Phenotypic variability in a French family with a novel mutation in the BEST1 gene causing multifocal best vitelliform macular dystrophy

摘要

Aims: To describe genetic and clinicalfindings in a French family affected by best vitelliform maculardystrophy (BVMD). Methods: We screened eight at-riskmembers of a family, including a BVMD-affected proband, by directsequencing of 11 bestrophin-1 (BEST1) exons. Individualsunderwent ophthalmic examination and autofluorescent fundus imaging,indocyanine green angiography, electro-oculogram (EOG),electroretinogram (ERG), multifocal ERG, optical coherence tomography(OCT), and where possible, spectral domain OCT. Results: The sequence analysis of the BEST1gene revealed one previously unknown mutation, c.15CA (p.Y5X), intwo family members and one recently described mutation, c.430AG(p.S144G), in five family members. Fundus examination andelectrophysiological responses provided no evidence of the disease inthe patient carrying only the p.Y5X mutation. Three patients with thep.S144G mutation did not show any preclinical sign of BVMD exceptaltered EOGs. Two individuals of the family exhibited a particularlysevere phenotype of multifocal BVMD—one individual carrying the p.S144Gmutation heterozygously and one individual harboring both BEST1mutations (p.S144G inherited from his mother and p.Y5X from hisfather). Both of these family members had multifocal vitelliformautofluorescent lesions combined with abnormal EOG, and the spectraldomain OCT displayed a serous retinal detachment. In addition, ERGsdemonstrated widespread retinal degeneration and multifocal ERGs showeda reduction in the central retina function, which could be correlatedwith the decreased visual acuity and visual field scotomas. Conclusions: A thorough clinicalevaluation found no pathological phenotype in the patient carrying theisolated p.Y5X mutation. The patients carrying the p.S144G variation inthe protein exhibited considerable intrafamilial phenotypicvariability. Two young affected patients in this family exhibited anearly onset, severe, multifocal BVMD with a diffuse distribution ofautofluorescent deposits throughout the retina and rapid evolutiontoward the loss of central vision. The other genetically affectedrelatives had only abnormal EOGs and displayed no or extremely slowelectrophysiological evolution.