Mutations in ABCR (ABCA4) in patients with Stargardt macular degeneration or cone-rod degeneration

PURPOSE. To determine the spectrum of ABCR mutations associated with Starga rdt macular degeneration and cone-rod degeneration (CRD). METHODS. One hundred eighteen unrelated patients with recessive Stargardt m acular degeneration and eight with recessive CRD were screened for mutation s in ABCR (ABCA4) by single-strand conformation polymorphism analysis. Vari ants were characterized by direct genomic sequencing. Segregation analysis was performed on the families of 20 patients in whom at least two or more l ikely pathogenic sequence changes were identified. RESULTS. The authors found 77 sequence changes likely to be pathogenic: 21 mill mutations (15 novel), 55 missense changes (26 novel), and one deletion of a consensus glycosylation site (also novel). Fifty-two patients with St argardt macular degeneration (44% of those screened) and five with CRD each had two of these sequence changes or were homozygous for one of them. Segr egation analyses in the families of 19 of these patients were informative a nd revealed that the index cases and all available affected siblings were c ompound heterozygotes or homozygotes. The authors found one instance of an apparently de novo mutation, Ile824Thr, in a patient. Thirty-seven (31%) of the 118 patients with Stargardt disease and one with CRD had only one like ly pathogenic sequence change. Twenty-nine patients with Stargardt disease (25%) and two with CRD had no identified sequence changes. CONCLUSIONS. This report of 42 novel mutations brings the growing number of identified likely pathogenic sequence changes in ABCR. to approximately 25 0.