Phenotypic variability due to a novel Glu292Lys variation in exon 8 of the BEST1 gene causing best macular dystrophy

Abstract

Objective: To study the phenotypic characteristics of patients with a novel p.E292K mutation in BEST1.

Methods: Affected individuals underwent ophthalmic examination and testing that included photography, autofluorescence, optical coherence tomography, and electrophysiological testing. Their DNA was analyzed for BEST1 mutations.

Results: Five patients aged 5 to 59 years who expressed the p.E292K mutation in BEST1 were identified in 3 families. Electro-oculographic light-rise was subnormal in all probands and carriers. Carriers had normal findings from fundus examination, multifocal electroretinography, and visual acuity, and were emmetropic or myopic. Only probands had hyperopia and fundus findings typical of Best macular dystrophy. Optical coherence tomography of vitelliform lesions demonstrated retinal pigment epithelium elevation without subretinal fluid; atrophic lesions exhibited disruption of the hyperreflective outer retina-retinal pigment epithelium complex. Intense hyperautofluorescence correlated with the vitelliform lesion.

Conclusions: Patients with the Glu292Lys variation in BEST1 exhibit intrafamilial and interfamilial phenotypic variability. A disproportionate fraction (26%) of Best disease-causing mutations occurs in exon 8, suggesting that the portion of protein encoded by this exon (amino acids 290-316) may be especially important to bestrophin's function. Relatively good visual acuity with vitelliform lesions can be explained by preservation of the outer retina, demonstrated by optical coherence tomography. Clinical Relevance A novel mutation in this region of BEST1 carries implications for disease pathogenesis.

Figure 1

A,B, Fundus of proband 1 shows well-demarcated vitelliform lesions in the central macula. C, D, Corresponding OCT sections shows elevation at the level of the RPE with preservation of the outer retina layer.

Figure 2

Pedigree of proband 1 (indicated by shaded box) demonstrates lack of penetrant fundus findings and hyperopia in carriers.

Figure 3

A, B, Proband 2 fundus demonstrates central atrophy OD and a vitelliform lesion OS, respectively. Both exhibit fleck-like changes nasal to the disc and around the arcades. C, OCT OD reflects RPE atrophy with disruption in the outer retina-RPE complex. D, OCT OS shows discrete RPE elevation. E, AF OD demonstrates a central hypoautofluorescent lesion. Fleck-like lesions around the disc and arcades reveal mixed hyper- and hypoautofluorescence in both eyes. F, AF OS shows central hyperautofluorescence corresponding to the vitelliform lesion.

Figure 4

mfERG OS from proband 2 demonstrates reduced responses from the central 1–5 degrees OS with relative preservation of the response amplitude and timing from the surrounding macula.

Figure 5

A, B, Fundus of proband 3 reveals bilateral central atrophy with few drusen in the mid-periphery of both eyes. C, D, Optical coherence tomography indicates areas of atrophy seen with increased signal posterior to the retinal pigment epithelium and attenuation of the outer retina.

Figure 6

mfERG of proband 3 demonstrates attenuation of amplitude and latency delay most prominent in the central macula with relative sparing of the periphery.