Retinal phenotypes in patients homozygous for the G1961E mutation in the ABCA4 gene.
OBJECTIVE
We evaluated the pathogenicity of the G1961E mutation in the ABCA4 gene, and present the range of retinal phenotypes associated with this mutation in homozygosity in a patient cohort with ABCA4-associated phenotypes.


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.


RESULTS
We evaluated 12 patients homozygous for the G1961E mutation. All patients had evidence of retinal pathology consistent with the range of phenotypes observed in ABCA4 disease. The latest age of onset was recorded at 64 years, in a patient diagnosed initially with age-related macular degeneration (AMD). Of 6 patients in whom severe structural (with/without functional) fundus changes were detected, 5 had additional, heterozygous or homozygous, variants detected in the ABCA4 gene.


CONCLUSIONS
Homozygous G1961E mutation in ABCA4 results in a range of retinal pathology. The phenotype usually is at the milder end of the disease spectrum, with severe phenotypes linked to the presence of additional ABCA4 variants. Our report also highlights that milder, late-onset Stargardt disease may be confused with AMD.
Department of Ophthalmology, Columbia University, New York, New York 10032, USA.
Tomas R
TR
Burke
Gerald A
GA
Fishman
Jana
J
Zernant
Carl
C
Schubert
Stephen H
SH
Tsang
R Theodore
RT
Smith
Radha
R
Ayyagari
Robert K
RK
Koenekoop
Allison
A
Umfress
Maria Laura
ML
Ciccarelli
Alfonso
A
Baldi
Alessandro
A
Iannaccone
Frans P M
FP
Cremers
Caroline C W
CC
Klaver
Rando
R
Allikmets
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D004596:Electroretinography; D005091:Exons / Q000235:genetics; D005260:Female; D005451:Fluorescein Angiography; D006720:Homozygote; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D016366:Open Reading Frames; D010375:Pedigree; D010641:Phenotype; D012160:Retina / Q000503:physiopathology*; D012164:Retinal Diseases / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D012189:Retrospective Studies; D000080362:Stargardt Disease; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology; D058609:Visual Field Tests; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult
C056475:ABCA4 protein, human; D018528:ATP-Binding Cassette Transporters