Sorsby Fundus Dystrophy via the TIMP3 Gene

Sorsby fundus dystrophy, also called hemorrhagic macular dystrophy (SFD), is a rare maculopathy. The hallmark of SFD is a sudden reduction in visual acuity presenting in middle age, usually between the third and fifth decades in life. Additional symptoms include night blindness, prolongation of dark adaptation, and color vision deficiency. Clinical findings consist of drusen-like deposits at the level of Bruch’s membrane, subretinal deposits of yellow material, angioid streaks, and exudative lesions of the macula (Sorsby and Mason 1949; Jacobson et al. 1995). Optical coherence tomography (OCT) findings include hyperreflectivity of the retinal pigment epithelium-photoreceptor-choroid complex (Saihan et al. 2009). As the disease progresses, subretinal neovascularization and atrophy of the retinal pigment epithelium may also occur. This results in rapid bilateral loss of central vision in mid age and ultimately loss of peripheral vision later in life. Although rare, SFD has been reported in patients from various populations.

Sorsby Fundus Dystrophy (SFD) is inherited in an autosomal dominant manner with age-dependent penetrance (Felbor et al. 1997). It is caused by heterozygous pathogenic variants in the TIMP3 gene (Weber et al. 1994). Over 15 pathogenic variants have been reported to date. Only two are truncating variants and the rest are missense (Human Gene Mutation Database). The TIMP3 gene encodes the tissue inhibitor of the metalloproteinase-3 protein, which is secreted by the retinal pigment epithelium (RPE) and incorporated into Bruch’s membrane (Della et al. 1996). Accumulation of TIMP3 has been reported in eyes of patients affected with SFD (Fariss et al. 1998).

A study by Ayyagari et al. (2000) detected causative variants in TIMP3 in all Sorsby's fundus dystrophy (SFD) affected patients. However, a 4-generation pedigree with several affected family members with SFD-like phenotype did not have causative variants in TIMP3 (Ayyagari et al. 2000).

No large deletions or duplications in TIMP3 have been reported to date (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TIMP3 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).