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K. E. Branham, W. R. Rhoades, K. T. Jayasundera, R. Ayyagari, J. R. Heckenlively; A Phenotype Ranking System and Genotype-Phenotype Correlations for Truncation Mutations in Stargardt Disease. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3088.
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© ARVO (1962-2015); The Authors (2016-present)
To investigate the relationship between phenotype and genotype in patients with nonsense mutations in ABCA4.
A retrospective review of 90 patients with a molecular diagnosis of Stargardt disease was conducted among patients with 1 or 2 proven mutations in ABCA4. Demographic and clinical data were collected. Goldmann perimetry was quantified using digital planimetry for the purpose of recording scotoma size. A phenotype ranking system was devised and implemented, taking into account the following clinical variables: age of onset, visual acuity, visual field, and electroretinographic findings. Scoring was based on the severity of each clinical variable and the age at which data were acquired. A phenotypic analysis of the 12 patients with truncation mutations was performed.
Of the 12 patients with truncation mutations, the average phenotype score was 21.5 (range: 8-44). Patients with truncation mutations occurring before the first nucleotide binding domain (AA 929, N = 5) had a lower average severity score (mean: 14.4, range: 7-26) than patients with truncation mutations downstream (AA 930+, N=7, average: 26.6, range: 9-44). This difference was marginally significant. Among the patients with missense mutations, the average score was 18.8 (range: 3-44). Scores for truncation mutation patients were not statistically different from those with missense mutations. The phenotype score results correlated with clinical severity as determined by an ophthalmologist.
The range of phenotype scores we observed in the subgroup with truncation mutations (8-44) was inconsistent with our prediction that truncation mutations would produce consistently severe phenotypes. Further, the fact that upstream truncations resulted in less severe phenotypes than those truncations that occurred downstream suggests that a process is taking place to ameliorate the effects of these earlier truncations. Future basic science research may reveal the mechanisms involved in ABCA4 expression and explain the resulting genotype-phenotype correlations.
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