Purpose: We describe the phenotypes associated with nullizigosity and nine splicing mutations in the ABCA4 gene.
Methods: The study included 19 patients with biallelic null mutations (Group A, nullizygous), 27 with splicing mutations in the homozygous state or in trans with a null mutation (Group B), and 20 with p.G1961E in trans with a null mutation (Group C, control). Ages at onset and visual acuities were determined from medical histories. Area of decreased autofluorescence within a 30° × 30° fundus autofluorescence (FAF) image was measured with the Region Finder (N = 58). Full-field electroretinography (ERG) was performed incorporating the International Society for Clinical Electrophysiology of Vision (ISCEV) standard (N = 40).
Results: For groups A to C, the median ages of onset were 6, 8, and 17, respectively. Kaplan Meier survival analysis estimated that 50% of patients reached visual acuity below 20/400 at the ages of 29, 48, and 66 years, respectively. The area of reduced FAF was estimated to increase by 1.5, 1.2, and 0.03 mm2 per year, respectively, and cone-rod dystrophy was present in 10/12, 13/15, and 0/13 of cases, respectively. Splicing mutation c.5714+5G>A was associated with a significantly milder phenotype in comparison with nullizygous patients for all parameters.
Conclusions: Nullizygosity for ABCA4 is associated with early onset cone-rod dysfunction with rapid progression shown by enlargement of central atrophy on FAF, decline of ERG amplitudes with age, and a high risk of reaching legal blindness by the fourth decade. Most studied splicing mutations were associated with a similarly severe phenotype. Estimated rates of progression may facilitate further genotype-phenotype correlations and inform the design of treatment trials.