Submission Details

ClinGen Gene Curation Standardized Evidence Summary:

General Description: The tissue inhibitor of metalloproteinases 3 (TIMP3) gene was first reported in relation to the autosomal dominant condition known as Sorsby fundus dystrophy (also called Sorsby pseudoinflammatory fundus dystrophy or hemorrhagic macular dystrophy) in 1994 (Weber et al., PMID:7894485). Sorsby fundus dystrophy is an inherited disorder with clinical features similar to age-related macular degeneration, but exhibits earlier onset, typically between the third and sixth decades of life (PMID:7894485). This inherited disorder is caused by variants that modify the tertiary structure, intermolecular interactions, or turnover of the TIMP3 protein, which normally functions in the extracellular matrix (ECM) to inhibit matrix metalloproteinase enzymes that degrade the ECM. While TIMP3 is expressed throughout the body including in the lungs, its expression within the human eye is strongest within Bruch’s membrane, a five-layered ECM structure adjacent to the retinal pigment epithelial cells, as well as within subretinal lipid deposits known as drusen that are associated with age-related macular degeneration (PMID:9006347). Disease-associated TIMP3 variant proteins continue to localize to the ECM and often retain function as inhibitors of matrix metalloproteinase activity, but also exhibit abnormal properties such as slower turnover from the ECM (PMID:16223891), aberrant intramolecular disulfide bonding (PMID:30668888), and especially the ability to form dimers (PMID:10854443).

The early stages of Sorsby fundus dystrophy are characterized by the formation of drusen throughout the fundus and thickening of the inner part of Bruch’s membrane, with strong TIMP3 localization to both structures (PMID:9924344). As the disease progresses, affected individuals present with a range of clinical features including yellow/white lesions of the retina, nyctalopia, progressive loss of central vision, disciform macular scar, central scotoma, retinal exudate, subretinal hemorrhage, atrophy of the retina / choriocapillaris / retinal pigment epithelium, and choroidal neovascularization (CNV). CNV appears to be a driver of vision loss, and clinical benefit / preservation of vision has been shown for CNV treatment with thermal laser coagulation, photodynamic therapy, and/or injection of the VEGF inhibitor bevacizumab.

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and inheritance pattern (autosomal dominant) to be consistent among unrelated patients, while the phenotypic variability among them (particularly early onset vs. late onset) appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited TIMP3 variants have been lumped into a single disease entity, referred to as Sorsby fundus dystrophy. A proposed alternative mechanism of autosomal recessive inheritance of Sorsby fundus dystrophy that involved a consanguineous family and preceded mapping of the disease locus (PMID:7143944) was refuted by identification of a heterozygous TIMP3 variant specific to the affected family members (PMID:8981947).

A recent study of two unrelated families harboring two previously-reported TIMP3 variants described recognized phenotypes of Sorsby fundus dystrophy alongside pulmonary features such as bronchial wall thickening, air trapping, and severe emphysema without history of asthma or smoking (PMID:27601084). An earlier study had similarly reported retinal features co-segregating with emphysema (with reduced penetrance) in yet another unrelated family harboring a different TIMP3 variant (PMID:8981947). Myotonic dystrophy, myopia, glaucoma, and periodontitis were also reported as non-retinal findings co-segregating with affected individuals in some families (PMID:8981947). More recent reports have evaluated pulmonary function in affected individuals and found them to be normal, indicating that modifier genes and/or environmental exposures likely affect the penetrance of non-retinal features of Sorsby fundus dystrophy. Collectively, these findings suggest that affected patients should be advised to avoid tobacco products and undergo regular pulmonary exams.

Summary of Case Level Data: 8.5 POINTS Disease-associated TIMP3 variants are predominantly missense and occur within the final exon (exon 5), consistent with mechanism mediated at least in part by the continued presence of a dysfunctional variant protein product. Most but not all variants add or subtract a cysteine residue at the protein level, which is predicted to disturb the arrangement of twelve conserved cysteines and six disulfide bonds that hold together the tertiary structure of the protein product. Fifteen variants were selected for this curation in an attempt to represent a cross-section of those reported in the literature. These included twelve missense in exon 5 (PMID:7894485, PMID:8634721, PMID:16989765, PMID:19536307, PMID:8728699, PMID:27601084, PMID:7550309, PMID:8981947, PMID:25766588, PMID:32715858), one nonsense in exon 5 (PMID:10854443), one disrupting exon 5 splicing (PMID:9760202), and one missense in exon 1 (PMID:30668888). Eleven of these variants add a cysteine residue, while four do not (PMID:16989765, PMID:19536307). Seven different published pedigrees were sufficiently large and well-studied to yield segregation data (PMID:16989765, PMID:27601084, PMID:30668888, PMID:7550309, PMID:8981947, PMID:25766588). Variant-level data indicate that some variants have the aberrant ability to form disulfide bond-mediated dimers in the ECM (PMID:9642234) and/or exhibit slower-than-wild-type turnover from the ECM fraction in cell culture (PMID:16223891). Additional variants are available from the literature, but the maximum score for this type of case-level evidence has been reached. In addition to the 7 points for these variants (none of them de novo), 1.5 points were assigned to segregation data (from a candidate gene sequencing approach used in six different studies, including PMID:30668888).

Summary of Case-Control Data: 0 POINTS This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level.

Mechanism for Disease: The mechanism of pathogenicity appears to be monoallelic dysfunction. All genotyped patients harbored a heterozygous variant within the TIMP3 locus.

Experimental Evidence: 5.5 POINTS This gene-disease association is supported by experimental evidence of functional alternation showing that TIMP3 variant proteins not only aberrantly dimerize but exhibit enhanced affinity for the ECM (PMID:11827795). As mentioned above, wild-type TIMP3 expression within the eye is strongest within disease-relevant structures such as Bruch’s membrane and associated drusen (PMID:9006347). TIMP3 continues to associate strongly with these structures in eye sections from Sorsby fundus dystrophy patients, and also localizes to other accumulating retinal deposits characteristic of the disorder (PMID:9924344). In retinal pigment epithelium generated from patient-derived induced pluripotent stem cells, variant-harboring epithelium exhibited enhanced retention of monomeric TIMP3 within either the cells themselves or the associated extracellular matrix, as well as reduced transepithelial electrical resistance (abnormal barrier function) and aberrant proteomic profiles of extracellular matrix and angiogenesis-related factors (PMID:32666594). The normal functions of TIMP3 have been found to include activity as a matrix metalloproteinase inhibitor (PMID:1845973), and the ability to inhibit angiogenesis by disrupting the interaction between VEGF and the VEGFR-2 receptor (PMID:10854443). The anti-angiogenic function has been mapped to amino acids 160-211 within its C-terminus, a region that is mostly or completely lost in the less common nonsense (PMID:10854443) and splice site-disrupting (PMID:9760202) variants. Experimental evidence also includes multiple mouse models that disrupt the murine Timp3 ortholog by either homozygous knockout (PMID:18408187) or knock-in mimicking a human disease-associated variant (PMID:32828705, PMID:12147610). Each model recapitulates at least some features of the human disease state, but none of them closely models the significant phenotypes developed by affected patients over the course of decades. 5.5 points total were assigned to the existing experimental evidence, nearing the limit of scoring in this category.

Summary Statement: In summary, TIMP3 is strongly associated with Sorsby fundus dystrophy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification.