Retinal Phenotypes in Patients Homozygous for the G1961E Mutation in the ABCA4 gene

Abstract

Purpose: : To evaluate the pathogenicity of the G1961E mutation in the ABCA4 gene and to present the range of retinal phenotypes associated with this mutation in homozygosity in a patient cohort with ABCA4-associated phenotypes. The pathogenicity of this mutation, the most common in the ABCA4 gene, has previously been disputed given the high carrier frequency (~ 10%) of this mutation in some ethnic groups, such as Somalis.

Methods: : Patients were enrolled from the ABCA4 disease database at Columbia University or by inquiry from collaborating physicians. Only patients homozygous for the G1961E mutation were enrolled. The entire ABCA4 gene open reading frame, including all exons and flanking intronic sequences, was sequenced in all patients. Phenotype data were obtained from clinical history and examination, fundus photography, infrared imaging, fundus autofluorescence, fluorescein angiography and spectral domain-optical coherence tomography. Additional functional data were obtained using the full-field electroretinogram, and static or kinetic perimetry. Depending on the retinal phenotype present, patients were divided into those with 'mild' (Stages I or II) or 'severe' (Stages III or IV) disease phenotypes as previously described.[1]

Results: : Twelve patients homozygous for the G1961E mutation were evaluated. All patients had evidence of retinal pathology consistent with the range of phenotypes observed in ABCA4 disease. Six patients were classified as having 'mild' disease phenotypes. One of the patients in this sub-group had the latest age of onset for all patients in the study, i.e. at 64 years. This patient had initially been diagnosed with age-related macular degeneration (AMD). Six patients were also classified as having 'severe' disease phenotypes. In 5 of these cases additional, heterozygous or homozygous, mutations were detected in the ABCA4 gene. In the 6th case, a diagnosis of retinitis pigmentosa was made in a Somali male, although no additional ABCA4 mutations were detected.

Conclusions: : Homozygous G1961E mutation in ABCA4 results in a range of retinal pathology. The phenotype is often at the milder end of the disease spectrum, with severe phenotypes linked to the presence of additional ABCA4 mutations. This report also highlights that milder, late-onset Stargardt disease may be confused with AMD.Fishman GA. (1976) Arch Ophthalmol;94:2061-67.

Keywords: retinal degenerations: hereditary • retina • mutations