A novel TIMP3 mutation associated with a retinitis pigmentosa-like phenotype

Background Sorsby Fundus Dystrophy is an inherited macular degeneration caused by pathogenic variants in theTIMP3gene. Clinical exam findings typically drusen -like deposits beneath the RPE or reticular pseudo drusen deposits above the RPE with a majority of patients developing choroidal neovascularization. Materials and Methods Case report of two members of a family that present with atypical clinical exam findings. Protein modeling of the novel Y137CTIMP3 variant was performed and compared with other known variants. Results In this study we describe a father and son initially diagnosed with retinitis pigmentosa of unknown genetic origin. More recent genetic testing of the patients, identified a novel c.410A>G; p.Tyr137Cys variant of uncertain clinical significance in the Tissue Inhibitor of Metalloproteinase-3 (TIMP3) gene. The atypical clinical findings led us to compare the theoretical molecular effects of this variant on the TIMP3 protein structure and interactions with other proteins using homology modeling and machine learning predictions. Conclusions It is important to consider mutations in TIMP3 in atypical cases of Retinitis Pigmentosa particularly in the absence of known variants.