EPOS

European Paediatric Ophthalmological Society

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05 Modification of genotype-phenotype-associations: Insights from retinoblastoma

Lohmann, D.
Institute of Human Genetics, University of Essen, Germany>

Variable phenotypic expression is a common finding in genetic disorders. Understanding of the geno­type-pheno­type-associations is important because this knowlege is a pre­requi­site for accurate genetic counselling and may help to predict the course of the disease in an individual patient. The most prominent genetic source of phenotypic variance is allelic heterogeneity (distinct mutations in the same gene). To some extent, phenotypic variation can be due to differences in environmental conditions (in a broad sense) or is caused by stochastic effects. However, as it is not uncommon to find that a distinct mutation is associated with a spectrum of phenotypes, additional modifying genetic factors have been hypothesized.

We have obtained evidence for the effect of modifiers by analysis of patients with hereditary retinoblastoma, which is an autosomal dominant trait caused by oncogenic mutations in the RB1 gene. Development of individual tumors is initiated by a mutation of the second allele and, as these are chance events, the number of tumors is expected to follow a random distribution. Despite this strong stochastic influence on phenotypic expression, we have detect the effect of genetic modifiers.

Modification in cis. (i) In unrelated families segregating identical oncogenic RB1-gene mutations, variation between families can be higher than within families (modification of penetrance/expressivity). This effect is possibly due to distinct iso-alleles of the RB1-gene. (ii) About 3% of patients with bilateral retinoblastoma develop multiple lipoma, benign neoplasms of adipose tissue. High interfamilial variation in families with identical mutations indicates that presentation of lipoma depends on the presence of a modifying factor. Cosegregation in a large family shows that this locus is linked to the RB1 gene (modification of pleiotropy).

Modification in trans. Specific RB1-gene mutations show an intrafamilial phenotypic variation that exceeds the variance expected of chance distribution. Interestingly, expressivity and penetrance are linked to the abundance of the mutant transcript: in unaffected mutation carriers but not in patients with bilateral retinoblastoma mutant transcripts evade targeted degradation. This indicates that the modifying factor acts on the level of RNA processing.

The examples from retinoblastoma show that quantitative analysis of the phenotype and molecular investigations can help to dissect modifiying effects in human monogenetic disorders.