Abstract
Purpose :
Sorsby fundus dystrophy (SFD) is a rare, autosomal dominant macular dystrophy caused by variants in the Tissue Inhibitor of Metalloproteinase 3 (TIMP3) gene. We identified a novel pathogenic variant in the C-terminal domain of TIMP3 in two unrelated families.
Methods :
Clinical imaging included spectral domain optical coherence tomography (SD-OCT), ultra-widefield pseudocolor, autofluorescence and fundus fluorescein angiogram (FFA) imaging, electroretinography (ERGs) and genetic testing.
Results :
The 44-year-old proband from pedigree 1, developed nyctalopia and initially presented at the age of 41 with choroidal neovascularization in the left eye, treated with anti-VEGF injections. Her most recent vision was 20/25 OD and 20/60 OS. Ultra-widefield imaging demonstrated multiple discrete areas of nummular peripheral pigmentation and subretinal fibrosis near the fovea in the left eye (Figure 1). FFA showed masking in the areas of pigmentation, staining of deposits in the periphery bilaterally and leakage near the fovea in the left eye. SD-OCT confirmed choroidal neovascularization with development of a juxta foveal sub-retinal pigment epithelium deposit in the left eye. Scotopic ERGs demonstrated a marked reduction in response with standard dark adaptation.
The 64-year-old proband from pedigree 2 developed a sudden drop in central vision with choroidal neovascularization at the age of 39 treated with macular laser, and continued to develop central and peripheral vision loss. His most recent vision was hand motion at 4 feet OD and 20/100 OS. Imaging revealed a foveal scar OD, subretinal deposits and widespread discrete areas of chorioretinal atrophy bilaterally associated with severely reduced photopic and scotopic ERGs (Figure 2). The findings in both patients are consistent with SFD.
Genetic testing in both patients identified a heterozygous missense variant for TIMP3 c.446C>G, p.(Ser149Cys). This variant affects a moderately conserved amino acid at the C-terminal domain of TIMP3, and most of the in silico tools predict the variant as deleterious. To our knowledge, the variant has not been published or reported in the disease related variation databases such as ClinVar or HGMD.
Conclusions :
A novel pathogenic variant of TIMP3 was identified in two unrelated families with SFD. To date The HGMD database reports 17 variants in TIMP3 in association with SFD. This expands the spectrum of disease-causing mutations in the TIMP3.
This is a 2021 ARVO Annual Meeting abstract.