Abstract
Purpose :
In age-related macular degeneration (AMD), both genetic and environmental factors play a role. Genome-wide association studies (GWAS) have identified multiple susceptibility loci, including the RPE-specific monocarboxylate transporter 3 (MCT3). Vitelliform macular dystrophies (VMD) are a group of Mendelian diseases clinically mimicking AMD. Several genes have been associated with VMD including BEST1, IMPG1 and IMPG2. We aim to describe the clinical and molecular findings of a 3-generation family affected by VMD.
Methods :
Genome sequencing was performed on two affected family members after a negative panel testing. A custom pipeline was used for prioritization of small indels, structural, and single nucleotide variants, followed by segregation analyses and molecular modeling to evaluate candidate variants.
Results :
A family with three affected individuals in three generations (Fig.A) presented with macular degeneration (age of onset range: 23-47 years). The phenotypic presentation extended from a vitelliform lesion to choroidal neovascularization and geographic atrophy (Fig.B). Panel sequencing identified a frameshift IMPG1 variant, which was rejected by segregation. Genome sequencing identified a single plausible variant, namely c.1070A>G:p.(Y357C) in the SLC16A8 gene encoding MCT3. This variant is absent in gnomAD and present in all affected individuals. As predicted by AlphaFold, it is located in the helical transmembrane domain 7, of a total of 12, and replaces an aromatic ring of a highly conserved residue (Fig.C) with a strongly reactive sulfur group facing the pore of the channel (Fig.D), which might affect its permeability to lactate. The AlphaMissense tool predicts it to be likely pathogenic (score 0.7631).
Conclusions :
Previous GWAS found the SLC16A8 variant c.214+1G>C to be enriched in AMD cohorts, while Slc16a8 knockout mice presented reduced scotopic retinal function. Our findings and these observations suggest that the relatively common variant c.214+1G>C (0.0096 allele frequency in Europeans¾gnomAD v4) is pathogenic for AMD with reduced penetrance, and the ultra-rare variant p.(Y357C) is associated with VMD. Thus, these data support that protein-altering variants in the SCL16A8 gene are associated with AMD and VMD. Future functional studies may provide new insights in disease mechanism as well as show the potential of this gene and the lactate pathway as candidates for therapies.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.