Methods: Eighty-two patients harboring 15 distinct ABCA4 mutations in trans with null (hemizygous), 10 homozygous, and 20 nullizygous patients were recruited. Age of onset was determined from medical histories. Electroretinography (ERG) responses were classified into three groups (normal; cone dysfunction; cone and rod dysfunction). The dark-adapted bright-flash (DA 10.0) a-wave amplitudes and the light-adapted flicker ERG (LA 3.0 30 Hz) amplitudes were plotted against age and compared with the nullizygous patients. Fundus autofluorescence imaging (FAF) was assessed when available.

Results: Patients hemizygous for p. G1961E and p. R2030Q had normal ERGs. Patients harboring p. R24H, p. R212C, p. G863A/delG, p. R1108C, p. P1380L, p. L2027F, and c. 5714+ 5G> A had abnormal ERGs (ERG group 2 or 3) at older ages, in most cases with significantly higher amplitudes than nullizygous patients. Mutations p. L541P+ A1038V, p. E1022K, p. C1490Y, p. E1087K, p. T1526M, and p. C2150Y were associated with abnormal ERGs (group 2 or 3) and amplitudes comparable to those of nullizygous patients. The majority of patients, including those harboring p. G1961E, had foveal atrophy; while both patients harboring p. R2030Q had foveal sparing. Most patients harboring intermediate and null-like mutations displayed FAF abnormalities extending beyond the vascular arcades.

Conclusions: In the hemizygous state, 2/15 ABCA4 alleles retain preserved peripheral retinal function; 7/15 are associated with either preserved or only mildly abnormal retinal function, worse in older patients; 6/15 behave like null mutations. These data help characterize the degree of dysfunction conferred by specific mutant ABCA4 proteins in the human retina.