Disease-Causing TIMP3 Variants and Deep Phenotyping of Two Czech Families with Sorsby Fundus Dystrophy Associated with Novel p.(Tyr152Cys) Mutation

Abstract

We aim to report the ocular phenotype and molecular genetic findings in two Czech families with Sorsby fundus dystrophy and to review all the reported TIMP3 pathogenic variants. Two probands with Sorsby fundus dystrophy and three first-degree relatives underwent ocular examination and retinal imaging, including optical coherence tomography angiography. The DNA of the first proband was screened using a targeted ocular gene panel, while, in the second proband, direct sequencing of the TIMP3 coding region was performed. Sanger sequencing was also used for segregation analysis within the families. All the previously reported TIMP3 variants were reviewed using the American College of Medical Genetics and the Association for Molecular Pathology interpretation framework. A novel heterozygous variant, c.455A>G p.(Tyr152Cys), in TIMP3 was identified in both families and potentially de novo in one. Optical coherence tomography angiography documented in one patient the development of a choroidal neovascular membrane at 54 years. Including this study, 23 heterozygous variants in TIMP3 have been reported as disease-causing. Application of gene-specific criteria denoted eleven variants as pathogenic, eleven as likely pathogenic, and one as a variant of unknown significance. Our study expands the spectrum of TIMP3 pathogenic variants and highlights the importance of optical coherence tomography angiography for early detection of choroidal neovascular membranes.

Keywords: Sorsby fundus dystrophy; TIMP3; choroidal neovascular membrane; optical coherence tomography angiography; pathogenic variants.

Figure 1

Pedigrees and sequence chromatogram. (A) Pedigrees of family 1, (B) family 2, and (C) sequence chromatogram of the detected heterozygous TIMP3 variant (blue arrow) altering a tyrosine to cysteine NM_000362.5:c.455A>G p.(Tyr152Cys). Black squares and circles indicate clinically affected individuals, white symbols represent clinically unaffected individuals. Arrows indicate probands. Abbreviation: wt, wild type.

Figure 2

Retinal imaging in the proband from family 1 documenting development of CNV in the right eye. (A) Baseline SD-OCT horizontal scans through the macula (cross-sectional plane is provided in the insert) performed at the age of 54 years, showing small subfoveolar drusen, irregularities within the photoreceptors layer (white arrow), and a partial vitreous detachment. (B) SD-OCT scan performed 6 months later; note a small area of neuroretinal detachment in the central foveolar region (red asterisk). (C) Baseline fundus photography documenting irregular pigment distribution and drusen in the macular and paramacular area, and (D) OCTA image within avascular complex with no signs of neovascularization. (E) Fundus photography taken after CNV development; only subtle pigmentary changes in the macular can be recognized (white asterisk), and (F) OCTA scan of the deep vascular and (G) avascular complex demonstrating the presence of a subfoveolar CNV (red arrow). Abbreviations: CNV, choroidal neovascularization; SD-OCT, spectral domain optical coherence tomography; OCTA, optical coherence tomography angiography.

Figure 3

Retinal imaging in the proband from family 2. (A) Fundus photography of the right eye and (C) left eye showing severe atrophy of the whole macular region with patchy pigmentation. (B,D) Central macular hypoautofluorescence dominates in FAF images. (E,F) OCTA scans demonstrate no lesion within the deep vascular complex, while an extensive presumably long-lasting CNV is identified bilaterally in the avascular complex layer (G,H), corresponding to complete loss of the external retinal layers as demonstrated by transversal SD-OCT scans passing through the fovea (I) in the right and (J) left eye. Abbreviations: CNV, choroidal neovascularization; FAF, fundus autofluorescence; SD-OCT, spectral domain optical coherence tomography; OCTA, optical coherence tomography angiography.