title: Stargardt disease: towards developing a model to predict phenotype.
abstract: Stargardt disease is an ABCA4-associated retinopathy, which generally follows an autosomal recessive inheritance pattern and is a frequent cause of macular degeneration in childhood. ABCA4 displays significant allelic heterogeneity whereby different mutations can cause retinal diseases with varying severity and age of onset. A genotype-phenotype model has been proposed linking ABCA4 mutations, purported ABCA4 functional protein activity and severity of disease, as measured by degree of visual loss and the age of onset. It has, however, been difficult to verify this model statistically in observational studies, as the number of individuals sharing any particular mutation combination is typically low. Seven founder mutations have been identified in a large number of Caucasian Afrikaner patients in South Africa, making it possible to test the genotype-phenotype model. A generalised linear model was developed to predict and assess the relative pathogenic contribution of the seven mutations to the age of onset of Stargardt disease. It is shown that the pathogenicity of an individual mutation can differ significantly depending on the genetic context in which it occurs. The results reported here may be used to identify suitable candidates for inclusion in clinical trials, as well as guide the genetic counselling of affected individuals and families.
authors.affiliation: UCT/MRC Human Genetics Research Unit, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Faculty of Health Science, University of Cape Town, Cape Town, South Africa.
authors.forename: Laura
authors.initials: L
authors.lastname: Heathfield
authors.forename: Miguel
authors.initials: M
authors.lastname: Lacerda
authors.forename: Christel
authors.initials: C
authors.lastname: Nossek
authors.forename: Lisa
authors.initials: L
authors.lastname: Roberts
authors.forename: Rajkumar S
authors.initials: RS
authors.lastname: Ramesar
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000367:Age Factors; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics; D008957:Models, Genetic; D009154:Mutation; D010641:Phenotype; D000080362:Stargardt Disease
chemical_list: C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters