BEST1 sequence variants in Italian patients with vitelliform macular dystrophy

Abstract

Purpose: To analyze the spectrum of sequence variants in the BEST1 gene in a group of Italian patients affected by Best vitelliform macular dystrophy (VMD).

Methods: Thirty Italian patients with a diagnosis of VMD and 20 clinically healthy relatives were recruited. They belonged to 19 Italian families predominantly originating from central Italy. They received a standard ophthalmologic examination, OCT scan, and electrophysiological tests (ERG and EOG). Fluorescein and ICG angiographies and fundus autofluorescence imaging were performed in selected cases. DNA samples were analyzed for sequence variants of the BEST1 gene by direct sequencing techniques.

Results: Nine missense variants and one deletion were found in the affected patients; each patient carried one mutation. Five variants [c.73C>T (p.Arg25Trp), c.652C>T (p.Arg218Cys), c.652C>G (p.Arg218Gly), c.728C>T (p.Ala243Val), c.893T>C (p.Phe298Ser)] have already been described in literature while another five variants [c.217A>C (p.Ile73Leu), c.239T>G (p.Phe80Cys), c.883_885del (p.Ile295del), c.907G>A (p.Asp303Asn), c.911A>G (p.Asp304Gly)] had not previously been reported. Affected patients, sometimes even from the same family, occasionally showed variable phenotypes. One heterozygous variant was also found in five clinically healthy relatives with normal fundus, visual acuity and ERG but with abnormal EOG.

Conclusions: Ten variants in the BEST1 gene were detected in a group of individuals with clinically apparent VMD, and in some clinically normal individuals with an abnormal EOG. The high prevalence of novel variants and the frequent report of a specific variant (p.Arg25Trp) that has rarely been described in other ethnic groups suggests a distribution of BEST1 variants peculiar to Italian VMD patients.

Figure 1

Different stages of VMD (Fundus photographs and OCT). A, B: Vitellifom disc (Patient R-II-1). C, D: Vitelliruptive stage (Patient C-II-1). E, F: Pseudohypopyon stage (Patient B-II-1). G, H: Macular atrophy (Patient Q-I:-1). I, J: Macular fibrosis (Patient I-II-1). OD represents the right eye, OS represents the left eye.

Figure 2

Pedigrees of the families included in the study, showing the autosomal dominant mode of inheritance of VMD. The asterisk * indicates the family members who have not been clinically examined; in these cases the classification affected/not affected is based on the proband’s report.

Figure 3

Fundus photographs, OCT and EOG of Patient M-II-1 carrying the novel sequence variant p.Ile295del. A, B: Vitelliform lesion with partial re-absorption of the vitelliform material. C, D: Macular detachment of the neurosensory retina partially occupied by hyperreflective material. E, F: Reduced Arden Test. OD represents the right eye, OS represents the left eye.

Figure 4

Fundus photographs and OCT of patients J-III-1 (proband) and J-II-2 (proband’s father) showing intrafamilial phenotypic variability. A, B, C, D: Fibrotic lesion at the posterior pole centered in the macula; the patient received bilateral PDT treatment for CNV (Patient J-III-1). E, F, G, H: Vitelliruptive stage (Patient J-II-2). OD represents the right eye, OS represents the left eye.