Purpose: To report genetic and phenotypic discordance across two generations of a family with autosomal recessive Stargardt disease (STGD1) and to compare pathogenicities of the G1961E and A1038V alleles of the ATP-binding cassette transporter, subfamily A, member 4 (ABCA4) gene.
Methods: Five members of a family with STGD1 (patients 1-4, affected; patient 5, carrier) were included. Clinical assessment was performed together with fundus autofluorescence and spectral domain-optical coherence tomography. Patients were stratified based on the results of electroretinogram testing. Genotyping of the ABCA4 gene was performed with the ABCR500 microarray.
Results: STGD1 was diagnosed in the male proband and his female sibling (patients 1 and 2, respectively). Two children of patient 2 (patients 3 and 4) were also affected. Genotyping revealed the W663X stop mutation in all affected patients. Patients 3 and 4, who were compound heterozygous for the G1961E mutation, had earlier ages of onset than patients 1 and 2, who were compound heterozygous for the A1038V mutation. Patient 1 had an age of onset 28 years younger than patient 2, whose delayed onset can be explained by relative foveal sparing, while patient 4 had an age of onset 44 years younger than patient 2.
Conclusions: The G1961E mutation, which has been considered "mild," yields a more severe phenotype in this family than the A1038V mutation, which has been considered "severe." Marked intrasibship discordance in clinical course is described, suggesting an additional role for modifying factors in ABCA4 pleiotropism.