described. These include missense and promoter mutations, as well as some splice site mutations, in particular those at less well-conserved residues (32,33). Intra-and interfamily variation in phenotypic expressivity suggests there may be other modifying factors (32,33).…”

“…These include missense and promoter mutations, as well as some splice site mutations, in particular those at less well-conserved residues (32,33). Intra-and interfamily variation in phenotypic expressivity suggests there may be other modifying factors (32,33). In a large retrospective cohort of RB survivors, individuals with lower penetrance mutations were also found to have a lower risk of second primary malignancies (34).…”

Retinoblastoma - Genetic Counseling and Molecular Diagnosis

“…The type of lesion then varies according to the type of mutation (Lohmann&Gallie, 2004, Harbour, 2001, Taylor et al, 2007.…”

“…This mutation is actually associated with an extraordinary variability of intrafamily and interfamily penetrance. The mechanisms proposed to account for this phenomenon are maintenance and therefore translation of the truncated messenger, possibly related to a parental effect (Klutz et al, 2002) or overexpression of the wild-type allele, resulting in a normal level of RB1 expression (Taylor et al, 2007).…”