Clinical phenotype and genetic characteristics in a Chinese Han family affected by autosomal dominant multifocal BVMD

Objective  To investigate the clinical characteristics and pathogenic causes of a family pedigree with multifocal Best vitelliform macular dystrophy (BVMD), and to analyze the impact of candidate variants on the protein structure.

Methods  A Chinese Han family of four individuals, including one patient diagnosed with BVMD, was identified and studied after the patient was admitted to Henan Eye Hospital in August 2024. A thorough medical history was obtained from the patient and their family members. Comprehensive ophthalmic examinations were conducted, including visual acuity testing, intraocular pressure measurement, color fundus photography, fundus fluorescein angiography (FFA), indocyanine green angiography (ICGA), fundus autofluorescence (FAF), optical coherence tomography (OCT), and electrooculography (EOG). Peripheral venous blood samples were collected from members of this family. Whole-exome sequencing (WES) was performed on the proband to screen for pathogenic variants. Sanger sequencing was used to verify the variants in other family members. Additionally, pathogenicity analysis and protein structure prediction were conducted on the identified variant sites. This study adhered to the Declaration of Helsinki. The study protocol was approved by the Ethics Committee of Henan Eye Hospital (No. HNEEC-2024[34]). Written informed consent was obtained from each subject.

Results  The best corrected visual acuity of both eyes of the proband was 0.5, and the intraocular pressure was normal. Multiple vitelliform lesions with clear boundaries were observed around the macula and vascular arcades. FAF examination revealed that the vitelliform substances in the macular area of both eyes of the proband showed hyperfluorescence, with multiple lesions observed. OCT showed separation between the retinal neuroepithelial layer and the retinal pigment epithelium (RPE) layer in the macular area of both eyes, hyperreflective material deposition under the RPE in the macular fovea, choroidal thickening, and dilation of large choroidal vessels. FFA examination showed strong fluorescence areas in the macular region of posterior pole of both eyes with unclear boundaries, and scattered punctate strong fluorescence outside the macular area; the punctate strong fluorescence in the late stage of angiography did not fade with the regression of background fluorescence. ICGA examination showed strong fluorescence of choroidal vessels in the early stage of angiography in both eyes, accompanied by punctate hypofluorescent foci, and punctate strong fluorescence was concentrated in the macular area in the late stage of angiography. EOG examination showed a decrease in the Arden ratio of both eyes (right eye: 1.2, left eye: 1.1), and a significant reduction in the peak value of light response in both eyes (right eye: 332.6 μV/div, left eye: 354.6 μV/div). The clinical phenotype of the proband was consistent with multifocal BVMD; no obvious abnormality was found in the clinical phenotypes of the proband’s parents and elder sister. WES showed that the proband and his mother carried a heterozygous missense variant c. 37C>T (p.Arg13Cys) in exon 2 of the BEST1 gene, resulting in the substitution of arginine at position 13 with cysteine, and the inheritance pattern was consistent with autosomal dominant inheritance. According to the Standards and Guidelines for the Interpretation of Sequence Variants by the American College of Medical Genetics and Genomics, this variant was classified as a likely pathogenic variant. Protein structure prediction showed that the p. Arg13Cys variant caused changes in the spatial conformation of the residue.

Conclusions  The association between the c. 37C>T (p.Arg13Cys) variant of the BEST1 gene and multifocal BVMD is identified in a Chinese Han family, and this variant can cause changes in the spatial conformation of the residue.