Variable expression of TIMP3-related maculopathy due to an atypical mutation in a large family

Abstract

Purpose : Sorsby fundus dystrophy is an autosomal dominant progressive macular degeneration with typical onset in the 4^th to 6^th decade of life. Sorsby-associated TIMP3 mutations typically reside near the C-terminal. A new N-terminal substitution (p.Ser38Cys) has recently been reported in several unrelated individuals. Here, we describe a large family harboring this variant and evaluate the intrafamilial variability and genetic basis for this allele.

Methods : From a large North American pedigree, 6 affected and 2 unaffected individuals from 3 generations were enrolled. Retinal phenotypes were analyzed by visual acuity, fundus photography, autofluorescence, optical coherence tomography (OCT), fluorescein angiography (FA), and electroretinography (ERG). Whole exome sequencing was performed on DNA of two affected first cousins followed by segregation analysis through Sanger sequencing for participating family members. Haplotypes were constructed by genotyping 30 single nucleotide polymorphisms (SNPs) in a 1.1Mb interval surrounding the TIMP3 mutation.

Results : Onset of macular degeneration ranged from the 4^th to 6^th decade of life, with follow-up on certain patients for 20 years. Macular degeneration presented unilaterally or bilaterally with different combinations of drusen, macular disciform scar, or retinal pigment epithelium mottling. Progression of disease was noted by geographic atrophy, peripheral pavingstone degeneration, choroidal neovascularization with or without hemorrhage, or angioid streaks. All patients with extensive follow-up demonstrated bilateral central and peripheral involvement, including chorioretinal atrophy and pigment deposition. Molecular investigations revealed an N-terminal mutation in TIMP3 [c.113C>G;p.Ser38Cys] present in 6 affected and absent in 2 unaffected individuals. Initial SNP genotype analysis of this family and 2 previously reported unrelated patients with the p.Ser38Cys mutation indicates a common haplotype.

Conclusions : TIMP3 p.Ser38Cys-related macular degeneration encompasses a wide range of phenotypes, from typical Sorsby fundus dystrophy to early onset macular degeneration, with extensive intrafamilial variability as shown here. Vascular phenotypes are common, and we add angioid streaks to the TIMP3-related vasculopathies. Preliminary evidence supports that the p.Ser38Cys mutation is a founder allele, and ongoing studies will estimate the age of this haplotype.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.